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Harvard University is a private Ivy League research university in Cambridge, Massachusetts, established in 1636. Its history, influence and wealth have made it one of the most prestigious universities in the world.Established originally by the Massachusetts legislature and soon thereafter named for John Harvard , Harvard is the United States' oldest institution of higher learning, and the Harvard Corporation is its first chartered corporation. Although never formally affiliated with any denomination, the early College primarily trained Congregation­alist and Unitarian clergy. Its curriculum and student body were gradually secularized during the 18th century, and by the 19th century Harvard had emerged as the central cultural establishment among Boston elites. Following the American Civil War, President Charles W. Eliot's long tenure transformed the college and affiliated professional schools into a modern research university; Harvard was a founding member of the Association of American Universities in 1900. James Bryant Conant led the university through the Great Depression and World War II and began to reform the curriculum and liberalize admissions after the war. The undergraduate college became coeducational after its 1977 merger with Radcliffe College.The University is organized into eleven separate academic units—ten faculties and the Radcliffe Institute for Advanced Study—with campuses throughout the Boston metropolitan area: its 209-acre main campus is centered on Harvard Yard in Cambridge, approximately 3 miles northwest of Boston; the business school and athletics facilities, including Harvard Stadium, are located across the Charles River in the Allston neighborhood of Boston and the medical, dental, and public health schools are in the Longwood Medical Area. Harvard has the largest financial endowment of any academic institution in the world, standing at $32.3 billion as of June 2013.Harvard is a large, highly residential research university. The nominal cost of attendance is high, but the University's large endowment allows it to offer generous financial aid packages. It operates several arts, cultural, and scientific museums, alongside the Harvard University Library which is the world's largest academic and private library system, comprising 79 individual libraries with over 18 million volumes.It has many eminent alumni. Eight U.S. presidents and several foreign heads of state have been graduates. It is also the alma mater of 62 living billionaires and 335 Rhodes Scholars, both the most in the country. To date, some 150 Nobel laureates have been affiliated as students, faculty, or staff. Wikipedia.


Evans D.A.,Harvard University
Angewandte Chemie - International Edition | Year: 2014

Remember when...? This Essay describes the collaboration between Stewart Rubenstein and David and Sally Evans to develop the chemical graphics program ChemDraw, which was introduced in 1986. Now, three decades later, this software has become the dominant vehicle for drawing chemical structures in the organic chemistry community. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Beckwith J.,Harvard University
Research in Microbiology | Year: 2013

The Sec pathway for export of proteins across the cytoplasmic membrane to the bacterial periplasm and outer membrane was the first secretion pathway to be discovered in bacteria. A combination of bacterial genetics, development of an invitro membrane vesicle system and the concurrent elaboration of the signal hypothesis from studies on eukaryotes led to the identification and characterization of two pathways leading to protein export through the SecYEG cytoplasmic membrane translocon. The Sec pathway is also required for assembly of proteins into the cytoplasmic membrane. Since the membrane translocon for Sec pathways is conserved across the three domains of life, the history of research progress in eukaryotes and bacteria was facilitated by the close interaction between those studying both classes of organisms. © 2013 Institut Pasteur.


Lieber C.M.,Harvard University
MRS Bulletin | Year: 2011

Advances in nanoscience and nanotechnology critically depend on the development of nanostructures whose properties are controlled during synthesis. We focus on this critical concept using semiconductor nanowires, which provide the capability through design and rational synthesis to realize unprecedented structural and functional complexity in building blocks as a platform material. First, a brief review of the synthesis of complex modulated nanowires in which rational design and synthesis can be used to precisely control composition, structure, and, most recently, structural topology is discussed. Second, the unique functional characteristics emerging from our exquisite control of nanowire materials are illustrated using several selected examples from nanoelectronics and nano-enabled energy. Finally, the remarkable power of nanowire building blocks is further highlighted through their capability to create unprecedented, active electronic interfaces with biological systems. Recent work pushing the limits of both multiplexed extracellular recording at the single-cell level and the first examples of intracellular recording is described, as well as the prospects for truly blurring the distinction between nonliving nanoelectronic and living biological systems. Copyright © Materials Research Society 2011.


The mechanisms underlying Plasmodium falciparum resistance in persons with sickle trait have been under active investigation for more than a half century. This Perspective reviews progress in solving this challenging problem, including recent studies that have exploited the genomics and proteomics of the parasite. The formation of Hb S polymer in the parasitized AS RBC leads to impaired parasite growth and development along with enhanced clearance from the circulation and reduced deposition in deep postcapillary vascular beds. Enhanced generation of reactive oxygen species in sickled AS RBCs is a pathogenetic feature shared by parasitized thalassemic and G6PD-deficient RBCs, triggering abnormal topology of the RBC plasma membrane with decreased and disordered display of PfEMP-1, a P falciparum adhesion protein critical for endothelial adherence. A mouse model of Hb S confers host tolerance to P berghei, through inhibition of pathogenic CD8+ T cells and induction of heme oxygenase-1. An additional and apparently independent mode of protection is provided by the selective expression in AS RBCs of 2 species of microRNA that integrate into P falciparum mRNAs and inhibit translation and parasite growth. © 2013 by The American Society of Hematology.


Sullivan P.F.,University of North Carolina at Chapel Hill | Daly M.J.,Harvard University | O'Donovan M.,University of Cardiff
Nature Reviews Genetics | Year: 2012

Psychiatric disorders are among the most intractable enigmas in medicine. In the past 5 years, there has been unprecedented progress on the genetics of many of these conditions. In this Review, we discuss the genetics of nine cardinal psychiatric disorders (namely, Alzheimer's disease, attention-deficit hyperactivity disorder, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence and schizophrenia). Empirical approaches have yielded new hypotheses about aetiology and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies. Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings. © 2012 Macmillan Publishers Limited. All rights reserved.


Rabeling C.,Harvard University | Kronauer D.J.C.,Rockefeller University
Annual Review of Entomology | Year: 2013

Female parthenogenesis, or thelytoky, is particularly common in solitary Hymenoptera. Only more recently has it become clear that many eusocial species also regularly reproduce thelytokously, and here we provide a comprehensive overview. Especially in ants, thelytoky underlies a variety of idiosyncratic life histories with unique evolutionary and ecological consequences. In all eusocial species studied, thelytoky probably has a nuclear genetic basis and the underlying cytological mechanism retains high levels of heterozygosity. This is in striking contrast to many solitary wasps, in which thelytoky is often induced by cytoplasmic bacteria and results in an immediate loss of heterozygosity. These differences are likely related to differences in haplodiploid sex determination mechanisms, which in eusocial species usually require heterozygosity for female development. At the same time, haplodiploidy might account for important preadaptations that can help explain the apparent ease with which Hymenoptera transition between sexual and asexual reproduction. © 2013 by Annual Reviews. All rights reserved.


O'Connell D.J.,Harvard University
Science signaling | Year: 2012

Many vertebrate organs form through the sequential and reciprocal exchange of signaling molecules between juxtaposed epithelial and mesenchymal tissues. We undertook a systems biology approach that combined the generation and analysis of large-scale spatiotemporal gene expression data with mouse genetic experiments to gain insight into the mechanisms that control epithelial-mesenchymal signaling interactions in the developing mouse molar tooth. We showed that the shift in instructive signaling potential from dental epithelium to dental mesenchyme was accompanied by temporally coordinated genome-wide changes in gene expression in both compartments. To identify the mechanism responsible, we developed a probabilistic technique that integrates regulatory evidence from gene expression data and from the literature to reconstruct a gene regulatory network for the epithelial and mesenchymal compartments in early tooth development. By integrating these epithelial and mesenchymal gene regulatory networks through the action of diffusible extracellular signaling molecules, we identified a key epithelial-mesenchymal intertissue Wnt-Bmp (bone morphogenetic protein) feedback circuit. We then validated this circuit in vivo with compound genetic mutations in mice that disrupted this circuit. Moreover, mathematical modeling demonstrated that the structure of the circuit accounted for the observed reciprocal signaling dynamics. Thus, we have identified a critical signaling circuit that controls the coordinated genome-wide expression changes and reciprocal signaling molecule dynamics that occur in interacting epithelial and mesenchymal compartments during organogenesis.


Dumais J.,Harvard University | Forterre Y.,Aix - Marseille University
Annual Review of Fluid Mechanics | Year: 2011

Although they lack muscle, plants have evolved a remarkable range of mechanisms to create motion, from the slow growth of shoots to the rapid snapping of carnivorous plants and the explosive rupture of seed pods. Here we review the key fluid mechanics principles used by plants to achieve movements, summarizing current knowledge and recent discoveries. We begin with a brief overview of water transport and material properties in plants and emphasize that the poroelastic timescale of water diffusion through soft plant tissue imposes constraints on the possible mechanisms for motion. We then discuss movements that rely only on the transport of water, from irreversible growth to reversible swelling/shrinking due to osmotic or humidity gradients. We next show how plants use mechanical instabilitiessnap buckling, cavitation, and fractureto speed up their movements beyond the limits imposed by simple hydraulic mechanisms. Finally, we briefly discuss alternative schemes, involving capillarity or complex fluids.


Drummond I.A.,Harvard University
Current Opinion in Cell Biology | Year: 2012

Recent advances in developmental genetics and human disease gene cloning have highlighted the essential roles played by cilia in developmental cell fate decisions, left-right asymmetry, and the pathology of human congenital disorders. Hedgehog signaling in sensory cilia illustrates the importance of trafficking receptors to the cilia membrane (Patched and Smoothened) and the concept of cilia 'gatekeepers' that restrict entry and egress of cilia proteins (Suppressor of fused: Gli complexes). Cilia-driven fluid flow in the embryonic node highlights the role of motile cilia in both generation and detection of mechanical signals in development. In this brief review I select examples of recent studies that have clarified and consolidated our understanding of the role of cilia in development. © 2012 Elsevier Ltd.


Tewari S.,Clemson University | Sau J.D.,Harvard University
Physical Review Letters | Year: 2012

We show that the Hamiltonian of a multiband spin-orbit coupled semiconductor nanowire with Zeeman splitting and s-wave superconductivity is approximately chiral symmetric. The chiral symmetry becomes exact when only one pair of confinement bands is occupied and the Zeeman splitting is parallel to the nanowire. In this idealized case the Hamiltonian is in the BDI symmetry class of the topological classification of band Hamiltonians, allowing an arbitrary integer number of zero-energy Majorana fermion modes at each end. In the realistic case of multiband wires (Zeeman splitting still parallel to the length) the chiral symmetry is approximate and results in multiple near-zero-energy end states with increasing Zeeman splitting. The existence of such low energy end states implies the vanishing of the minigap with increased Zeeman splitting which can only be restored by breaking the approximate chiral symmetry by a second Zeeman field. © 2012 American Physical Society.


McQuilton P.,University of Cambridge | St Pierre S.E.,Harvard University | Thurmond J.,Indiana University
Nucleic Acids Research | Year: 2012

FlyBase (http://flybase.org) is the leading database and web portal for genetic and genomic information on the fruit fly Drosophila melanogaster and related fly species. Whether you use the fruit fly as an experimental system or want to apply Drosophila biological knowledge to another field of study, FlyBase can help you successfully navigate the wealth of available Drosophila data. Here, we review the FlyBase web site with novice and less-experienced users of FlyBase in mind and point out recent developments stemming from the availability of genome-wide data from the modENCODE project. The first section of this paper explains the organization of the web site and describes the report pages available on FlyBase, focusing on the most popular, the Gene Report. The next section introduces some of the search tools available on FlyBase, in particular, our heavily used and recently redesigned search tool QuickSearch, found on the FlyBase homepage. The final section concerns genomic data, including recent modENCODE (http://www.modencode.org) data, available through our Genome Browser, GBrowse. © The Author(s) 2011.


Floreano D.,Ecole Polytechnique Federale de Lausanne | Wood R.J.,Harvard University
Nature | Year: 2015

We are witnessing the advent of a new era of robots-drones-that can autonomously fly in natural and man-made environments. These robots, often associated with defence applications, could have a major impact on civilian tasks, including transportation, communication, agriculture, disaster mitigation and environment preservation. Autonomous flight in confined spaces presents great scientific and technical challenges owing to the energetic cost of staying airborne and to the perceptual intelligence required to negotiate complex environments. We identify scientific and technological advances that are expected to translate, within appropriate regulatory frameworks, into pervasive use of autonomous drones for civilian applications. © 2015 Macmillan Publishers Limited. All rights reserved.


Kirchhausen T.,Harvard University
Nature Cell Biology | Year: 2012

It is widely assumed that peripheral membrane proteins induce intracellular membrane curvature by the asymmetric insertion of a protein segment into the lipid bilayer, or by imposing shape by adhesion of a curved protein domain to the membrane surface. Two papers now provide convincing evidence challenging these views. The first shows that specific assembly of a clathrin protein scaffold, coupled to the membrane, seems to be the most prevalent mechanism for bending a lipid bilayer in a cell. The second reports that membrane crowding, driven by protein-protein interactions, can also drive membrane bending, even in the absence of any protein insertion into the bilayer. © 2012 Macmillan Publishers Limited. All rights reserved.


Goldhaber S.Z.,Harvard University
Best Practice and Research: Clinical Haematology | Year: 2012

Pulmonary embolism is the third most common cardiovascular disease after myocardial infarction and stroke. The death rate from pulmonary embolism exceeds the death rate from myocardial infarction, because myocardial infarction is much easier to detect and to treat. Among survivors of pulmonary embolism, chronic thromboembolic pulmonary hypertension occurs in 2-4 of every 100 patients. Post-thrombotic syndrome of the legs, characterized by chronic venous insufficiency, occurs in up to half of patients who suffer deep vein thrombosis or pulmonary embolism. We have effective pharmacological regimens using fixed low dose unfractionated or low molecular weight heparin to prevent venous thromboembolism among hospitalized patients. There remains the problem of low rates of utilization of pharmacological prophylaxis. The biggest change in our understanding of the epidemiology of venous thromboembolism is that we now believe that deep vein thrombosis and pulmonary embolism share similar risk factors and pathophysiology with atherothrombosis and coronary artery disease. © 2012 Published by Elsevier Ltd.


Detournay S.,Harvard University
Physical Review Letters | Year: 2012

We investigate properties of the inner horizons of certain black holes in higher-derivative three-dimensional gravity theories. We focus on Bañados-Teitelboim-Zanelli and spacelike warped anti-de Sitter black holes, as well as on asymptotically warped de Sitter solutions exhibiting both a cosmological and a black hole horizon. We verify that a first law is satisfied at the inner horizon, in agreement with the proposal of Castro and Rodriguez. We then show that, in topologically massive gravity, the product of the areas of the inner and outer horizons fails to be independent on the mass, and we trace this to the diffeomorphism anomaly of the theory. © 2012 American Physical Society.


Giomi L.,Harvard University
Physical Review Letters | Year: 2012

Fluid interfaces, such as soap films, liquid droplets, or lipid membranes, are known to give rise to several special geometries, whose complexity and beauty continue to fascinate us, as observers of the natural world, and challenge us as scientists. Here I show that a special class of surfaces of constant negative Gaussian curvature can be obtained in fluid interfaces equipped with an orientational ordered phase. These arise in various soft and biological materials, such as nematic liquid crystals, cytoskeletal assemblies, or hexatic colloidal suspensions. The purely hyperbolic morphology originates from the competition between surface tension, that reduces the area of the interface at the expense of increasing its Gaussian curvature, and the orientational elasticity of the ordered phase, that in turn suffers for the distortion induced by the underlying curvature. © 2012 American Physical Society.


Since their introduction to clinical practice in the 1950s, sulfonylureas have been widely prescribed for use in patients with type 2 diabetes. Of all the other medications currently available for clinical use, only metformin has been used more frequently. However, several new drug classes have emerged that are reported to have equal glucose-lowering efficacy and greater safety when added to treatment of patients in whom metformin monotherapy is no longer sufficient. Moreover, current arguments also suggest that the alternative drugs may be superior to sulfonylureas with regard to the risk of cardiovascular complications. Thus, while there is universal agreement that metformin should remain the first-line pharmacologic therapy for those in whom lifestyle modification is insufficient to control hyperglycemia, there is no consensus as to which drug should be added to metformin. Therefore, given the current controversy, we provide a Point-Counterpoint on this issue. In the point narrative presented below, Dr. Abrahamson provides his argument suggesting that avoiding use of sulfonylureas as a class of medication as an add-on to metformin is not appropriate as there are many patients whose glycemic control would improve with use of these drugs with minimal risk of adverse events. In the following counterpoint narrative, Dr. Genuth suggests there is no longer a need for sulfonylureas to remain a first-line addition to metformin for those patients whose clinical characteristics are appropriate and whose health insurance and/or financial resources make an alternative drug affordable. © 2015 by the American Diabetes Association.


Odze R.D.,Harvard University
Modern Pathology | Year: 2015

Distinguishing ulcerative colitis (UC) from Crohn's disease (CD) is normally based on evaluation of a variety of clinical, radiologic, serologic and pathologic findings, the latter in biopsy and/or resection specimens. Unfortunately, some patients with IBD show overlapping pathologic features of UC and CD, which makes definite distinction between these two disorders difficult or even impossible. In most instances of uncertainty, the patient shows clinical and pathologic features of UC, but in addition, the patient's colon resection specimen reveals one or more CD-like features. In this setting, a diagnosis of indeterminate colitis (IC) is often rendered. IC is not a distinct disease entity, and, thus, it has no diagnostic criteria. The most common causes of uncertainty in IBD pathology that may lead to a diagnosis of IC in a colon resection specimen includes the presence of fulminant (severe and toxic) colitis, insufficient radiologic, endoscopic, or pathologic information (including analysis of prior biopsies) on the patient, failure to utilize major diagnostic criteria as hard evidence in favor of CD, failure to recognize unusual variants of UC and CD that may mimic each other, failure to recognize non-IBD mimics and other superimposed diseases that cause unusual pathologic features in a resection specimen, an attempt to distinguish UC from CD in mucosal biopsies of the colon and ileum, or an attempt to change the patients diagnosis (of UC or CD) based on pouch or diversion-related complications. Details of each of these causes of uncertainty are discussed, in detail, in this review article. A diagnosis of IC should never be made clinically or by pathologists based on evaluation of pre-resection colonic mucosal biopsies. Ultimately, the majority of indeterminate cases represent UC, and, thus, most of these patient can be treated safely with a colectomy combined with an ileal pouch anal anastomosis procedure. © 2015 USCAP, Inc.


Oaklander A.L.,Harvard University
Seminars in Cutaneous Medicine and Surgery | Year: 2011

Chronic itch can be caused by dysfunctions of itch-sensing neurons that produce sensory hallucinations of pruritogenic stimuli. The cellular and molecular mechanisms are still unknown. All neurological disease categories have been implicated, and neurological causes should be considered for patients with otherwise-unexplained itch. The same neurological illnesses that cause neuropathic pain can also or instead cause itch. These include shingles (particularly of the head or neck), small-fiber polyneuropathies, radiculopathies (eg, notalgia paresthetica and brachioradial pruritis), and diverse lesions of the trigeminal nerve, root, and central tracts. Central nervous system lesions affecting sensory pathways, including strokes, multiple sclerosis, and cavernous hemangiomas, can cause central itch. Neuropathic itch is a potent trigger of reflex and volitional scratching although this provides only fleeting relief. Rare patients whose lesion causes sensory loss as well as neuropathic itch can scratch deeply enough to cause painless self-injury. The most common location is on the face (trigeminal trophic syndrome). Treating neuropathic itch is difficult; antihistamines, corticosteroids, and most pain medications are largely ineffective. Current treatment recommendations include local or systemic administration of inhibitors of neuronal excitability (especially local anesthetics) and barriers to reduce scratching. © 2011 Elsevier Inc.


Krolewski A.S.,Harvard University
Diabetes Care | Year: 2015

On the basis of extensive studies in Joslin Clinic patients over 25 years, we propose a new model of diabetic nephropathy in type 1 diabetes. In this model, the predominant clinical feature of both early and late stages of diabetic nephropathy is progressive renal decline, not albuminuria. Progressive renal decline (estimated glomerular filtration rate loss >3.5 mL/min/year) is a unidirectional process that develops while patients have normal renal function. It progresses at an almost steady rate until end-stage renal disease is reached, albeit at widely differing rates among individuals. Progressive renal decline precedes the onset of microalbuminuria, and as it continues, it increases the risk of proteinuria. Therefore, study groups ascertained for microalbuminuria/proteinuria are enriched for patients with renal decline (decliners). We found prevalences of decliners in 10%, 32%, and 50% of patients with normoalbuminuria, microalbuminuria, and proteinuria, respectively. Whether the initial lesion of progressive renal decline is in the glomerulus, tubule, interstitium, or vasculature is unknown. Similarly unclear are the initiating mechanism and the driver of progression. No animal model mimics progressive renal decline, so etiological studies must be conducted in humans with diabetes. Prospective studies searching for biomarkers predictive of the onset and rate of progression of renal decline have already yielded positive findings that will help to develop not only accurate methods for early diagnosis but also new therapeutic approaches. Detecting in advance which patients will have rapid, moderate, or minimal rates of progression to endstage renal disease will be the foundation for developing personalizedmethods of prevention and treatment of progressive renal decline in type 1 diabetes. ©2015 by the American Diabetes Association.


Objective: This study examined changes in white-black and white-Latino disparities in the use of any mental health care and minimally adequate mental health care. Methods: Using data from the 1990-1992 National Comorbidity Survey (NCS) and the 2001-2003 National Comorbidity Survey Replication (NCS-R), this study examined changes by race-ethnicity in use of mental health care among individuals age 18 to 54 with a 12-month mood or anxiety disorder. The sample consisted of 1,198 NCS respondents and 929 NCS-R respondents. Changes in disparities were estimated in the use of any mental health care in the general medical sector, the specialty mental health sector, and in total. Changes in disparities were also estimated in the use of minimally adequate mental health care (in total only). Results: Disparities in the use of any mental health care increased over time, particularly between non-Latino whites and non-Latino blacks in the general medical sector and between non-Latino whites and Latinos in the specialty mental health sector. Disparities in the use of minimally adequate mental health care persisted between whites and blacks over time but were not detected between whites and Latinos in either period. Conclusions: The findings of greater racial-ethnic disparities in the general medical and specialty mental health sectors indicate that more targeted policies and programs are needed to increase use of mental health care in these health sectors among persons from racialethnic minority groups. The persistence of white-black disparities in the use of minimally adequate mental health care warrants further examination.


Wyers M.C.,Harvard University
Seminars in Vascular Surgery | Year: 2010

Mortality related to acute mesenteric arterial occlusion remains very high. Patient survival is dependent on prompt recognition and revascularization before ischemia progresses to intestinal gangrene. Biphasic computed tomography angiography has surpassed angiography as the diagnostic test of choice due to its ability to define the arterial anatomy and to evaluate secondary signs of mesenteric ischemia. Unlike chronic mesenteric ischemia, the treatment of acute arterial mesenteric ischemia, either embolic or thrombotic, remains largely surgical. This is due to the emergent need for revascularization combined with a careful evaluation of the intestines. Endovascular techniques remain useful, however, and can save precious time in the treatment of these challenging patients if integrated into a treatment pathway combined with definitive surgical treatment. A new hybrid endovascular-surgical treatment for the treatment of acute mesenteric thrombosis is described. © 2010 Elsevier Inc.


Neder I.,Harvard University
Physical Review Letters | Year: 2012

A theoretical calculation is presented of current noise which is due charge fractionalization, in two interacting edge channels in the integer quantum Hall state at filling factor ν=2. Because of the capacitive coupling between the channels, a tunneling event, in which an electron is transferred from a biased source lead to one of the two channels, generates propagating plasma mode excitations which carry fractional charges on the other edge channel. When these excitations impinge on a quantum point contact, they induce low-frequency current fluctuations with no net average current. A perturbative treatment in the weak tunneling regime yields analytical integral expressions for the noise as a function of the bias on the source. Asymptotic expressions of the noise in the limits of high and low bias are found. © 2012 American Physical Society.


Hartnoll S.A.,Stanford University | Hofman D.M.,Harvard University
Physical Review Letters | Year: 2012

Efficient momentum relaxation through umklapp scattering, leading to a power law in temperature dc resistivity, requires a significant low energy spectral weight at finite momentum. One way to achieve this is via a Fermi surface structure, leading to the well-known relaxation rate Γ∼T2. We observe that local criticality, in which energies scale but momenta do not, provides a distinct route to efficient umklapp scattering. We show that umklapp scattering by an ionic lattice in a locally critical theory leads to Γ∼T2Δk L. Here Δk L≥0 is the dimension of the (irrelevant or marginal) charge density operator Jt(ω,k L) in the locally critical theory, at the lattice momentum k L. We illustrate this result with an explicit computation in locally critical theories described holographically via Einstein-Maxwell theory in Anti-de Sitter spacetime. We furthermore show that scattering by random impurities in these locally critical theories gives a universal Γ∼(log-1T) -1. © 2012 American Physical Society.


Xu J.-M.,Southern Medical University | Shi G.-P.,Harvard University
Endocrine Reviews | Year: 2012

Mast cells are essential in allergic immune responses. Recent discoveries have revealed their direct participation in cardiovascular diseases and metabolic disorders. Although more sophisticated mechanisms are still unknown, data fromanimal studies suggest that mast cells act similarly to macrophagesandother inflammatory cellsandcontribute to human diseases through cell- cell interactions and the release of proinflammatory cytokines, chemokines, and proteases to induce inflammatory cell recruitment, cell apoptosis, angiogenesis, and matrix protein remodeling. Reduced cardiovascular complications and improved metabolic symptoms in animals receiving over-the-counter antiallergy medications that stabilize mast cells open another era of mast cell biology and bringnewhope tohuman patients suffering from these conditions. © 2012 by The Endocrine Society.


McClatchey A.I.,Harvard University | Yap A.S.,University of Queensland
Current Opinion in Cell Biology | Year: 2012

It has long been appreciated that proliferation of many cells is inhibited by density, a phenomenon that is often attributed to cell-cell contact. The basic properties of this phenomenon were established in the 1960s, along with the observation that such density-dependence was also lost in transformed cells. The mechanistic basis of contact inhibition of proliferation (CIP) has been slower to reveal itself. Here we discuss recent progress in elucidating the roles that cell-cell adhesion molecules play as receptors for CIP and in characterising the intracellular signaling pathways that mediate adhesion-dependent proliferative inhibition. © 2012 Elsevier Ltd.


Tissue engineering holds great promise as a way of enhancing the normal regenerative potential of bone. By deconstructing the skeleton into its components and examining how each component influences the reparative response, it is clear that cells resident in bone, bioactive molecules produced by these cells and those brought into bone via the circulation and the unique extracellular matrix that makes up the bone itself are involved in a continuous and ever-changing set of reciprocal interactions during regeneration. Reviewed here is current information regarding the efficacy of 3 prominent signaling cascades that orchestrate bone formation, parathyroid hormone, Wnt and bone morphogenetic proteins, in enhancing bone repair. I suggest how we might successfully generate new bone in increasingly complex clinical situations by modulating the availability of these signals to cells already present within bone tissue. © 2011, Mary Ann Liebert, Inc.


Clark R.A.,Harvard University
Science Translational Medicine | Year: 2015

Resident memory T cells are non-recirculating memory T cells that persist long-term in epithelial barrier tissues, including the gastrointestinal tract, lung, skin, and reproductive tract. Resident memory T cells persist in the absence of antigens, have impressive effector functions, and provide rapid on-site immune protection against known pathogens in peripheral tissues. A fundamentally distinct gene expression program differentiates resident memory T cells from circulating T cells. Although these cells likely evolved to provide rapid immune protection against pathogens, autoreactive, aberrantly activated, and malignant resident memory cells contribute to numerous human inflammatory diseases including mycosis fungoides and psoriasis. This review will discuss both the science and medicine of resident memory T cells, exploring how these cells contribute to healthy immune function and discussing what is known about how these cells contribute to human inflammatory and autoimmune diseases.


Nelson D.R.,Harvard University
Annual Review of Biophysics | Year: 2012

Three areas where time-independent disorder plays a key role in biological dynamics far from equilibrium are reviewed. We first discuss the anomalous localization dynamics that arises when a single species spreads in space and time via diffusion and fluid advection in the presence of frozen heterogeneities in the growth rate. Next we treat the unzipping of double-stranded DNA as a function of force and temperature, a challenge that must be surmounted every time a cell divides. Heterogeneity in the DNA sequence dominates the physics of single-molecule force-extension curves for a broad range of forces upon approaching a sharp unzipping transition. The dynamics of the unzipping fork exhibits anomalous drift and diffusion in a similar range above this transition, with energy barriers that scale as the square root of the genome size. Finally, we describe how activated peptidoglycan strand extension sites, called dislocations in materials science, can mediate the growth of bacterial cell walls. Enzymatically driven circumferential motions of a few dozen of these defects are sufficient to describe the exponential elongation rates observed in experiments on Escherichia coli in a nutrient-rich environment. However, long-range elastic forces transmitted by the peptidoglycan meshwork cause the moving dislocations to interact not only with each other, but also with a disorderly array of frozen, inactivated strand ends. © 2012 by Annual Reviews. All rights reserved.


Motterlini R.,Italian Institute of Technology | Otterbein L.E.,Harvard University
Nature Reviews Drug Discovery | Year: 2010

Carbon monoxide (CO) is increasingly being accepted as a cytoprotective and homeostatic molecule with important signalling capabilities in physiological and pathophysiological situations. The endogenous production of CO occurs through the activity of constitutive (haem oxygenase 2) and inducible (haem oxygenase 1) haem oxygenases, enzymes that are responsible for the catabolism of haem. Through the generation of its products, which in addition to CO includes the bile pigments biliverdin, bilirubin and ferrous iron, the haem oxygenase 1 system also has an obligatory role in the regulation of the stress response and in cell adaptation to injury. This Review provides an overview of the physiology of CO, summarizes the effects of CO gas and CO-releasing molecules in preclinical animal models of cardiovascular disease, inflammatory disorders and organ transplantation, and discusses the development and therapeutic options for the exploitation of this simple gaseous molecule. © 2010 Macmillan Publishers Limited. All rights reserved.


Litonjua A.A.,Harvard University
Current Opinion in Allergy and Clinical Immunology | Year: 2012

PURPOSE OF REVIEW: Over the past 2 years, the number of studies relating vitamin D deficiency and asthma and allergies has increased significantly. The purpose of this review is to update the last review in this journal and examine the evidence of the relationship between vitamin D deficiency and childhood asthma and allergies. RECENT FINDINGS: In the past 2 years since the last review, there have been many studies, both cross-sectional and prospective, that have investigated the effects of vitamin D on the inception and severity of asthma and allergies. Most, but not all, studies have shown that low vitamin D levels increase the risk for asthma and allergies, but a few suggest an increased risk with high levels. Results from small trials of short duration suggest that vitamin D supplementation decreases severity of eczema and decreases the risk for asthma exacerbations. SUMMARY: Data that vitamin D deficiency results in increased risks for asthma and allergies continues to accumulate. However, the optimal level of vitamin D that decreases both the risk for development and severity of these disorders remains elusive. Results of ongoing clinical trials of vitamin D supplementation will be needed before recommendations can be firmly established. © 2012 Lippincott Williams & Wilkins, Inc.


Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-β are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Razzaque M.S.,Harvard University
Nature Reviews Endocrinology | Year: 2012

A disproportionate expansion of white adipose tissue and abnormal recruitment of adipogenic precursor cells can not only lead to obesity but also impair glucose metabolism, which are both common causes of insulin resistance and diabetes mellitus. The development of novel and effective therapeutic strategies to slow the progression of obesity, diabetes mellitus and their associated complications will require improved understanding of adipogenesis and glucose metabolism. Klotho might have a role in adipocyte maturation and systemic glucose metabolism. Klotho increases adipocyte differentiation in vitro, and mice that lack Klotho activity are lean owing to reduced white adipose tissue accumulation; moreover, mice that lack the Kl gene (which encodes Klotho) are resistant to obesity induced by a high-fat diet. Knockout of Kl in leptin-deficient Lep ob/ob mice reduces obesity and increases insulin sensitivity, which lowers blood glucose levels. Energy metabolism might also be influenced by Klotho. However, further studies are needed to explore the possibility that Klotho could be a novel therapeutic target to reduce obesity and related complications, and to determine whether and how Klotho might influence the regulation and function of a related protein, β-Klotho, which is also involved in energy metabolism. © 2012 Macmillan Publishers Limited. All rights reserved.


Kaushansky A.,Harvard University
Nature protocols | Year: 2010

Protein microarrays provide an efficient way to identify and quantify protein-protein interactions in high throughput. One drawback of this technique is that proteins show a broad range of physicochemical properties and are often difficult to produce recombinantly. To circumvent these problems, we have focused on families of protein interaction domains. Here we provide protocols for constructing microarrays of protein interaction domains in individual wells of 96-well microtiter plates, and for quantifying domain-peptide interactions in high throughput using fluorescently labeled synthetic peptides. As specific examples, we will describe the construction of microarrays of virtually every human Src homology 2 (SH2) and phosphotyrosine binding (PTB) domain, as well as microarrays of mouse PDZ domains, all produced recombinantly in Escherichia coli. For domains that mediate high-affinity interactions, such as SH2 and PTB domains, equilibrium dissociation constants (K(D)s) for their peptide ligands can be measured directly on arrays by obtaining saturation binding curves. For weaker binding domains, such as PDZ domains, arrays are best used to identify candidate interactions, which are then retested and quantified by fluorescence polarization. Overall, protein domain microarrays provide the ability to rapidly identify and quantify protein-ligand interactions with minimal sample consumption. Because entire domain families can be interrogated simultaneously, they provide a powerful way to assess binding selectivity on a proteome-wide scale and provide an unbiased perspective on the connectivity of protein-protein interaction networks.


Finley L.W.S.,Sloan Kettering Cancer Center | Haigis M.C.,Harvard University
Trends in Molecular Medicine | Year: 2012

Cancer cells meet their needs for energy and biomass production by consuming high levels of nutrients and rewiring metabolism to support macromolecular biosynthesis. Mitochondrial enzymes play central roles in anabolic growth, and acetylation may provide a key layer of regulation over mitochondrial metabolic pathways. As a major mitochondrial deacetylase, SIRT3 regulates the activity of enzymes to coordinate global shifts in cellular metabolism. SIRT3 promotes the function of the tricarboxylic acid (TCA) cycle and the electron transport chain and reduces oxidative stress. Loss of SIRT3 triggers oxidative damage, reactive oxygen species (ROS)-mediated signaling, and metabolic reprogramming to support proliferation and tumorigenesis. Thus, SIRT3 is an intriguing example of how nutrient-sensitive, post-translational regulation may provide integrated regulation of metabolic pathways to promote metabolic homeostasis in response to diverse nutrient signals. © 2012 Elsevier Ltd.


Spiegelman D.,Harvard University
American Journal of Public Health | Year: 2016

In the first contribution to a new section in AJPH that will address critical methodological issues in evaluations of public health interventions, I will discuss topics in study design and analysis, covering the most innovative emerging methodologies and providing an overview of best practices. The methods considered are motivated by public health evaluations, bothdomestic and global. In this first contribution, I also define implementation science, program evaluation, impact evaluation, and costeffectiveness research, disciplines that have tremendous methodological and substantive overlap with evaluation of public health interventions-the focus of this section.


Taychatanapat T.,Harvard University | Jarillo-Herrero P.,Massachusetts Institute of Technology
Physical Review Letters | Year: 2010

We study the electronic transport properties of dual-gated bilayer graphene devices. We focus on the regime of low temperatures and high electric displacement fields, where we observe a clear exponential dependence of the resistance as a function of displacement field and density, accompanied by a strong nonlinear behavior in the transport characteristics. The effective transport gap is typically 2 orders of magnitude smaller than the optical band gaps reported by infrared spectroscopy studies. Detailed temperature dependence measurements shed light on the different transport mechanisms in different temperature regimes. ©2010 The American Physical Society.


Elman I.,Wright State University | Borsook D.,Harvard University
Neuron | Year: 2016

While chronic pain is considered by some to be a CNS disease, little is understood about underlying neurobiological mechanisms. Addiction models have heuristic value in this regard, because both pain and addictive disorders are characterized by impaired hedonic capacity, compulsive drug seeking, and high stress. In drug addiction such symptomatology has been attributed to reward deficiency, impaired inhibitory control, incentive sensitization, aberrant learning, and anti-reward allostatic neuroadaptations. Here we propose that similar neuroadaptations exist in chronic pain patients. Pain and addictive disorders are characterized by impaired hedonic capacity, preoccupation with and compulsive seeking of drugs, and a heightened level of stress. Elman and Borsook propose that neuroadaptations underlying this symptomatology in drug addiction also exist in pain patients. © 2016 Elsevier Inc.


Kellermann A.L.,RAND Corporation | Jones S.S.,Harvard University
Health Affairs | Year: 2013

A team of RAND Corporation researchers projected in 2005 that rapid adoption of health information technology (IT) could save the United States more than 81 billion annually. Seven years later the empirical data on the technologys impact on health care efficiency and safety are mixed, and annual health care expenditures in the United States have grown by 800 billion. In our view, the disappointing performance of health IT to date can be largely attributed to several factors: sluggish adoption of health IT systems, coupled with the choice of systems that are neither interoperable nor easy to use; and the failure of health care providers and institutions to reengineer care processes to reap the full benefits of health IT. We believe that the original promise of health IT can be met if the systems are redesigned to address these flaws by creating more-standardized systems that are easier to use, are truly interoperable, and afford patients more access to and control over their health data. Providers must do their part by reengineering care processes to take full advantage of efficiencies offered by health IT, in the context of redesigned payment models that favor value over volume. © 2013 Project HOPE.


Ridker P.M.,Harvard University
Journal of the American College of Cardiology | Year: 2016

The inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) adds prognostic information on cardiovascular risk comparable to blood pressure or cholesterol. Values <1, 1 to 3, and >3 mg/l indicate lower, average, or higher relative cardiovascular risk, respectively. Global risk algorithms that include hsCRP outperform those solely using Framingham covariates. Although diet, exercise, and smoking cessation are first steps for patients with a proinflammatory response, JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial data demonstrate that statins reduce by 47% the rate of first myocardial infarction, stroke, or confirmed cardiovascular death when given to patients with low-density lipoprotein-C levels of <130 mg/dl and hsCRP of >2 mg/l (hazard ratio: 0.53; 95% confidence interval: 0.40 to 0.69; p < 0.00001). In current U.S. guidelines, hsCRP carries a class IIb assessment and is most appropriate in primary prevention when clinical decisions to initiate statin therapy are uncertain. Ongoing multinational trials are pursuing whether reducing inflammation will decrease vascular event rates. © 2016 American College of Cardiology Foundation.


Foody J.M.,Harvard University
Clinical Cardiology | Year: 2014

Familial hypercholesterolemia (FH) is a common disorder in which genetic mutations in at least 1 of several genes lead to significantly increased levels of lipoproteins, in particular, low-density lipoprotein cholesterol. Most commonly, mutations in the low-density lipoprotein receptor gene result in high plasma levels of apolipoprotein B-containing lipoproteins (eg, low-density lipoprotein and lipoprotein(a)). High plasma levels of lipoproteins increase the risk of cardiovascular events by as much as 20-fold if left untreated. A 2011 survey of cardiologists performed by the American College of Cardiology (ACC) suggests that there is a need for greater awareness of FH among cardiologists with regard to its prevalence and heritability, and of the risk of cardiovascular (CV) disease associated with the disorder, such as premature coronary heart disease. Given that many patients with FH may first present to CV specialists at the time of a major coronary event, it is critical that cardiologists have strategies to manage this high-risk subset of patients. This brief review responds to areas of need identified in the ACC survey and is intended to provide current information about FH and increase awareness about this disorder among cardiologists. © 2013 Wiley Periodicals, Inc.


Otite F.O.,Harvard University
Preventing chronic disease | Year: 2013

Although some US food manufacturers have reduced trans fatty acids (TFA) in their products, it is unknown how much TFA is being reduced, whether pace of reformulation has changed over time, or whether reformulations vary by food type or manufacturer. In 2007, we identified 360 brand-name products in major US supermarkets that contained 0.5 g TFA or more per serving. In 2008, 2010, and 2011, product labels were re-examined to determine TFA content; ingredients lists were also examined in 2011 for partially hydrogenated vegetable oils (PHVO). We assessed changes in TFA content among the 270 products sold in all years between 2007 and 2011 and conducted sensitivity analyses on the 90 products discontinued after 2007. By 2011, 178 (66%) of the 270 products had reduced TFA content. Most reformulated products (146 of 178, 82%) reduced TFA to less than 0.5 g per serving, although half of these 146 still contained PHVO. Among all 270 products, mean TFA content decreased 49% between 2007 and 2011, from 1.9 to 0.9 g per serving. Yet, mean TFA reduction slowed over time, from 30.3% (2007-2008) to 12.1% (2008-2010) to 3.4% (2010-2011) (P value for trend < .001). This slowing pace was due to both fewer reformulations among TFA-containing products at start of each period and smaller TFA reductions among reformulated products. Reformulations also varied substantially by both food category and manufacturer, with some eliminating or nearly eliminating TFA and others showing no significant changes. Sensitivity analyses were similar to main findings. Some US products and food manufacturers have made progress in reducing TFA, but substantial variation exists by food type and by parent company, and overall progress has significantly slowed over time. Because TFA consumption is harmful even at low levels, our results emphasize the need for continued efforts toward reformulating or discontinuing foods to eliminate PHVO.


Hetz C.,University of Chile | Hetz C.,Harvard University
Nature Reviews Molecular Cell Biology | Year: 2012

Protein-folding stress at the endoplasmic reticulum (ER) is a salient feature of specialized secretory cells and is also involved in the pathogenesis of many human diseases. ER stress is buffered by the activation of the unfolded protein response (UPR), a homeostatic signalling network that orchestrates the recovery of ER function, and failure to adapt to ER stress results in apoptosis. Progress in the field has provided insight into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1Î ± (IRE1Î ±) and activating transcription factor 6 (ATF6). In addition, novel physiological outcomes of the UPR that are not directly related to protein-folding stress, such as innate immunity, metabolism and cell differentiation, have been revealed. © 2012 Macmillan Publishers Limited. All rights reserved.


Vasudevan S.,Harvard University
Wiley Interdisciplinary Reviews: RNA | Year: 2012

MicroRNAs are small non-coding RNA guide molecules that regulate gene expression via association with effector complexes and sequence-specific recognition of target sites on other RNAs; misregulated microRNA expression and functions are linked to a variety of tumors, developmental disorders, and immune disease. MicroRNAs have primarily been demonstrated to mediate posttranscriptional downregulation of expression; translational repression, and deadenylation-dependent decay of messages through partially complementary microRNA target sites in mRNA untranslated regions (UTRs). However, an emerging assortment of studies, discussed in this review, reveal that microRNAs and their associated protein complexes (microribonucleoproteins or microRNPs) can additionally function to posttranscriptionally stimulate gene expression by direct and indirect mechanisms. These reports indicate that microRNA-mediated effects can be selective, regulated by the RNA sequence context, and associated with RNP factors and cellular conditions. Like repression, translation upregulation by microRNAs has been observed to range from fine-tuning effects to significant alterations in expression. These studies uncover remarkable, new abilities of microRNAs and associated microRNPs in gene expression control and underscore the importance of regulation, in cis and trans, in directing appropriate microRNP responses. © 2011 John Wiley & Sons, Ltd.


Rinn J.L.,Harvard University
Cold Spring Harbor Perspectives in Biology | Year: 2014

Numerous studies over the past decade have identified increasing numbers of long noncoding RNAs (lncRNAs) across many organisms. Research since has shown that lncRNAs constitute an important layer of genome regulation in diverse biological processes and disease. Here, we discuss the common emerging theme of lncRNAs interfacing with epigenetic machinery. This, in turn, modulates the activity and localization of the epigenetic machinery during cell fate specification. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.


Gunawardena J.,Harvard University
BMC Biology | Year: 2014

In this essay I will sketch some ideas for how to think about models in biology. I will begin by trying to dispel the myth that quantitative modeling is somehow foreign to biology. I will then point out the distinction between forward and reverse modeling and focus thereafter on the former. Instead of going into mathematical technicalities about different varieties of models, I will focus on their logical structure, in terms of assumptions and conclusions. A model is a logical machine for deducing the latter from the former. If the model is correct, then, if you believe its assumptions, you must, as a matter of logic, also believe its conclusions. This leads to consideration of the assumptions underlying models. If these are based on fundamental physical laws, then it may be reasonable to treat the model as 'predictive', in the sense that it is not subject to falsification and we can rely on its conclusions. However, at the molecular level, models are more often derived from phenomenology and guesswork. In this case, the model is a test of its assumptions and must be falsifiable. I will discuss three models from this perspective, each of which yields biological insights, and this will lead to some guidelines for prospective model builders. © 2014 Gunawardena; licensee BioMed Central Ltd.


Lee S.C.,University of Waterloo | Lo W.,University of Waterloo | Holm R.H.,Harvard University
Chemical Reviews | Year: 2014

A review discusses developments in the biomimetic chemistry of cubane-type and higher nuclearity iron-sulfur clusters. It presents a classification of the primary tactics employed in the synthesis and related reactions of metal-sulfur weak-field clusters by use of illustrative cases, the majority of which are drawn from our own work. Biomimetic synthesis is an endeavor directed toward synthetic representations of protein-bound metal sites with the attendant potential benefit of the discovery of new reactions and structures regardless of biological relevance. Depicted structures have been authenticated by X-ray crystallography, redox potentials are quoted vs the SCE, and 57Fe isomer shifts in Moössbauer spectroscopy are referenced to iron metal at room temperature.


Manson J.E.,Harvard University
Menopause | Year: 2014

Current recommendations for calcium intake call for 1,000 mg per day for women ages 19-50 and 1,200 mg per day for women over age 50 to ensure bone health. Given recent concerns that calcium supplements may raise risk for cardiovascular disease and kidney stones, women should aim to meet this recommendation primarily by eating a calcium-rich diet and taking calcium supplements only if needed to reach the RDA goal (often only ∼500 mg per day in supplements is required). Copyright © 2013 The North American Menopause Society.


Ahveninen J.,Harvard University
Journal of cognitive neuroscience | Year: 2013

In everyday listening situations, we need to constantly switch between alternative sound sources and engage attention according to cues that match our goals and expectations. The exact neuronal bases of these processes are poorly understood. We investigated oscillatory brain networks controlling auditory attention using cortically constrained fMRI-weighted magnetoencephalography/EEG source estimates. During consecutive trials, participants were instructed to shift attention based on a cue, presented in the ear where a target was likely to follow. To promote audiospatial attention effects, the targets were embedded in streams of dichotically presented standard tones. Occasionally, an unexpected novel sound occurred opposite to the cued ear to trigger involuntary orienting. According to our cortical power correlation analyses, increased frontoparietal/temporal 30-100 Hz gamma activity at 200-1400 msec after cued orienting predicted fast and accurate discrimination of subsequent targets. This sustained correlation effect, possibly reflecting voluntary engagement of attention after the initial cue-driven orienting, spread from the TPJ, anterior insula, and inferior frontal cortices to the right FEFs. Engagement of attention to one ear resulted in a significantly stronger increase of 7.5-15 Hz alpha in the ipsilateral than contralateral parieto-occipital cortices 200-600 msec after the cue onset, possibly reflecting cross-modal modulation of the dorsal visual pathway during audiospatial attention. Comparisons of cortical power patterns also revealed significant increases of sustained right medial frontal cortex theta power, right dorsolateral pFC and anterior insula/inferior frontal cortex beta power, and medial parietal cortex and posterior cingulate cortex gamma activity after cued versus novelty-triggered orienting (600-1400 msec). Our results reveal sustained oscillatory patterns associated with voluntary engagement of auditory spatial attention, with the frontoparietal and temporal gamma increases being best predictors of subsequent behavioral performance.


Jaqaman K.,Harvard University | Grinstein S.,Li Ka Shing Knowledge Institute
Trends in Cell Biology | Year: 2012

There is mounting evidence that the plasma membrane is highly dynamic and organized in a complex manner. The cortical cytoskeleton is proving to be a particularly important regulator of plasmalemmal organization, modulating the mobility of proteins and lipids in the membrane, facilitating their segregation, and influencing their clustering. This organization plays a critical role in receptor-mediated signaling, especially in the case of immunoreceptors, which require lateral clustering for their activation. Based on recent developments, we discuss the structures and mechanisms whereby the cortical cytoskeleton regulates membrane dynamics and organization, and how the nonuniform distribution of immunoreceptors and their self-association may affect activation and signaling. © 2012 Elsevier Ltd.


Braunwald E.,Brigham and Womens Hospital | Braunwald E.,Harvard University
The Lancet | Year: 2015

Heart failure is a global problem with an estimated prevalence of 38 million patients worldwide, a number that is increasing with the ageing of the population. It is the most common diagnosis in patients aged 65 years or older admitted to hospital and in high-income nations. Despite some progress, the prognosis of heart failure is worse than that of most cancers. Because of the seriousness of the condition, a declaration of war on five fronts has been proposed for heart failure. Efforts are underway to treat heart failure by enhancing myofilament sensitivity to Ca2+; transfer of the gene for SERCA2a, the protein that pumps calcium into the sarcoplasmic reticulum of the cardiomyocyte, seems promising in a phase 2 trial. Several other abnormal calcium-handling proteins in the failing heart are candidates for gene therapy; many short, non-coding RNAs - ie, microRNAs (miRNAs) - block gene expression and protein translation. These molecules are crucial to calcium cycling and ventricular hypertrophy. The actions of miRNAs can be blocked by a new class of drugs, antagomirs, some of which have been shown to improve cardiac function in animal models of heart failure; cell therapy, with autologous bone marrow derived mononuclear cells, or autogenous mesenchymal cells, which can be administered as cryopreserved off the shelf products, seem to be promising in both preclinical and early clinical heart failure trials; and long-term ventricular assistance devices are now used increasingly as a destination therapy in patients with advanced heart failure. In selected patients, left ventricular assistance can lead to myocardial recovery and explantation of the device. The approaches to the treatment of heart failure described, when used alone or in combination, could become important weapons in the war against heart failure. © 2015 Elsevier Ltd.


Sperling R.,Harvard University
Neurobiology of Aging | Year: 2011

Functional magnetic resonance imaging (fMRI) is a relative newcomer in the field of biomarkers for Alzheimer's disease (AD). fMRI has several potential advantages, particularly for clinical trials, as it is a noninvasive imaging technique that does not require the injection of contrast agent or radiation exposure and thus can be repeated many times during a longitudinal study. fMRI has relatively high spatial and reasonable temporal resolution, and can be acquired in the same session as structural magnetic resonance imaging. Perhaps most importantly, fMRI may provide useful information about the functional integrity of brain networks supporting memory and other cognitive domains, including the neural correlates of specific behavioral events, such as successful versus failed memory formation. © 2011 Elsevier Inc.


Dehaene-Lambertz G.,University Paris - Sud | Spelke E.S.,Harvard University
Neuron | Year: 2015

The human infant brain is the only known machine able to master a natural language and develop explicit, symbolic, and communicable systems of knowledge that deliver rich representations of the external world. With the emergence of noninvasive brain imaging, we now have access to the unique neural machinery underlying these early accomplishments. After describing early cognitive capacities in the domains of language and number, we review recent findings that underline the strong continuity between human infants' and adults' neural architecture, with notably early hemispheric asymmetries and involvement of frontal areas. Studies of the strengths and limitations of early learning, and of brain dynamics in relation to regional maturational stages, promise to yield a better understanding of the sources of human cognitive achievements. © 2015 Elsevier Inc.


The functionality of standard zoological DNA barcoding practice (the identification of unknown specimens by comparison of COI sequences) is contingent on working barcode databases with sufficient taxonomic coverage. It has already been established that the main barcoding repositories, NCBI and BOLD, are devoid of data for many animal groups but the specific taxonomic coverage of the repositories across animal biodiversity remains unexplored. Here, I shed light on this mystery by contrasting the number of unique taxon labels in the two databases with the number of currently recognized species for each animal phylum. The numbers reveal an overall paucity of COI sequence data in the repositories (15.13% total coverage across the recognized biodiversity on Earth, and 20.76% average taxonomic coverage for each phylum) and, more importantly, bear witness to the idleness towards numerous phyla, rendering current barcoding efforts either ineffective or inaccurate. The importance of further integrating taxonomic expertise into barcoding practice is briefly discussed and some guidelines, previously mentioned in the barcoding literature, are suggested anew. Finally, the asserted values concerning the taxonomic coverage in barcoding databases for Animalia are contrasted with those of Plantae and Fungi. © 2013 Elsevier Inc.


Flaherty K.T.,Harvard University
Annual Review of Medicine | Year: 2012

Metastatic melanoma has historically been one of the most treatment-refractory types of cancer. Recent headway has been made in understanding the genetic underpinnings of this cancer. A subset of oncogenic events is amenable to targeting with drug therapy. BRAF-targeted therapies represent the first major breakthrough in systemic therapy for melanoma leveraging the new genetic knowledge. Ongoing translational research seeks to identify the most scientifically rational combination treatment strategies to build on single-agent targeted therapy. © 2012 by Annual Reviews. All rights reserved.


Flaherty K.T.,Harvard University
Clinical and Experimental Metastasis | Year: 2012

For decades, therapy for advanced melanoma has lagged behind most of the cancer field owing to its intrinsic resistance to conventional cytotoxic chemotherapy and limited impact of cytokine-based immunotherapy. The opportunity to develop molecularly targeted therapy emerged with the discovery of activating mutations in BRAF, a component of the long studied MAP kinase pathway. These mutations are found in approximately 50 % of patients with regionally advanced or metastatic melanoma and appear to be one of the initiating steps in the development of primary melanoma. Additional oncogenic events, particularly those that affect tumor suppressor genes, are essential for development of invasive and metastatic melanoma. Nonetheless, mutated BRAF retains its central contribution to melanoma pathophysiology even in advanced stage disease as manifested by the remarkable antitumor effects and alteration the natural history of metastatic melanoma of selective BRAF inhibitors. After initial response, resistance commonly emerges within a few months' time and the field has focused on delineating molecular mechanisms of resistance toward the goal of improving upon the early therapeutic effects of single agent BRAF inhibition. Combination regimens are currently undergoing clinical investigation. NRAS and CKIT mutant melanoma represent the next oncogene defined melanoma subsets for which initial targeted therapy approaches are being explored, with early evidence suggesting progress with MEK and CKIT inhibitors, respectively. A considerable subset of patients have melanomas that are not defined by the presence of BRAF, NRAS, or CKIT mutations and, thus, the elucidation of the entire melanoma genome is being pursued with the hope of identifying additional therapeutic targets. © Springer Science+Business Media B.V. 2012.


Willett W.,Harvard University
Nutritional Epidemiology | Year: 2013

This book is about the complex relationships between diet and risks of important diseases, such as cancer and cardiovascular disease. The book starts with an overview of research strategies in nutritional epidemiology - still a relatively new discipline that combines the vast knowledge compiled by nutritionists during this century with the methodologies developed by epidemiologists to study the determinants of diseases with multiple etiologies and long latent periods. A major section is devoted to the methods of dietary assessment using data on food intake, biochemical indicators of diet, and measures of body composition and size. The reproducibility and validity of each approach and the implications of measurement error are considered in detail. The analysis, presentation, and interpretation of data from epidemiologic studies of diet and disease are explored in depth. Particular attention is paid to the important influence of total energy intake on findings in such studies. To illustrate methodological issues in nutritional epidemiology, the relationships of dietary factors to the incidence of lung and breast cancer, heart disease, and birth defects are examined in depth. This new edition, in addition to updating existing chapters, includes new chapters on assessment of physical activity, nutrition, and genetic epidemic ology, and the role of nutritional epidemiology in policy. © 2013 by Oxford University Press. All rights reserved.


Misdraji J.,Harvard University
Modern Pathology | Year: 2015

The classification of appendiceal mucinous neoplasms has been controversial, largely focused on a particular subset of low-grade mucinous tumors that, despite their innocuous appearance, can disseminate to the peritoneal cavity as pseudomyxoma peritonei (PMP). Recent WHO classification of these tumors as low-grade appendiceal mucinous neoplasms acknowledges their unique morphologic appearance and biologic behavior. Still, debate about the use of this term and its parameters continues to impede the adoption of consensus classification for appendiceal mucinous neoplasms. The classification of PMP has also been the subject of debate, with international authorities advocating for the use of malignant terminology to describe all grades of PMP, even though some authorities consider low-grade PMP to be dissemination of adenomatous epithelium in the peritoneum. Recent data also emphasize the importance of histologic grade of the peritoneal tumors in defining prognosis of these patients. © 2014 USCAP, Inc.


Sankaran V.G.,Harvard University
Blood | Year: 2013

The development of novel technologies for high-throughput DNA sequencing is having a major impact on our ability to measure and define normal and pathologic variation in humans. This review discusses advances in DNA sequencing that have been applied to benign hematologic disorders, including those affecting the red blood cell, the neutrophil, and other white blood cell lineages. Relevant examples of how these approaches have been used for disease diagnosis, gene discovery, and studying complex traits are provided. High-throughput DNA sequencing technology holds significant promise for impacting clinical care. This includes development of improved disease detection and diagnosis, better understanding of disease progression and stratification of risk of disease-specific complications, and development of improved therapeutic strategies, particularly patient-specific pharmacogenomics-based therapy, with monitoring of therapy by genomic biomarkers.


Sunyaev S.R.,Harvard University
Human Molecular Genetics | Year: 2012

Sequencing technology enables the complete characterization of human genetic variation. Statistical genetics studies identify numerous loci linked to or associated with phenotypes of direct medical interest. The major remaining challenge is to characterize functionally significant alleles that are causally implicated in the genetic basis of human traits. Here, I review three sources of evidence for the functional significance of human DNA variants in protein-coding genes. These include (i) statistical genetics considerations such as co-segregation with the phenotype, allele frequency in unaffected controls and recurrence; (ii) in vitro functional assays and model organism experiments; and (iii) computational methods for predicting the functional effect of amino acid substitutions. In spite of many successes of recent studies, functional characterization of human allelic variants remains problematic. © The Author 2012. Published by Oxford University Press. All rights reserved.


Housden B.E.,Harvard University | Perrimon N.,Howard Hughes Medical Institute
Trends in Biochemical Sciences | Year: 2014

The development and maintenance of the many different cell types in metazoan organisms requires robust and diverse intercellular communication mechanisms. Relatively few such signaling pathways have been identified, leading to the question of how such a broad diversity of output is generated from relatively simple signals. Recent studies have revealed complex mechanisms integrating temporal and spatial information to generate diversity in signaling pathway output. We review some general principles of signaling pathways, focusing on transcriptional outputs in Drosophila. We consider the role of spatial and temporal aspects of different transduction pathways and then discuss how recently developed tools and approaches are helping to dissect the complex mechanisms linking pathway stimulation to output. © 2014 Elsevier Ltd. All rights reserved.


Gheorghiade M.,Northwestern University | Vaduganathan M.,Harvard University | Fonarow G.C.,University of California at Los Angeles | Bonow R.O.,Northwestern University
Journal of the American College of Cardiology | Year: 2013

With a prevalence of 5.8 million in the United States alone, heart failure (HF) is associated with high morbidity, mortality, and healthcare expenditures. Close to 1 million hospitalizations for heart failure (HHF) occur annually, accounting for over 6.5 million hospital days and a substantial portion of the estimated $37.2 billion that is spent each year on HF in the United States. Although some progress has been made in reducing mortality in patients hospitalized with HF, rates of rehospitalization continue to rise, and approach 30% within 60 to 90 days of discharge. Approximately half of HHF patients have preserved or relatively preserved ejection fraction (EF). Their post-discharge event rate is similar to those with reduced EF. HF readmission is increasingly being used as a quality metric, a basis for hospital reimbursement, and an outcome measure in HF clinical trials. In order to effectively prevent HF readmissions and improve overall outcomes, it is important to have a complete and longitudinal characterization of HHF patients. This paper highlights management strategies that when properly implemented may help reduce HF rehospitalizations and include adopting a mechanistic approach to cardiac abnormalities, treating noncardiac comorbidities, increasing utilization of evidence-based therapies, and improving care transitions, monitoring, and disease management. © 2013 American College of Cardiology Foundation.


Hill K.P.,Substance Abuse Consultation Service | Hill K.P.,Harvard University
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE: As of March 2015, 23 states and the District of Columbia had medical marijuana laws in place. Physicians should know both the scientific rationale and the practical implications for medical marijuana laws. OBJECTIVE: To review the pharmacology, indications, and laws related to medical marijuana use. EVIDENCE REVIEW: The medical literature on medical marijuana was reviewed from 1948 to March 2015 via MEDLINE with an emphasis on 28 randomized clinical trials of cannabinoids as pharmacotherapy for indications other than those for which there are 2 US Food and Drug Administration-approved cannabinoids (dronabinol and nabilone), which include nausea and vomiting associated with chemotherapy and appetite stimulation in wasting illnesses. FINDINGS: Use of marijuana for chronic pain, neuropathic pain, and spasticity due to multiple sclerosis is supported by high-quality evidence. Six trials that included 325 patients examined chronic pain, 6 trials that included 396 patients investigated neuropathic pain, and 12 trials that included 1600 patients focused on multiple sclerosis. Several of these trials had positive results, suggesting that marijuana or cannabinoids may be efficacious for these indications. CONCLUSIONS AND RELEVANCE: Medical marijuana is used to treat a host of indications, a few of which have evidence to support treatment with marijuana and many that do not. Physicians should educate patients about medical marijuana to ensure that it is used appropriately and that patients will benefit from its use. Copyright 2015 American Medical Association. All rights reserved.


Progressive accumulation of α-synuclein is key to the pathology of many neurodegenerative diseases, including Parkinson disease and dementia with Lewy bodies. Increased intracellular levels of α-synuclein may be caused by enhanced expression or alterations in protein degradation pathways. Here we review our recent study showing that the ubiquitin-proteasome system and the autophagy-lysosomal pathway are differentially involved in α-synuclein's degradation in vivo. We discuss the key findings obtained with our novel in vivo approach and also present a model for the progression of protein aggregation and dysfunctional degradation in Parkinson disease.


Valiant L.G.,Harvard University
Journal of Computer and System Sciences | Year: 2011

Writing software for one parallel system is a feasible though arduous task. Reusing the substantial intellectual effort so expended for programming a second system has proved much more challenging. In sequential computing algorithms textbooks and portable software are resources that enable software systems to be written that are efficiently portable across changing hardware platforms. These resources are currently lacking in the area of multi-core architectures, where a programmer seeking high performance has no comparable opportunity to build on the intellectual efforts of others. In order to address this problem we propose a bridging model aimed at capturing the most basic resource parameters of multi-core architectures. We suggest that the considerable intellectual effort needed for designing efficient algorithms for such architectures may be most fruitfully expended in designing portable algorithms, once and for all, for such a bridging model. Portable algorithms would contain efficient designs for all reasonable combinations of the basic resource parameters and input sizes, and would form the basis for implementation or compilation for particular machines. Our Multi-BSP model is a multi-level model that has explicit parameters for processor numbers, memory/cache sizes, communication costs, and synchronization costs. The lowest level corresponds to shared memory or the PRAM, acknowledging the relevance of that model for whatever limitations on memory and processor numbers it may be efficacious to emulate it. We propose parameter-aware portable algorithms that run efficiently on all relevant architectures with any number of levels and any combination of parameters. For these algorithms we define a parameter-free notion of optimality. We show that for several fundamental problems, including standard matrix multiplication, the Fast Fourier Transform, and comparison sorting, there exist optimal portable algorithms in that sense, for all combinations of machine parameters. Thus some algorithmic generality and elegance can be found in this many parameter setting. © 2010 Elsevier Inc. All rights reserved.


Lestas I.,University of Cambridge | Vinnicombe G.,University of Cambridge | Paulsson J.,Harvard University
Nature | Year: 2010

Negative feedback is common in biological processes and can increase a system's stability to internal and external perturbations. But at the molecular level, control loops always involve signalling steps with finite rates for randombirths and deaths of individual molecules. Here we show, by developing mathematical tools that merge control and information theory with physical chemistry, that seemingly mild constraints on these rates place severe limits on the ability to suppress molecular fluctuations. Specifically, the minimum standard deviation in abundances decreases with the quartic root of the number of signalling events, making it extremely expensive to increase accuracy. Our results are formulated in terms of experimental observables, and existing data show that cells use brute force when noise suppression is essential; for example, regulatory genes are transcribed tens of thousands of times per cell cycle. The theory challenges conventional beliefs about biochemical accuracy and presents an approach to the rigorous analysis of poorly characterized biological systems. © 2010 Macmillan Publishers Limited. All rights reserved.


Rashba E.I.,Harvard University
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

Recent progress in experimental studies of low-dimensional systems with strong spin-orbit coupling poses a question on the effect of this coupling on the energy spectrum of electrons in semiconductor nanostructures. It is shown in this paper that this effect is profound in the strong coupling limit. In circular quantum dots a soft mode develops, in strongly elongated dots electron spin becomes protected from the effects of the environment, and the lower branch of the energy spectrum of quantum wires becomes nearly flat in a wide region of the momentum space. © 2012 American Physical Society.


Hayes J.,St Jamess Hospital | Peruzzi P.P.,Ohio State University | Lawler S.,Harvard University
Trends in Molecular Medicine | Year: 2014

The emergence of microRNAs has been one of the defining developments in cancer biology over the past decade, and the explosion of knowledge in this area has brought forward new diagnostic and therapeutic opportunities. The importance of microRNAs in cancer has been underlined by the identification of alterations in microRNA target binding sites and the microRNA processing machinery in tumor cells. Clinical trials utilizing microRNA profiling for patient prognosis and clinical response are now underway, and the first microRNA mimic entered the clinic for cancer therapy in 2013. In this article we review the potential applications of microRNAs for the clinical assessment of patient outcome in cancer, as well as in cancer monitoring and therapy. © 2014 Elsevier Ltd.


Knoll A.H.,Harvard University
Annual Review of Earth and Planetary Sciences | Year: 2011

Simple multicellularity has evolved numerous times within the Eukarya, but complex multicellular organisms belong to only six clades: animals, embryophytic land plants, florideophyte red algae, laminarialean brown algae, and two groups of fungi. Phylogeny and genomics suggest a generalized trajectory for the evolution of complex multicellularity, beginning with the co-optation of existing genes for adhesion. Molecular channels to facilitate cell-cell transfer of nutrients and signaling molecules appear to be critical, as this trait occurs in all complex multicellular organisms but few others. Proliferation of gene families for transcription factors and cell signals accompany the key functional innovation of complex multicellular clades: differentiated cells and tissues for the bulk transport of oxygen, nutrients, and molecular signals that enable organisms to circumvent the physical limitations of diffusion. The fossil records of animals and plants document key stages of this trajectory. Copyright © 2011 by Annual Reviews. All rights reserved.


Montez J.K.,Harvard University
Journal of health and social behavior | Year: 2013

Over the past half century the gap in mortality across education levels has grown in the United States, and since the mid-1980s, the growth has been especially pronounced among white women. The reasons for the growth among white women are unclear. We investigated three explanations-social-psychological factors, economic circumstances, and health behaviors-for the widening education gap in mortality from 1997 to 2006 among white women aged 45 to 84 years using data from the National Health Interview Survey Linked Mortality File (N = 46,744; 4,053 deaths). Little support was found for social-psychological factors, but economic circumstances and health behaviors jointly explained the growing education gap in mortality to statistical nonsignificance. Employment and smoking were the most important individual components. Increasing high school graduation rates, reducing smoking prevalence, and designing work-family policies that help women find and maintain desirable employment may reduce mortality inequalities among women.


Xia L.,Harvard University
Proceedings of the ACM Conference on Electronic Commerce | Year: 2012

The margin of victory of an election, defined as the smallest number k such that k voters can change the winner by voting differently, is an important measurement for robustness of the election outcome. It also plays an important role in implementing efficient post-election audits, which has been widely used in the United States to detect errors or fraud caused by malfunctions of electronic voting machines. In this paper, we investigate the computational complexity and (in)approximability of computing the margin of victory for various voting rules, including approval voting, all positional scoring rules (which include Borda, plurality, and veto), plurality with runoff, Bucklin, Copeland, maximin, STV, and ranked pairs. We also prove a dichotomy theorem, which states that for all continuous generalized scoring rules, including all voting rules studied in this paper, either with high probability the margin of victory is Θ(√n), or with high probability the margin of victory is Θ(n), where n is the number of voters. Most of our results are quite positive, suggesting that the margin of victory can be efficiently computed. This sheds some light on designing efficient post-election audits for voting rules beyond the plurality rule. © 2012 ACM.


Woolf C.J.,Program in Neurobiology | Woolf C.J.,Harvard University
Journal of Clinical Investigation | Year: 2010

To paraphrase Cole Porter's famous 1926 song, "What is this thing called pain? This funny thing called pain, just who can solve its mystery?" Pain, like love, is all consuming: when you have it, not much else matters, and there is nothing you can do about it. Unlike love, however, we are actually beginning to tease apart the mystery of pain. The substantial progress made over the last decade in revealing the genes, molecules, cells, and circuits that determine the sensation of pain offers new opportunities to manage it, as revealed in this Review series by some of the foremost experts in the field.


Ubiquitylation is an important mechanism for regulating innate immune responses to viral infections. Attachment of lysine 63 (Lys(63))-linked ubiquitin chains to the RNA sensor retinoic acid-inducible gene-I (RIG-I) by the ubiquitin E3 ligase tripartite motif protein 25 (TRIM25) leads to the activation of RIG-I and stimulates production of the antiviral cytokines interferon-α (IFN-α) and IFN-β. Conversely, Lys(48)-linked ubiquitylation of TRIM25 by the linear ubiquitin assembly complex (LUBAC) stimulates the proteasomal degradation of TRIM25, thereby inhibiting the RIG-I signaling pathway. Here, we report that ubiquitin-specific protease 15 (USP15) deubiquitylates TRIM25, preventing the LUBAC-dependent degradation of TRIM25. Through protein purification and mass spectrometry analysis, we identified USP15 as an interaction partner of TRIM25 in human cells. Knockdown of endogenous USP15 by specific small interfering RNA markedly enhanced the ubiquitylation of TRIM25. In contrast, expression of wild-type USP15, but not its catalytically inactive mutant, reduced the Lys(48)-linked ubiquitylation of TRIM25, leading to its stabilization. Furthermore, ectopic expression of USP15 enhanced the TRIM25- and RIG-I-dependent production of type I IFN and suppressed RNA virus replication. In contrast, depletion of USP15 resulted in decreased IFN production and markedly enhanced viral replication. Together, these data identify USP15 as a critical regulator of the TRIM25- and RIG-I-mediated antiviral immune response, thereby highlighting the intricate regulation of innate immune signaling.


Marneros A.G.,Harvard University
PLoS Genetics | Year: 2013

Aplasia cutis congenita (ACC) manifests with localized skin defects at birth of unknown cause, mostly affecting the scalp vertex. Here, genome-wide linkage analysis and exome sequencing was used to identify the causative mutation in autosomal dominant ACC. A heterozygous Arg-to-His missense mutation (p.R930H) in the ribosomal GTPase BMS1 is identified in ACC that is associated with a delay in 18S rRNA maturation, consistent with a role of BMS1 in processing of pre-rRNAs of the small ribosomal subunit. Mutations that affect ribosomal function can result in a cell cycle defect and ACC skin fibroblasts with the BMS1 p.R930H mutation show a reduced cell proliferation rate due to a p21-mediated G1/S phase transition delay. Unbiased comparative global transcript and proteomic analyses of ACC fibroblasts with this mutation confirm a central role of increased p21 levels for the ACC phenotype, which are associated with downregulation of heterogenous nuclear ribonucleoproteins (hnRNPs) and serine/arginine-rich splicing factors (SRSFs). Functional enrichment analysis of the proteomic data confirmed a defect in RNA post-transcriptional modification as the top-ranked cellular process altered in ACC fibroblasts. The data provide a novel link between BMS1, the cell cycle, and skin morphogenesis. © 2013 Alexander G.


Torella J.P.,Harvard University
PLoS computational biology | Year: 2010

The rapid proliferation of antibiotic-resistant pathogens has spurred the use of drug combinations to maintain clinical efficacy and combat the evolution of resistance. Drug pairs can interact synergistically or antagonistically, yielding inhibitory effects larger or smaller than expected from the drugs' individual potencies. Clinical strategies often favor synergistic interactions because they maximize the rate at which the infection is cleared from an individual, but it is unclear how such interactions affect the evolution of multi-drug resistance. We used a mathematical model of in vivo infection dynamics to determine the optimal treatment strategy for preventing the evolution of multi-drug resistance. We found that synergy has two conflicting effects: it clears the infection faster and thereby decreases the time during which resistant mutants can arise, but increases the selective advantage of these mutants over wild-type cells. When competition for resources is weak, the former effect is dominant and greater synergy more effectively prevents multi-drug resistance. However, under conditions of strong resource competition, a tradeoff emerges in which greater synergy increases the rate of infection clearance, but also increases the risk of multi-drug resistance. This tradeoff breaks down at a critical level of drug interaction, above which greater synergy has no effect on infection clearance, but still increases the risk of multi-drug resistance. These results suggest that the optimal strategy for suppressing multi-drug resistance is not always to maximize synergy, and that in some cases drug antagonism, despite its weaker efficacy, may better suppress the evolution of multi-drug resistance.


Yu N.,Columbia University | Capasso F.,Harvard University
Nature Materials | Year: 2014

Conventional optical components such as lenses, waveplates and holograms rely on light propagation over distances much larger than the wavelength to shape wavefronts. In this way substantial changes of the amplitude, phase or polarization of light waves are gradually accumulated along the optical path. This Review focuses on recent developments on flat, ultrathin optical components dubbed 'metasurfaces' that produce abrupt changes over the scale of the free-space wavelength in the phase, amplitude and/or polarization of a light beam. Metasurfaces are generally created by assembling arrays of miniature, anisotropic light scatterers (that is, resonators such as optical antennas). The spacing between antennas and their dimensions are much smaller than the wavelength. As a result the metasurfaces, on account of Huygens principle, are able to mould optical wavefronts into arbitrary shapes with subwavelength resolution by introducing spatial variations in the optical response of the light scatterers. Such gradient metasurfaces go beyond the well-established technology of frequency selective surfaces made of periodic structures and are extending to new spectral regions the functionalities of conventional microwave and millimetre-wave transmit-arrays and reflect-arrays. Metasurfaces can also be created by using ultrathin films of materials with large optical losses. By using the controllable abrupt phase shifts associated with reflection or transmission of light waves at the interface between lossy materials, such metasurfaces operate like optically thin cavities that strongly modify the light spectrum. Technology opportunities in various spectral regions and their potential advantages in replacing existing optical components are discussed. © 2014 Macmillan Publishers Limited. All rights reserved.


Loeffler J.S.,Harvard University | Durante M.,TU Darmstadt
Nature Reviews Clinical Oncology | Year: 2013

The use of charged particle therapy to control tumours non-invasively offers advantages over conventional radiotherapy. Protons and heavy ions deposit energy far more selectively than X-rays, allowing a higher local control of the tumour, a lower probability of damage to healthy tissue, low risk of complications and the chance for a rapid recovery after therapy. Charged particles are also useful for treating tumours located in areas that surround tissues that are radiosensitive and in anatomical sites where surgical access is limited. Current trial outcomes indicate that accelerated ions can potentially replace surgery for radical cancer treatments, which might be beneficial as the success of surgical cancer treatments are largely dependent on the expertise and experience of the surgeon and the location of the tumour. However, to date, only a small number of controlled randomized clinical trials have made comparisons between particle therapy and X-rays. Therefore, although the potential advantages are clear and supported by data, the cost:benefit ratio remains controversial. Research in medical physics and radiobiology is focusing on reducing the costs and increasing the benefits of this treatment. © 2013 Macmillan Publishers Limited. All rights reserved.


Aspuru-Guzik A.,Harvard University | Walther P.,University of Vienna
Nature Physics | Year: 2012

Quantum simulators are controllable quantum systems that can be used to mimic other quantum systems. They have the potential to enable the tackling of problems that are intractable on conventional computers. The photonic quantum technology available today is reaching the stage where significant advantages arise for the simulation of interesting problems in quantum chemistry, quantum biology and solid-state physics. In addition, photonic quantum systems also offer the unique benefit of being mobile over free space and in waveguide structures, which opens new perspectives to the field by enabling the natural investigation of quantum transport phenomena. Here, we review recent progress in the field of photonic quantum simulation, which should break the ground towards the realization of versatile quantum simulators. © 2012 Macmillan Publishers Limited. All rights reserved.


Zhou S.,Harvard University
Journal of Cellular Biochemistry | Year: 2011

Human adult bone marrow-derived skeletal stem cells a.k.a mesenchymal stem cells (hMSCs) have been shown to be precursors of several different cellular lineages, including osteoblast, chondrocyte, myoblast, adipocyte, and fibroblast. Several studies have shown that cooperation between transforming growth factor β (TGF-β) and Wnt/β-catenin signaling pathways plays a role in controlling certain developmental events and diseases. Our previous data showed that agents like TGF-β, cooperation with Wnt signaling, promote chondrocyte differentiation at the expense of adipocyte differentiation in hMSCs. In this study, we tested mechanisms by which TGF-β activation of β-catenin signaling pathway and whether these pathways interact during osteoblast differentiation of hMSCs. With selective small chemical kinase inhibitors, we demonstrated that TGF-β1 requires TGF-β type I receptor ALK-5, Smad3, phosphoinositide 3-kinases (PI3K), and protein kinase A (PKA) to stabilize β-catenin, and needs ALK-5, PKA, and JNK to inhibit osteoblastogenesis in hMSCs. Knockdown of β-catenin with siRNA stimulated alkaline phosphatase activity and antagonized the inhibitory effects of TGF-β1 on bone sialoprotein (BSP) expression, suggested that TGF-β1 cooperated with β-catenin signaling in inhibitory of osteoblastogenesis in hMSCs. In summary, TGF-β1 activates β-catenin signaling pathway via ALK-5, Smad3, PKA, and PI3K pathways, and modulates osteoblastogenesis via ALK5, PKA, and JNK pathways in hMSCs; the interaction between TGF-β and β-catenin signaling supports the view that β-catenin signaling is a mediator of TGF-β's effects on osteoblast differentiation of hMSCs. Copyright © 2011 Wiley-Liss, Inc.


Patten M.M.,Harvard University
Proceedings. Biological sciences / The Royal Society | Year: 2013

Populations with two sexes are vulnerable to a pair of genetic conflicts: sexual antagonism that can arise when alleles have opposing fitness effects on females and males; and parental antagonism that arises when alleles have opposing fitness effects when maternally and paternally inherited. This paper extends previous theoretical work that found stable linkage disequilibrium (LD) between sexually antagonistic loci. We find that LD is also generated between parentally antagonistic loci, and between sexually and parentally antagonistic loci, without any requirement of epistasis. We contend that the LD in these models arises from the admixture of gene pools subject to different selective histories. We also find that polymorphism maintained by parental antagonism at one locus expands the opportunity for polymorphism at a linked locus experiencing parental or sexual antagonism. Taken together, our results predict the chromosomal clustering of loci that segregate for sexually and parentally antagonistic alleles. Thus, genetic conflict may play a role in the evolution of genomic architecture.


Hodgkin lymphomas (HLs) are neoplasms of large B cells. Two types are recognized: nodular lymphocyte predominant HL (NLPHL) and classical HL (CHL). In both types, there may be morphological and possibly biological overlap with large B-cell lymphomas (LBCLs) of non-HL types. These include nodular sclerosis CHL and primary mediastinal large B-cell lymphoma; CHL rich in lymphocytes and NLPHL; and NLPHL and T-cell/histiocyte-rich LBCL. This review covers the defining features of each of these diseases, the borderlines between them, and strategies for differential diagnosis. © 2013 USCAP, Inc. All rights reserved.


Fishman J.A.,Harvard University
American Journal of Transplantation | Year: 2013

Herpesviruses infect most animal species. Infections due to the eight human herpesviruses (HHV) are exacerbated by immunosuppression in organ transplantation. The special features of the herpesvirus life cycle include the ability to establish latent, nonproductive infection and the life-long capacity for reactivation to productive, lytic infection. Interactions between latent virus and the immune system determine the frequency and severity of symptomatic infections. The immunologic and cellular effects of herpesvirus infections contribute to risk for opportunistic infections and graft rejection. Among the most important advances in transplantation are laboratory assays for the diagnosis and monitoring of herpesvirus infections and antiviral agents with improved efficacy in prophylaxis and therapy. For herpes simplex virus, varicella zoster virus and cytomegalovirus, these advances have significantly reduced the morbidity of infection. The syndromes of EBV-associated posttransplant lymphoproliferative disorders (PTLD) and Kaposi's sarcoma remain important complications of immunosuppression. The epidemiology and essential biology of human herpesvirus is reviewed. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.


Adaptive radiation refers to diversification from an ancestral species that produces descendants adapted to use a great variety of distinct ecological niches. In this review, I examine two aspects of adaptive radiation: first, that it results from ecological opportunity and, second, that it is deterministic in terms of its outcome and evolutionary trajectory. Ecological opportunity is usually a prerequisite for adaptive radiation, although in some cases, radiation can occur in the absence of preexisting opportunity. Nonetheless, many clades fail to radiate although seemingly in the presence of ecological opportunity; until methods are developed to identify and quantify ecological opportunity, the concept will have little predictive utility in understanding a priori when a clade might be expected to radiate. Although predicted by theory, replicated adaptive radiations occur only rarely, usually in closely related and poorly dispersing taxa found in the same region on islands or in lakes. Contingencies of a variety of types may usually preclude close similarity in the outcome of evolutionary diversification in other situations. Whether radiations usually unfold in the same general sequence is unclear because of the unreliability of methods requiring phylogenetic reconstruction of ancestral events. The synthesis of ecological, phylogenetic, experimental, and genomic advances promises to make the coming years a golden age for the study of adaptive radiation; natural history data, however, will always be crucial to understanding the forces shaping adaptation and evolutionary diversification. © 2010 by The University of Chicago.


Ayata C.,Harvard University
Stroke | Year: 2010

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) syndrome is the most common monogenic inherited form of small vessel disease, characterized by frequent migraine attacks with aura, recurrent strokes and progressive white matter degeneration. Early vascular cognitive impairment progresses into frank dementia of subcortical type later in life. Linked to mutations in the NOTCH3 gene, CADASIL vasculopathy is associated with accumulation of granular osmiophilic material and NOTCH3 extracellular domain around small caliber arteries and arterioles, and eventual loss of vascular smooth muscle cells. Cerebral blood flow dysregulation has been hypothesized as a major mechanism, largely based on evidence from hemodynamic studies in CADASIL patients. Although animal models expressing CADASIL mutations reproduced the pathology and cerebrovascular dysfunction, the phenotypic spectrum has been quite heterogeneous, possibly due to the choice of genetic constructs and obvious species differences between mouse and man. Nevertheless, these experimental models provide new opportunities to explore the molecular and physiological mechanisms of CADASIL, and address the fundamental question of whether CADASIL phenotype represents loss of NOTCH3 function or gain of a novel and pathological function. Here, I provide an overview of existing animal models of CADASIL and the pathophysiological insights gained from these models. © 2010 American Heart Association, Inc.


Ananthakrishnan A.N.,Harvard University
Current Gastroenterology Reports | Year: 2013

Inflammatory bowel diseases [IBD; Crohn's disease (CD), ulcerative colitis (UC)] are chronic immunologically mediated diseases that are due to a dysregulated immune response to intestinal flora in a genetically susceptible host. Despite advances in genetics, the likelihood of occurrence of disease remains incompletely explained and there appears to be a strong role for the environment in mediating risk of disease. Smoking remains the most widely studied and replicated risk factor, contributing to increased risk and severity of CD while conferring protection against UC. Recent data has suggested novel risk factors. Lower plasma vitamin D is associated with an increased risk of Crohn's disease, and vitamin D supplementation may prevent relapse of disease. Several medications including oral contraceptives, post-menopausal hormone replacement, aspirin, NSAIDs, and antibiotics may increase risk of CD or UC with the mechanisms of effect remaining inadequately defined. There is continuing evidence that depression and psychosocial stress may play a role in the pathogenesis of both CD and UC, while at the same time also increasing risk for disease flares. There is also a growing understanding of the role of diet on IBD, in particular through its effect on the microbiome. Animal protein intake and n-6 fatty acids may increase risk of UC while n-3 fatty acids and dietary fiber may confer protection. The effect of diet on established disease remains poorly studied. There is need for routine measurement of a spectrum of environmental exposures in prospective studies to further our understanding. © 2012 Springer Science+Business Media New York.


Herpes simplex virus (HSV) undergoes a lytic infection in epithelial cells and a latent infection in neuronal cells, and epigenetic mechanisms play a major role in the differential gene expression under the two conditions. HSV viron DNA is not associated with histones but is rapidly loaded with heterochromatin upon entry into the cell. Viral proteins promote reversal of the epigenetic silencing in epithelial cells while the viral latency-associated transcript promotes additional heterochromatin in neuronal cells. The cellular sensors that initiate the chromatinization of foreign DNA have not been fully defined. IFI16 and cGAS are both essential for innate sensing of HSV DNA, and new evidence shows how they work together to initiate innate signaling. IFI16 also plays a role in the heterochromatinization of HSV DNA, and this review will examine how IFI16 integrates epigenetic regulation and innate sensing of foreign viral DNA to show how these two responses are related. © 2015 Elsevier Inc.


Patel D.D.,Novartis | Kuchroo V.K.,Harvard University
Immunity | Year: 2015

The T helper 17 (Th17) cell pathway has been linked by genome-wide association studies to multiple autoimmune diseases. Identification of the genetic causes of primary immunodeficiency diseases revealed that Th17 cells are also critical in host immunity to mucocutaneous candida infections and Staphylococcus aureus. Therapeutic interventions with inhibitors of the different components of the pathway such as interleukin-12 (IL-12), IL-23, IL-17A, and IL-17RA have variably beneficial effects in psoriasis, Crohn's disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-infectious uveitis, and multiple sclerosis. Thus, whereas Th17 cells are protective against Candida albicans and to a lesser degree Staphylococcus aureus, they are pathogenic in many autoimmune diseases. Here, we compare and contrast the effects of human genetic mutations of and therapeutic interventions targeted at Th17 cell molecules. We discuss that although there are similarities when Th17 cell pathway molecules are modulated, each molecule has unique non-Th17 cell features that lead to different functional outcomes. © 2015 Elsevier Inc.


Ananthakrishnan A.N.,Harvard University
Gastroenterology and Hepatology | Year: 2013

Crohn's disease (CD) and ulcerative colitis (UC) are chronic immunologically mediated diseases that often have a relapsing-remitting course in young persons. Genetic-risk polymorphisms explain less than one third of the heritability of disease. Epidemiologic and laboratory data suggest that environmental factors play a significant role in influencing the risk and natural history of disease. Smoking is the most widely and consistently described risk factor. It, however, increases the risk of CD while conferring protection against UC. The gut microbiome is a key component in the development of inflammatory bowel disease (IBD). Several external factors potentially exert an effect by influencing the composition of the gut microbiome or disrupting the intestinal barrier. These external influences include the use of antibiotics or nonsteroidal anti-inflammatory drugs and the presence of enteric infections. Data on diet have been inconsistent, but high fiber intake, particularly of soluble fiber, appears to protect against CD, whereas protein intake may increase disease risk. Vitamin D may also play an important protective role, particularly in patients with CD. Neurobehavioral factors, such as stress and depression, also influence the risk of IBD. Systematic and rigorous studies of environmental exposures in the management of IBD are needed. In particular, studies of whether environmental factors can be modified to reduce the likelihood of relapse or improve patient outcomes would be valuable.


Vanderweele T.J.,Harvard University
Biometrika | Year: 2010

Definitions are given for weak and strong sufficient cause interactions in settings in which the outcome is binary and in which there are two exposures of interest that are categorical or ordinal. Weak sufficient cause interactions concern cases in which a mechanism will operate under certain values of the two exposures but not when one or the other of the exposures takes some other value. Strong sufficient cause interactions concern cases in which a mechanism will operate under certain values of the two exposures but not when one or the other of the exposures takes any other value. Empirical conditions are derived for such interactions when exposures have two or three levels and are related to regression coefficients in linear and log-linear models. When the exposures are binary, the notions of a weak and a strong sufficient cause interaction coincide, but not when the exposures are categorical or ordinal. The results are applied to examples concerning gene-gene and gene-environment interactions. © 2010 Biometrika Trust.


Proton therapy treatments are based on a proton RBE (relative biological effectiveness) relative to high-energy photons of 1.1. The use of this generic, spatially invariant RBE within tumors and normal tissues disregards the evidence that proton RBE varies with linear energy transfer (LET), physiological and biological factors, and clinical endpoint. Based on the available experimental data from published literature, this review analyzes relationships of RBE with dose, biological endpoint and physical properties of proton beams. The review distinguishes between endpoints relevant for tumor control probability and those potentially relevant for normal tissue complication. Numerous endpoints and experiments on sub-cellular damage and repair effects are discussed. Despite the large amount of data, considerable uncertainties in proton RBE values remain. As an average RBE for cell survival in the center of a typical spread-out Bragg peak (SOBP), the data support a value of ∼1.15 at 2 Gy/fraction. The proton RBE increases with increasing LETd and thus with depth in an SOBP from ∼1.1 in the entrance region, to ∼1.15 in the center, ∼1.35 at the distal edge and ∼1.7 in the distal fall-off (when averaged over all cell lines, which may not be clinically representative). For small modulation widths the values could be increased. Furthermore, there is a trend of an increase in RBE as (α/β)x decreases. In most cases the RBE also increases with decreasing dose, specifically for systems with low (α/β)x. Data on RBE for endpoints other than clonogenic cell survival are too diverse to allow general statements other than that the RBE is, on average, in line with a value of ∼1.1. This review can serve as a source for defining input parameters for applying or refining biophysical models and to identify endpoints where additional radiobiological data are needed in order to reduce the uncertainties to clinically acceptable levels. © 2014 Institute of Physics and Engineering in Medicine.


Green 2nd. D.A.,Harvard University
Proceedings. Biological sciences / The Royal Society | Year: 2014

Phenotypic plasticity is the ability of a single genotype to yield distinct phenotypes in different environments. The molecular mechanisms linking phenotypic plasticity to the evolution of heritable diversification, however, are largely unknown. Here, we show that insulin/insulin-like growth factor signalling (IIS) underlies both phenotypic plasticity and evolutionary diversification of ovariole number, a quantitative reproductive trait, in Drosophila. IIS activity levels and sensitivity have diverged between species, leading to both species-specific ovariole number and species-specific nutritional plasticity in ovariole number. Plastic range of ovariole number correlates with ecological niche, suggesting that the degree of nutritional plasticity may be an adaptive trait. This demonstrates that a plastic response conserved across animals can underlie the evolution of morphological diversity, underscoring the potential pervasiveness of plasticity as an evolutionary mechanism.


Aghdaee S.M.,Harvard University
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

Processing of temporal information is critical to behaviour. Here, we review the phenomenology and mechanism of relative timing, ordinal comparisons between the timing of occurrence of events. Relative timing can be an implicit component of particular brain computations or can be an explicit, conscious judgement. Psychophysical measurements of explicit relative timing have revealed clues about the interaction of sensory signals in the brain as well as in the influence of internal states, such as attention, on those interactions. Evidence from human neurophysiological and functional imaging studies, neuropsychological examination in brain-lesioned patients, and temporary disruptive interventions such as transcranial magnetic stimulation (TMS), point to a role of the parietal cortex in relative timing. Relative timing has traditionally been modelled as a 'race' between competing neural signals. We propose an updated race process based on the integration of sensory evidence towards a decision threshold rather than simple signal propagation. The model suggests a general approach for identifying brain regions involved in relative timing, based on looking for trial-by-trial correlations between neural activity and temporal order judgements (TOJs). Finally, we show how the paradigm can be used to reveal signals related to TOJs in parietal cortex of monkeys trained in a TOJ task.


Hsieh S.-T.T.,Harvard University
PLoS ONE | Year: 2010

Background: Morphological innovations that significantly enhance performance capacity may enable exploitation of new resources and invasion of new ecological niches. The invasion of land from the aquatic realm requires dramatic structural and physiological modifications to permit survival in a gravity-dominated, aerial environment. Most fishes are obligatorily aquatic, with amphibious fishes typically making slow-moving and short forays on to land. Methodology/Principal Findings: Here I describe the behaviors and movements of a little known marine fish that moves extraordinarily rapidly on land. I found that the Pacific leaping blenny, Alticus arnoldorum, employs a tail-twisting movement on land, previously unreported in fishes. Focal point behavioral observations of Alticus show that they have largely abandoned the marine realm, feed and reproduce on land, and even defend terrestrial territories. Comparisons of these blennies' terrestrial kinematic and kinetic (i.e., force) measurements with those of less terrestrial sister genera show A. arnoldorum move with greater stability and locomotor control, and can move away more rapidly from impending threats. Conclusions/Significance: My results demonstrate that axial tail twisting serves as a key innovation enabling invasion of a novel marine niche. This paper highlights the potential of using this system to address general evolutionary questions about water-land transitions and niche invasions. © 2010 Shi-Tong Tonia Hsieh.


Kaltenegger L.,Harvard University
Astrophysical Journal Letters | Year: 2010

We discuss the possibility of screening the atmosphere of exomoons for habitability. We concentrate on Earth-like satellites of extrasolar giant planets (EGPs) that orbit in the Habitable Zone (HZ) of their host stars. The detectability of exomoons for EGPs in the HZ has recently been shown to be feasible with the Kepler Mission or equivalent photometry using transit duration observations. Transmission spectroscopy of exomoons is a unique potential tool to screen them for habitability in the near future, especially around low mass stars. Using the Earth itself as a proxy we show the potential and limits of spectroscopy to detect biomarkers on an Earth-like exomoon and discuss effects of tidal locking for such potential habitats. © 2010. The American Astronomical Society. All rights reserved.


Edwards B.A.,Harvard University
Respiratory physiology & neurobiology | Year: 2013

Any general model of respiratory control must explain a puzzling array of breathing patterns that are observed during the course of a lifetime. Particular challenges are to understand why periodic breathing is rarely seen in the first few days after birth, reaches a peak at 2-4 weeks postnatal age, and disappears by 6 months, why it is prevalent in preterm infants, and why it reappears in adults at altitude or with heart failure. In this review we use the concept of loop gain to obtain quantitative insight into the genesis of unstable breathing patterns with a particular focus on how changes in carotid body function could underlie the age-related dependence of periodic breathing. Copyright © 2012 Elsevier B.V. All rights reserved.


Stanton R.C.,Harvard University
Current Diabetes Reports | Year: 2011

The number of people with diabetic kidney disease continues to increase worldwide despite current treatments. Of the pathophysiologic mechanisms that have been identified in the development and progression of diabetic nephropathy, oxidative stress (more accurately described as increased levels of reactive oxygen species; ROS) is of major importance. The increase in ROS is due to both increased production and to decreased and/or inadequate antioxidant function. To date, human clinical trials with antioxidants have not been shown to be effective. This is likely due, at least in part, to the lack of specificity of current agents. Recent research has determined both major sources of high glucose-induced cellular ROS production as well as high glucose-induced changes in antioxidant function. Treatments targeted at one or more of the specific diabetes-induced alterations in the regulation of ROS levels will likely lead to effective treatments that prevent the development and progression of diabetic kidney disease. © 2011 Springer Science+Business Media, LLC.


The ATP:ADP ratio is a critical parameter of cellular energy status that regulates many metabolic activities. Here we report an optimized genetically encoded fluorescent biosensor, PercevalHR, that senses the ATP:ADP ratio. PercevalHR is tuned to the range of intracellular ATP:ADP expected in mammalian cells, and it can be used with one- or two-photon microscopy in live samples. We use PercevalHR to visualize activity-dependent changes in ATP:ADP when neurons are exposed to multiple stimuli, demonstrating that it is a sensitive reporter of physiological changes in energy consumption and production. We also use PercevalHR to visualize intracellular ATP:ADP while simultaneously recording currents from ATP-sensitive potassium (KATP) channels in single cells, showing that PercevalHR enables the study of coordinated variation in ATP:ADP and KATP channel open probability in intact cells. With its ability to monitor changes in cellular energetics within seconds, PercevalHR should be a versatile tool for metabolic research.


Selkoe D.J.,Harvard University
Annals of neurology | Year: 2013

Few diagnoses in modern medicine evoke more apprehension in patients and their families than Alzheimer disease (AD). Defined as a clinical and pathological entity a century ago, the disorder only came under intense molecular scrutiny in the mid-1980s. Genetic, histopathological, biochemical, and animal modeling studies have combined to provide evidence that the disease may begin with an imbalance between the production and clearance of the self-aggregating amyloid β protein (Aβ) in brain regions serving memory and cognition. This concept has been furthered by recent analyses in humans of cerebrospinal fluid and neuroimaging biomarkers that suggest an approximate sequence of AD-type brain alterations beginning >2 decades before the onset of dementia. Although the Aβ hypothesis of Alzheimer causation does not explain all features of this multifactorial syndrome, experimental agents that lower or neutralize Aβ have become the major focus of therapeutic research. Several clinical trials in mild-to-moderate AD have not met standard cognitive and functional endpoints, but there were important shortcomings in the agent and/or the trial design in each case. Based on the lessons learned, the field has moved on to test potentially disease-modifying agents in mild AD patients or via secondary prevention in presymptomatic subjects bearing amyloid plaques. Immunotherapeutic agents are receiving the most study, but other antiamyloid strategies and, importantly, nonamyloid targets such as tau and neuroinflammation are of great interest. The pace of recent developments augurs well for 1 or more experimental agents being shown to slow cognitive decline without major side effects. However, research funding from all sources will need to increase dramatically and soon to stave off the approaching tsunami of AD. Copyright © 2013 American Neurological Association.


Nestler E.J.,Mount Sinai School of Medicine | Hyman S.E.,Harvard University
Nature Neuroscience | Year: 2010

Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported. © 2010 Nature America, Inc. All rights reserved.


Jalian H.R.,Harvard University
Seminars in cutaneous medicine and surgery | Year: 2013

Dermatologists have long used cold-based therapeutic approaches for a variety of applications. Based on the differences in chemical composition, it is possible to selectively target certain tissues rich with lipid, while sparing the surrounding tissue predominantly containing water. With historical observations of cold-induced panniculitis suggesting the feasibility of this strategy, cryolipolysis has emerged as a new methodology using controlled cooling to selectively target fat. Both preclinical and clinical studies have established the safety and efficacy of cryolipolysis for noninvasive body contouring. This review will focus on the evolution of cryolipolysis from initial case reports of cold-induced panniculitis, to preclinical and clinical studies, and the current clinical practice.


Jain R.K.,Harvard University
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

For almost four decades, my work has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics. Working on the hypothesis that the abnormal tumor microenvironment-characterized by hypoxia and high interstitial fluid pressure--fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematic models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. We next hypothesized that agents that induce normalization of the microenvironment can improve treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents--originally designed to starve tumors--could transiently normalize tumor vasculature, alleviate hypoxia, increase delivery of drugs and antitumor immune cells, and improve the outcome of various therapies. Our trials of antiangiogenics in patients with newly diagnosed and recurrent glioblastoma supported this concept. They revealed that patients whose tumor blood perfusion increased in response to cediranib survived 6 to 9 months longer than those whose blood perfusion did not increase. The normalization hypothesis also opened doors to treating various nonmalignant diseases characterized by abnormal vasculature, such as neurofibromatosis type 2. More recently, we discovered that antifibrosis drugs capable of normalizing the tumor microenvironment can improve the delivery and efficacy of nano- and molecular medicines. Our current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies.


Wessling-Resnick M.,Harvard University
Annual Review of Nutrition | Year: 2010

Iron and its homeostasis are intimately tied to the lammatory response. The adaptation to iron deficiency, which confers resistance to ection and improves the lammatory condition, underlies what is probably the most obvious link: the anemia of lammation or chronic disease. A large number of stimulatory inputs must be integrated to tightly control iron homeostasis during the lammatory response. In order to understand the pathways of iron trafficking and how they are regulated, this article presents a brief overview of iron homeostasis. A major focus is on the regulation of the peptide hormone hepcidin during the lammatory response and how its function contributes to the process of iron withdrawal. The review also summarizes new and emerging ormation about other iron metabolic regulators and effectors that contribute to the lammatory response. Potential benefits of treatment to ameliorate the hypoferremic condition promoted by lammation are also considered. Copyright © 2010 by Annual Reviews. All rights reserved.


Stone J.H.,Harvard University
Seminars in Diagnostic Pathology | Year: 2012

Concepts about IgG4-related disease (IgG4-RD) are now emerging swiftly. The condition has been identified in virtually every organ system, and its features are often excellent mimickers of malignancies, infections, and other immune-mediated disorders. Recommendations for nomenclature were proposed by the Organizing Committee of the 2011 International IgG4-related disease Symposium, and guidelines for the pathologic diagnosis of this condition have been published by an international group of experts. Experience with treatment regimens is growing. Glucocorticoids and B-cell depletion strategies both appear to be effective and are the subject of ongoing studies. This article reviews the current thought and understanding of this disease with regard to nomenclature, organ system involvement, and approaches to therapy. © 2012 Elsevier Inc.


Fletcher C.D.M.,Harvard University
Modern Pathology | Year: 2014

Previously unrecognized but clinicopathologically (and often molecularly) distinct types of soft tissue tumor continue to be characterized, allowing wider recognition, more consistent application of diagnostic criteria, more reliable prediction of tumor behavior and enhancement of existing classification schemes. Examples of such 'entities' that have become much better understood over the past decade or so include deep 'benign' fibrous histiocytoma, hemosiderotic fibrolipomatous tumor, PEComa, spindle cell liposarcoma, myoepithelial tumors of soft tissue and spindle cell/sclerosing rhabdomyosarcoma. These tumor types, as well as the insights which they have engendered, are briefly reviewed here. © 2014 USCAP, Inc.


Sanders J.G.,Harvard University
Cladistics | Year: 2010

Examination of trees for the presence of particular nodes is a fundamental aspect of systematics, and is the basis of phylogenetic sensitivity analysis, but becomes unwieldy when performed manually for complex nodes or over large numbers of trees. The program Cladescan is presented here as a stand-alone application to facilitate the detection of nodes in such situations. Cladescan includes features useful for phylogenetic sensitivity analysis, such as automatic generation of "Navajo rug" sensitivity plots. In addition, researchers may find it useful for general comparisons among large data sets. © 2009 The Willi Hennig Society.


Bauman M.L.,Harvard University
Neurotherapeutics | Year: 2010

Ever since its original description by Leo Kanner in l943, autism has been generally defined by its clinical characteristics and core symptoms that include impaired social skills, isolated areas of interest, and delayed and disordered language. Over time, it has become apparent that autism is a heterogeneous disorder with regard to its clinical presentation, etiology, underlying neurobiology, and degree of severity. As a result, the termed diagnosis of autism spectrum disorders (ASDs) has come into common usage. With advancements in clinical care, there has come the appreciation that many ASD children, adolescents, and adults may have medically relevant disorders that may negatively impact their developmental progress and behavior, but which frequently go undetected. Many of these medical conditions are treatable, often resulting in improved developmental gains and quality of life for the patient and family. In addition, the possibility exists that some of these medical conditions may suggest the presence of important genetic and/or biologic markers, which, if identified, can refine our ability to be more precise in categorizing clinical and genetic subtypes within the autism spectrum. © 2010.


Dimitri K.,Harvard University
Archives of Neurology | Year: 2010

Accumulation and aggregation of disease-causing proteins is a hallmark of several neurodegenerative disorders such as Parkinson, Alzheimer, and Huntington diseases. One of the main goals of research in neurodegenerative disorders has been to improve clearance of these accumulated proteins. Using the example of Huntington disease, I discuss strategies to selectively activate cellular degradation machinery to improve clearance of the mutant protein and to identify therapeutic targets for the treatment of Huntington disease and related neurodegenerative disorders. ©2010 American Medical Association. All rights reserved.


Daffner K.R.,Harvard University
Journal of Alzheimer's Disease | Year: 2010

Promoting successful cognitive aging is a topic of major importance to individuals and the field of public health. This review presents a coherent framework not only for evaluating factors, protective activities, and enhancing agents that have already been proposed, but also ones that will be put forward in the future. The promotion of successful cognitive aging involves the dual goals of preventing loss of information processing capacity and cognitive reserve, and enhancing brain capacity and cognitive reserve. Four major lines of evidence are available for evaluating whether a proposed factor promotes successful cognitive aging: 1) epidemiologic/cohort studies; 2) animal/basic science studies; 3) human "proof-of-concept" studies; and 4) human intervention studies. Each line of evidence has advantages and limitations that will be discussed. Through illustrative examples, we trace the ways in which each method informs us about the potential value of several proposed factors. Currently, lines of converging evidence allow the strongest case to be made for physical and cognitively stimulating activities. Although epidemiological data seem to favor the use of statins to lower the risk of dementia, more definitive recommendations await further randomized controlled studies. There is presently no clear evidence that antioxidants or Ginkgo biloba promote successful cognitive aging. The impact of resveratrol, fish oil, and a long list of other proposed agents needs to be determined. Clinicians remain well-positioned to identify and aggressively treat vascular risk factors, diabetes, sleep disorders, and other conditions that may reduce brain capacity, and to encourage activities that can build cognitive reserve. © 2010-IOS Press and the authors. All rights reserved.


Muschamp J.W.,Harvard University
Cold Spring Harbor perspectives in medicine | Year: 2013

Psychostimulants such as amphetamine and cocaine are believed to produce dependence by causing rapid, supraphysiological elevations in synaptic dopamine (DA) within the nucleus accumbens (NAc) (Volkow et al. 2009, Neuropharmacology 56: 3-8). These changes in forebrain DA transmission are similar to those evoked by natural reinforcers (Louilot et al. 1991, Brain Res 553: 313-317; Roitman et al. 2004, J Neurosci 24: 1265-1271), but are of greater magnitude and longer duration. Repeated drug exposure causes compensatory neuroadaptations in neurons of the NAc, some of which may modulate excess DA in a homeostatic fashion. One such adaptation is the activation of the transcription factor CREB (cAMP response element-binding protein) within neurons of the NAc. Although elevated levels of transcriptionally active CREB appear to attenuate DA transmission by increasing expression of the endogenous κ opioid receptor (KOR) ligand dynorphin, increased dynorphin transmission may ultimately have undesirable effects that contribute to drug withdrawal states as well as comorbid psychiatric illnesses such as depression. This state may prompt a return to drug use to mitigate the adverse effects of withdrawal. This article summarizes our current understanding of how CREB and dynorphin contribute to the dysregulation of motivation and describes novel therapeutic strategies that derive from preclinical research in this area.


Chen J.,Harvard University
Investigative ophthalmology & visual science | Year: 2012

Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective β-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects. Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups. None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor. Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.


Haber D.A.,Harvard University | Haber D.A.,Howard Hughes Medical Institute | Velculescu V.E.,Johns Hopkins University
Cancer Discovery | Year: 2014

The ability to study nonhematologic cancers through noninvasive sampling of blood is one of the most exciting and rapidly advancing fields in cancer diagnostics. This has been driven both by major technologic advances, including the isolation of intact cancer cells and the analysis of cancer cell-derived DNA from blood samples, and by the increasing application of molecularly driven therapeutics, which rely on such accurate and timely measurements of critical biomarkers. Moreover, the dramatic efficacy of these potent cancer therapies drives the selection for additional genetic changes as tumors acquire drug resistance, necessitating repeated sampling of cancer cells to adjust therapy in response to tumor evolution. Together, these advanced noninvasive diagnostic capabilities and their applications in guiding precision cancer therapies are poised to change the ways in which we select and monitor cancer treatments. Significance: Recent advances in technologies to analyze circulating tumor cells and circulating tumor DNA are setting the stage for real-time, noninvasive monitoring of cancer and providing novel insights into cancer evolution, invasion, and metastasis. © 2014 American Association for Cancer Research.


Kleffel S.,Harvard University
Advances in experimental medicine and biology | Year: 2013

Increasing evidence suggests that tumor dormancy represents an important mechanism underlying the observed failure of existing therapeutic modalities to fully eradicate cancers. In addition to its more established role in maintaining minimal residual disease after treatment, dormancy might also critically contribute to early stages of tumor development and the formation of clinically undetectable micrometastatic foci. There are striking parallels between the concept of tumor dormancy and the cancer stem cell (CSC) theory of tumor propagation. For instance, the CSC hypothesis similarly predicts that a subset of self-renewing cancer cells-that is CSCs-is responsible for tumor initiation, bears the preferential ability to survive tumor therapy, and persists long term to ultimately cause delayed cancer recurrence and metastatic progression. Additionally, many of the biological mechanisms involved in controlling the dormant state of a tumor can also govern CSC behavior, including cell cycle modifications, alteration of angiogenic processes, and modulation of antitumor immune responses. In fact, quiescence and immune escape are emerging hallmark features of at least some CSCs, indicating significant overlap between dormant cancer populations and CSCs. Herein, we crucially dissect whether CSCs occupy specific roles in orchestrating the switch between dormancy and exuberant tumor growth. We elucidate how recently uncovered CSC biological features could enable these cells to evade immunologic clearance and regulate cancer expansion, relapse, and progression. We propose that the study of CSC immunobiological pathways holds the promise to critically advance our understanding of the processes mediating tumor dormancy. Ultimately, such research endeavors could unravel novel therapeutic avenues that efficiently target both proliferating and dormant CSCs to minimize the risk of tumor recurrence in cancer patients.


Benoist C.,Harvard University
Cold Spring Harbor perspectives in biology | Year: 2012

Regulatory T cells expressing the FoxP3 transcription factor have a profound and nonredundant role in several aspects of immunological tolerance. We will review here the specification of this lineage, its population dynamics, and the diversity of subphenotypes that correlate with their diverse roles in controlling inflammation in a variety of settings.


Huybers P.,Harvard University
Journal of Climate | Year: 2010

The spread in climate sensitivity obtained from 12 general circulation model runs used in the Fourth Assessment of the Intergovernmental Panel on Climate Change indicates a 95% confidence interval of 2.1°-5.5°C, but this reflects compensation between model feedbacks. In particular, cloud feedback strength negatively covaries with the albedo feedback as well as with the combined water vapor plus lapse rate feedback. If the compensation between feedbacks is removed, the 95% confidence interval for climate sensitivity expands to 1.9°-8.0°C. Neither of the quoted 95% intervals adequately reflects the understanding of climate sensitivity, but their differences illustrate that model interdependencies must be understood before model spread can be correctly interpreted. The degree of negative covariance between feedbacks is unlikely to result from chance alone. It may, however, result from the method by which the feedbacks were estimated, physical relationships represented in the models, or from conditioning the models upon some combination of observations and expectations. This compensation between model feedbacks-when taken together with indications that variations in radiative forcing and the rate of ocean heat uptake play a similar compensatory role in models-suggests that conditioning of the models acts to curtail the intermodel spread in climate sensitivity. Observations used to condition the models ought to be explicitly stated, or there is the risk of doubly calling on data for purposes of both calibration and evaluation. Conditioning the models upon individual expectation (e.g., anchoring to the Charney range of 3° ± 1.5°C), to the extent that it exists, greatly complicates statistical interpretation of the intermodel spread. © 2010 American Meteorological Society.


Spiegelman D.,Harvard University
American Journal of Public Health | Year: 2016

In a stepped wedge design (SWD), an intervention is rolled out in a staggered manner over time, in groups of experimental units, so that by the end, all units experience the intervention. For example, in the MaxART study, the date at which to offer universal antiretroviral therapy to otherwise ineligible clients is being randomly assignedin nine"steps" of four months duration so that after three years, all 14 facilities in northern and central Swaziland will be offering early treatment. Inthecommonalternative, the cluster randomized trial (CRT), experimental units are randomly allocated on a single common start date to the interventions to be compared. Often, the SWD is more feasible than the CRT, both for practical and ethical reasons, but takes longer to complete.The SWD permits both within- and between- unit comparisons,while the CRT only allows between-unit comparisons. Thus, confounding bias with respect totime-invariant factors tends to be lower in an SWD than a CRT, but the SWD cannot as readily control for confounding by time-varying factors. SWDs have generally morestatisticalpowerthanCRTs, especially as the intraunit correlation and the number of participants within unit increases. Software for both designs are available, although for a more limited set of SWD scenarios.


Munger K.L.,Harvard University
American Journal of Epidemiology | Year: 2013

To determine whether serum levels of 25-hydroxyvitamin D (25(OH)D) in young adults are associated with risk of type 1 diabetes mellitus (T1D), we conducted a prospective, nested case-control study among US active-duty military personnel with serum in the US Department of Defense Serum Repository, identifying 310 T1D cases diagnosed between 1997 and 2009 with at least 2 serum samples collected before disease onset and 613 controls matched to cases on age, sex, race/ethnicity, branch of military service, and dates of serum collection. Conditional logistic regression was used to estimate rate ratios and 95% confidence intervals. Among non-Hispanic whites, those with average 25(OH)D levels of ≥100 nmol/L had a 44% lower risk of developing T1D than those with average 25(OH)D levels <75 nmol/L (rate ratio = 0.56, 95% confidence interval: 0.35, 0.90, P for trend = 0.03) over an average follow-up of 5.4 years. In quintile analyses, T1D risk was highest among individuals whose 25(OH)D levels were in the lowest 20% of those measured. There was no association between 25(OH)D levels and risk of T1D among non-Hispanic blacks or Hispanics. Low 25(OH)D levels may predispose healthy, young, non-Hispanic white adults to the development of T1D. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.


Ozcan U.,Harvard University
Cell | Year: 2013

Mitochondria are central regulators of cellular metabolism but how their function in a subset of cells affects whole-body energy balance is less understood. Two studies in this issue of Cell identify how diet-dependent modulation of mitochondrial fusion in specific neuronal circuits impact the metabolic status of an animal. © 2013 Elsevier Inc.


Blumberg R.,Harvard University | Powrie F.,University of Oxford
Science Translational Medicine | Year: 2012

Alterations in the composition of the commensal microbiota have been observed in many complex diseases. Understanding the basis for these changes, how they relate to disease risk or activity, and the mechanisms by which the symbiotic state of colonization resistance and host homeostasis is restored is critical for future therapies aimed at manipulating the microbiota.


Braunwald E.,Brigham and Womens Hospital | Braunwald E.,Harvard University
European Heart Journal | Year: 2012

Modern cardiology was born at the turn of the nineteenth to twentieth centuries with three great discoveries: the X ray, the sphygmomanometer, and the electrocardiograph. This was followed by cardiac catheterization, which led to coronary angiography and to percutaneous coronary intervention. The coronary care units and early reperfusion reduced the early mortality owing to acute myocardial infarction, and the discovery of coronary risk factors led to the development of Preventive Cardiology. Other major advances include several cardiac imaging techniques, the birth and development of cardiac surgery, and the control of cardiac arrhythmias. The treatment of heart failure, although greatly improved, remains a challenge. Current cardiology practice is evidence-based and global in scope. Research and practice are increasingly conducted in cardiovascular centres and institutes. It is likely that in the future, a greater emphasis will be placed on prevention, which will be enhanced by genetic information. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012.


Trained fertility specialists possess a unique clinical perspective and an extensive medical and technological armamentarium to overcome reproductive dysfunction: it is their privilege and ethical duty to lead the field of reproductive surgery. However, modern reproductive surgery can no longer exist outside of the realm of advanced laparoscopy. This has been a major hurdle to the thriving of surgery within our subspecialty, owing to the time and effort required to achieve and maintain proficiency in the antiergonomic environment of conventional laparoscopy. Computer-assisted surgery minimizes aptitudinal restrictions to the adoption of advanced laparoscopy. As such, it promotes strategy over technique and may hold the key to the continued success of high-specialty reproductive surgery. © 2014 American Society for Reproductive Medicine.


Goldhaber S.Z.,Harvard University
Journal of the American College of Cardiology | Year: 2010

Risk factors for venous thromboembolism (VTE) are often modifiable and overlap with risk factors for coronary artery disease. Encouraging our patients to adopt a heart-healthy lifestyle by abstaining from cigarettes, maintaining lean weight, limiting red meat intake, and controlling hypertension might lower the risk of pulmonary embolism and deep vein thrombosis (DVT), although a cause-effect relationship has not been firmly established. For hospitalized patients, guidelines have provided evidence-based strategies to identify patients at risk, such as elderly persons and those with cancer, congestive heart failure, or chronic obstructive pulmonary disease or undergoing major surgery. Most should receive pharmacological prophylaxis, which will minimize the risk of VTE. Because approximately 3 of every 4 pulmonary embolism and DVT events occur outside the hospital setting, patients should also be assessed for persistent high-risk of VTE at the time of hospital discharge. © 2010 American College of Cardiology Foundation.


Expression of the pneumococcal type 1 pilus is bistable and positively regulated by the transcription factor RlrA. RlrA is also known to positively control its own expression. Here we present evidence that bistable expression of the type 1 pilus is mediated by the positive-feedback loop controlling rlrA expression.


Klemperer W.,Harvard University
Annual Review of Physical Chemistry | Year: 2011

The discovery of polar polyatomic molecules in higher-density regions of the interstellar medium by means of their rotational emission detected by radioastronomy has changed our conception of the universe from essentially atomic to highly molecular. We discuss models for molecule formation, emphasizing the general lack of thermodynamic equilibrium. Detailed chemical kinetics is needed to understand molecule formation as well as destruction. Ion molecule reactions appear to be an important class for the generally low temperatures of the interstellar medium. The need for the intrinsically high-quality factor of rotational transitions to definitively pin down molecular emitters has been well established by radioastronomy. The observation of abundant molecular ions both positive and, as recently observed, negative provides benchmarks for chemical kinetic schemes. Of considerable importance in guiding our understanding of astronomical chemistry is the fact that the larger molecules (with more than five atoms) are all organic. © 2011 by Annual Reviews. All rights reserved.


Recent cancellations of nongroup health insurance plans generated much policy debate and raised concerns that the Affordable Care Act (ACA) may increase the number of uninsured Americans in the short term. This article provides evidence on the stability of nongroup coverage using US census data for the period 2008-11, before ACA provisions took effect. The principal findings are threefold. First, this market was characterized by high turnover: Only 42 percent of people with nongroup coverage at the outset of the study period retained that coverage after twelve months. Second, 80 percent of people experiencing coverage changes acquired other insurance within a year, most commonly from an employer. Third, turnover varied across groups, with stable coverage more common for whites and self-employed people than for other groups. Turnover was particularly high among adults ages 19-35, with only 21 percent of young adults retaining continuous nongroup coverage for two years. Given estimates from 2012 that 10.8 million people were covered in this market, these results suggest that 6.2 million people leave nongroup coverage annually. This suggests that the nongroup market was characterized by frequent disruptions in coverage before the ACA and that the effects of the recent cancellations are not necessarily out of the norm. These results can serve as a useful pre-ACA baseline with which to evaluate the law's long-term impact on the stability of nongroup coverage. © 2014 Project HOPE.


Savir Y.,Harvard University | Tlusty T.,Institute for Advanced Study
Cell | Year: 2013

The ribosome is a complex molecular machine that, in order to synthesize proteins, has to decode mRNAs by pairing their codons with matching tRNAs. Decoding is a major determinant of fitness and requires accurate and fast selection of correct tRNAs among many similar competitors. However, it is unclear whether the modern ribosome, and in particular its large conformational changes during decoding, are the outcome of adaptation to its task as a decoder or the result of other constraints. Here, we derive the energy landscape that provides optimal discrimination between competing substrates and thereby optimal tRNA decoding. We show that the measured landscape of the prokaryotic ribosome is sculpted in this way. This model suggests that conformational changes of the ribosome and tRNA during decoding are means to obtain an optimal decoder. Our analysis puts forward a generic mechanism that may be utilized broadly by molecular recognition systems. © 2013 Elsevier Inc.


Volpe J.J.,Harvard University
Annals of Neurology | Year: 2012

This Point of View article addresses neonatal encephalopathy (NE) presumably caused by hypoxia-ischemia and the terminology currently in wide use for this disorder. The nonspecific term NE is commonly utilized for those infants with the clinical and imaging characteristics of neonatal hypoxic-ischemic encephalopathy (HIE). Multiple magnetic resonance imaging studies of term infants with the clinical setting of presumed hypoxia-ischemia near the time of delivery have delineated a topography of lesions highly correlated with that defined by human neuropathology and by animal models, including primate models, of hypoxia-ischemia. These imaging findings, coupled with clinical features consistent with perinatal hypoxic-ischemic insult(s), warrant the specific designation of neonatal HIE. Copyright © 2012 American Neurological Association.


Wintermute E.H.,Harvard University | Silver P.A.,Wyss Institute for Biologically Inspired Engineering
Genes and Development | Year: 2010

Isolated, clonal populations of cells are rarely found in nature. The emergent properties of microbial consortia present a challenge for the systems approach to biology, as chances for competition, communication, or collaboration multiply with the number of interacting agents. This review focuses on recent work on intercourse within bio-films, among quorum-sensing populations, and between cross-feeding metabolic cooperators. New tools from synthetic biology allow microbial interactions to be designed and tightly controlled, creating valuablemodel systems. We address both natural and synthetic partnerships, with an emphasis on how system behaviors derive from the properties of their components. Essential features of microbial biology arose in the context of a very mixed culture and cannot be understood without unscrambling it. © 2010 by Cold Spring Harbor Laboratory Press.


Bhattacharyya N.,Harvard University
Laryngoscope | Year: 2014

Objectives/Hypothesis: Determine the prevalence of voice problems and types of voice disorders among adults in the United States. Study Design: Cross-sectional analysis of a national health survey. Methods: The 2012 National Health Interview Survey was analyzed, identifying adult cases reporting a voice problem in the preceding 12 months. In addition to demographic data, specific data regarding visits to healthcare professionals for voice problems, diagnoses given, and severity of the voice problem were analyzed. The relationship between voice problems and lost workdays was investigated. Results: An estimated 17.9 ± 0.5 million adults (mean age, 49.1 years; 62.9% ± 1.2% female) reported a voice problem (7.6% ± 0.2%). Overall, 10.0% ± 0.1% saw a healthcare professional for their voice problem, and 40.3% ± 1.8% were given a diagnosis. Females were more likely than males to report a voice problem (9.3% ± 0.3% vs. 5.9% ± 0.3%, P<.001). Overall, 22% and 11% reported their voice problem to be a moderate or a big/very big problem, respectively. Infectious laryngitis was the most common diagnosis mentioned (685,000 ± 86,000 cases, 17.8% ± 2.0%). Gastroesophageal reflux disease was mentioned in 308,000 ± 54,000 cases (8.0% ± 1.4%). The mean number of days affected with the voice problem in the past year was 56.2 ± 2.6 days. Respondents with a voice problem reported 7.4 ± 0.9 lost workdays in the past year versus 3.4 ± 0.1 lost workdays for those without (contrast, +4.0 lost workdays; P<.001). Conclusions: Voice problems affect one in 13 adults annually. A relative minority seek healthcare for their voice problem, even though the self-reported subjective impact of the voice problem is significant. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.


Evins A.E.,Harvard University
The Journal of clinical psychiatry | Year: 2013

As more US states and other countries consider legalizing marijuana, clinicians need to know the possible effects of this drug. Research has shown a connection between marijuana use and an increased risk for schizophrenia in young people who are vulnerable to developing psychosis. An international panel of experts addresses topics such as risk factors for schizophrenia, the potency and effects of cannabis use on adolescents, the effects of concurrent drug use with cannabis on schizophrenia risk, and current attitudes toward marijuana. © Copyright 2013 Physicians Postgraduate Press, Inc.


The pathophysiology of stroke is complex. Adaptive and maladaptive signalling occurs between multiple cell types in the brain. There is crosstalk between central and systemic responses. And there are overlapping pathways during initial injury and subsequent repair. These numerous feed-forward and feed-back interactions have made it difficult to translate experimental discoveries into clinical applications. An emerging hypothesis in biomedical research now suggests that contrary to a traditional model, translation may not be efficiently obtained without a rigorous understanding of mechanisms. Hence, to optimize diagnostics and therapeutics for stroke patients, it is necessary to identify and define causal mechanisms. Mirroring the multi-compartment interactions in stroke pathophysiology, bench-to-bedside, and bedside-back-to-bench advances in stroke may be best achieved with inter-disciplinary collaborations between basic research, neuroimaging, and broadly based clinical science. Causation can then be two-fold, ie, dissecting mechanisms and targets, as well as developing future scientists who can blur the boundaries between basic, translational, and clinical research. In systems theory, a critical goal is to distinguish causation from correlation. In stroke research, causation may perhaps be found through a collaborative search for mechanisms. © 2013 American Heart Association, Inc.


Samocha K.E.,Harvard University
Nature Genetics | Year: 2014

Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases.


Bloom D.E.,Harvard University
Vaccine | Year: 2015

Current evaluation models for the value of vaccines typically account for a small subset of the full social and economic benefits of vaccination. Health investments yield positive economic benefits via several channels at the household, community, and national levels. Underestimating, or worse, not considering these benefits can lead to ill-founded recommendations regarding the introduction of vaccines into immunization programs. The clear and strong links between health and wealth suggest the need to redesign valuation frameworks for vaccination so that the full costs may be properly weighed against the full benefits of vaccines. © 2015 Elsevier Ltd.


Fischer S.E.J.,Harvard University
International Journal of Biochemistry and Cell Biology | Year: 2010

Small RNA pathways, including the RNA interference (RNAi) pathway and the microRNA (miRNA) pathway, regulate gene expression, defend against transposable elements and viruses, and, in some organisms, guide genome rearrangements. The nematode Caenorhabditis elegans (. C. elegans) has been at the forefront of small RNA research; not only were the first miRNAs and their function as regulators of gene expression discovered in C. elegans, but also double-stranded RNA-induced gene silencing by RNAi was discovered in this model organism. Since then, genetic and RNAi-mediated screens, candidate gene approaches, and biochemical studies have uncovered numerous factors in the small RNA pathways and painted a rich palette of interacting pathways. Here we review the different small RNAs that have been discovered in C. elegans and discuss our understanding of their biogenesis pathways and mechanisms of action. © 2010 Elsevier Ltd.


Baffy G.,Harvard University
American Journal of Gastroenterology | Year: 2012

Hepatocellular carcinoma (HCC), a disease with poor survival rates unless recognized and treated early, ranks as the fifth most common cancer worldwide and has a rising incidence in the United States. Recent data indicate that the growing epidemic of type 2 diabetes mellitus may contribute to this alarming trend. In this issue, Lai et al. utilize a large Taiwanese insurance claims database to demonstrate that diabetes is associated with an increased risk of HCC. Moreover, this risk escalates if diabetes coincides with chronic hepatitis C and cirrhosis. Lai et al. also show that treatment with metformin or thiazolidinediones may reduce the risk of HCC. The findings may prompt risk stratification for HCC surveillance and improved disease control in diabetes as measures of cancer prevention. © 2012 by the american College of Gastroenterology.


Patti M.-E.,Harvard University
Cellular and Molecular Life Sciences | Year: 2013

We are in the midst of unparalleled epidemics of obesity and type 2 diabetes - complex phenotypes originating at the intersection of genetic and environmental risk. As detailed in other chapters, evidence indicates that non-genetic, or environmental, risk may initiate during prenatal and early postnatal life [1]. Striking examples in humans include the association of low birth weight (LBW) and/or accelerated early growth with increased risk of insulin resistance, obesity, type 2 diabetes (T2DM), and cardiovascular disease (CVD), and the close relationship between maternal obesity or diabetes with childhood obesity. In this chapter, we will focus on the intriguing emerging data from both human and animal models that indicate that intrauterine and childhood exposures can also influence risk for diabetes and cardiovascular disease in subsequent generations. Understanding the mechanisms responsible for these effects is critical in order to develop effective metabolic and nutritional interventions to interrupt such vicious intergenerational cycles potentiating risk for metabolic disorders. © 2013 Springer Basel.


Barth W.H.,Harvard University
Obstetrics and Gynecology | Year: 2015

Persistent occiput posterior (OP) is associated with increased rates of maternal and newborn morbidity. Its diagnosis by physical examination is challenging but is improved with bedside ultrasonography. Occiput posterior discovered in the active phase or early second stage of labor usually resolves spontaneously. When it does not, prophylactic manual rotation may decrease persistent OP and its associated complications. When delivery is indicated for arrest of descent in the setting of persistent OP, a pragmatic approach is suggested. Suspected fetal macrosomia, a biparietal diameter above the pelvic inlet or a maternal pelvis with android features should prompt cesarean delivery. Nonrotational operative vaginal delivery is appropriate when the maternal pelvis has a narrow anterior segment but ample room posteriorly, like with anthropoid features. When all other conditions are met and the fetal head arrests in an OP position in a patient with gynecoid pelvic features and ample room anteriorly, options include cesarean delivery, nonrotational operative vaginal delivery, and rotational procedures, either manual or with the use of rotational forceps. Recent literature suggests that maternal and fetal outcomes with rotational forceps are better than those reported in older series. Although not without significant challenges, a role remains for teaching and practicing selected rotational forceps operations in contemporary obstetrics. © 2015 by The American College of Obstetricians and Gynecologists.


Pauls D.L.,Harvard University
Dialogues in Clinical Neuroscience | Year: 2010

Obsessive-compulsive disorder (OCD) is a serious psychiatric disorder that affects approximately 2% of the populations of children and adults. Family aggregation studies have demonstrated that OCD is familial, and results from twin studies demonstrate that the familiality is due in part to genetic factors. Only three genome-wide linkage studies have been completed to date, with suggestive but not definitive results. In addition, over 80 candidate gene studies have been published. Most of these studies have focused on genes in the serotonergic and dopaminergic pathways. Unfortunately, none have achieved genome-wide significance, and, with the exception of the glutamate transporter gene, none have been replicated. Future research will require the collaboration of multidisciplinary teams of investigators to (i) achieve sufficiently large samples of individuals with OCD; (ii) apply the state-of-the-art laboratory techniques; and (iii) perform the bioinformatic analyses essential to the identification of risk loci. © 2010, LLS SAS. All rights reserved.


Zhu C.,Harvard University
Current topics in microbiology and immunology | Year: 2011

T cell immunoglobulin mucin-(TIM)-3 was first identified as a molecule specifically expressed on IFN-γ-secreting CD4(+) T helper 1 (Th1) and CD8(+) T cytotoxic (Tc1) cells in both mice and humans. TIM-3 acts as a negative regulator of Th1/Tc1 cell function by triggering cell death upon interaction with its ligand, galectin-9. This negative regulatory function of TIM-3 has now been expanded to include its involvement in establishing and/or maintaining a state of T cell dysfunction or "exhaustion" observed in chronic viral diseases. In addition, it is now appreciated that TIM-3 has other ligands and is expressed on other cell types, where it may function differently. Given that an increasing body of data support an important role for TIM-3 in both autoimmune and chronic inflammatory diseases in humans, deciphering the function of TIM-3 on different cell types during different immune conditions and how these can be regulated will be critical for harnessing the therapeutic potential of TIM-3 for the treatment of disease.


Lauder G.V.,Harvard University
Annual Review of Marine Science | Year: 2015

Research on fish locomotion has expanded greatly in recent years as new approaches have been brought to bear on a classical field of study. Detailed analyses of patterns of body and fin motion and the effects of these movements on water flow patterns have helped scientists understand the causes and effects of hydrodynamic patterns produced by swimming fish. Recent developments include the study of the center-of-mass motion of swimming fish and the use of volumetric imaging systems that allow three-dimensional instantaneous snapshots of wake flow patterns. The large numbers of swimming fish in the oceans and the vorticity present in fin and body wakes support the hypothesis that fish contribute significantly to the mixing of ocean waters. New developments in fish robotics have enhanced understanding of the physical principles underlying aquatic propulsion and allowed intriguing biological features, such as the structure of shark skin, to be studied in detail. Copyright © 2015 by Annual Reviews. All rights reserved.


Li Y.,Harvard University
Nature Photonics | Year: 2015

Metamaterials with a refractive index of zero exhibit physical properties such as infinite phase velocity and wavelength. However, there is no way to implement these materials on a photonic chip, restricting the investigation and application of zero-index phenomena to simple shapes and small scales. We designed and fabricated an on-chip integrated metamaterial with a refractive index of zero in the optical regime. Light refracts perpendicular to the facets of a prism made of this metamaterial, directly demonstrating that the index of refraction is zero. The metamaterial consists of low-aspect-ratio silicon pillar arrays embedded in a polymer matrix and clad by gold films. This structure can be fabricated using standard planar processes over a large area in arbitrary shapes and can efficiently couple to photonic integrated circuits and other optical elements. This novel on-chip metamaterial platform opens the door to exploring the physics of zero index and its applications in integrated optics. © 2015 Nature Publishing Group


Haider B.A.,Harvard University
BMJ (Clinical research ed.) | Year: 2013

To summarise evidence on the associations of maternal anaemia and prenatal iron use with maternal haematological and adverse pregnancy outcomes; and to evaluate potential exposure-response relations of dose of iron, duration of use, and haemoglobin concentration in prenatal period with pregnancy outcomes. Systematic review and meta-analysis Searches of PubMed and Embase for studies published up to May 2012 and references of review articles. Randomised trials of prenatal iron use and prospective cohort studies of prenatal anaemia; cross sectional and case-control studies were excluded. 48 randomised trials (17 793 women) and 44 cohort studies (1 851 682 women) were included. Iron use increased maternal mean haemoglobin concentration by 4.59 (95% confidence interval 3.72 to 5.46) g/L compared with controls and significantly reduced the risk of anaemia (relative risk 0.50, 0.42 to 0.59), iron deficiency (0.59, 0.46 to 0.79), iron deficiency anaemia (0.40, 0.26 to 0.60), and low birth weight (0.81, 0.71 to 0.93). The effect of iron on preterm birth was not significant (relative risk 0.84, 0.68 to 1.03). Analysis of cohort studies showed a significantly higher risk of low birth weight (adjusted odds ratio 1.29, 1.09 to 1.53) and preterm birth (1.21, 1.13 to 1.30) with anaemia in the first or second trimester. Exposure-response analysis indicated that for every 10 mg increase in iron dose/day, up to 66 mg/day, the relative risk of maternal anaemia was 0.88 (0.84 to 0.92) (P for linear trend<0.001). Birth weight increased by 15.1 (6.0 to 24.2) g (P for linear trend=0.005) and risk of low birth weight decreased by 3% (relative risk 0.97, 0.95 to 0.98) for every 10 mg increase in dose/day (P for linear trend<0.001). Duration of use was not significantly associated with the outcomes after adjustment for dose. Furthermore, for each 1 g/L increase in mean haemoglobin, birth weight increased by 14.0 (6.8 to 21.8) g (P for linear trend=0.002); however, mean haemoglobin was not associated with the risk of low birth weight and preterm birth. No evidence of a significant effect on duration of gestation, small for gestational age births, and birth length was noted. Daily prenatal use of iron substantially improved birth weight in a linear dose-response fashion, probably leading to a reduction in risk of low birth weight. An improvement in prenatal mean haemoglobin concentration linearly increased birth weight.


Selkoe D.J.,Harvard University
Cold Spring Harbor Perspectives in Biology | Year: 2011

Over the last three decades, advances in biochemical pathology and human genetics have illuminated one of the most enigmatic subjects in biomedicine-neurodegeneration. Eponymic diseases of the nervous system such as Alzheimer's, Parkinson's, and Huntington's diseases that were long characterized by mechanistic ignorance have yielded striking progress in our understanding of their molecular underpinnings. A central theme in these and related disorders is the concept that certain normally soluble neuronal proteins can misfold and aggregate into oligomers and amyloid fibrilswhich can confer profound cytotoxicity. Perhaps the foremost example, both in terms of its societal impact and how far knowledge has moved toward the clinic, is that of Alzheimer's disease (AD). Here, we will review the classical protein lesions of the disorder that have provided a road map to etiology and pathogenesis. We will discuss how elucidating the genotype-to-phenotype relationships of familial forms of Alzheimer's disease has highlighted the importance of the misfolding and altered proteostasis of two otherwise soluble proteins, amyloid β-protein and tau, suggesting mechanism-based therapeutic targets that have led to clinical trials. © 2011 Cold Spring Harbor Laboratory Press.


Regehr W.G.,Harvard University
Cold Spring Harbor perspectives in biology | Year: 2012

Different types of synapses are specialized to interpret spike trains in their own way by virtue of the complement of short-term synaptic plasticity mechanisms they possess. Numerous types of short-term, use-dependent synaptic plasticity regulate neurotransmitter release. Short-term depression is prominent after a single conditioning stimulus and recovers in seconds. Sustained presynaptic activation can result in more profound depression that recovers more slowly. An enhancement of release known as facilitation is prominent after single conditioning stimuli and lasts for hundreds of milliseconds. Finally, tetanic activation can enhance synaptic strength for tens of seconds to minutes through processes known as augmentation and posttetantic potentiation. Progress in clarifying the properties, mechanisms, and functional roles of these forms of short-term plasticity is reviewed here.


Ishizawa Y.,Harvard University
Anesthesia and Analgesia | Year: 2011

General anesthetics are administered to approximately 50 million patients each year in the United States. Anesthetic vapors and gases are also widely used in dentists' offices, veterinary clinics, and laboratories for animal research. All the volatile anesthetics that are currently used are halogenated compounds destructive to the ozone layer. These halogenated anesthetics could have potential significant impact on global warming. The widely used anesthetic gas nitrous oxide is a known greenhouse gas as well as an important ozone-depleting gas. These anesthetic gases and vapors are primarily eliminated through exhalation without being metabolized in the body, and most anesthesia systems transfer these gases as waste directly and unchanged into the atmosphere. Little consideration has been given to the ecotoxicological properties of gaseous general anesthetics. Our estimation using the most recent consumption data indicates that the anesthetic use of nitrous oxide contributes 3.0% of the total emissions in the United States. Studies suggest that the influence of halogenated anesthetics on global warming will be of increasing relative importance given the decreasing level of chlorofluorocarbons globally. Despite these nonnegligible pollutant effects of the anesthetics, no data on the production or emission of these gases and vapors are publicly available. The primary goal of this article is to critically review the current data on the potential effects of general anesthetics on the global environment and to describe possible alternatives and new technologies that may prevent these gases from being discharged into the atmosphere. © 2010 International Anesthesia Research Society.


Shore S.A.,Harvard University
Journal of Applied Physiology | Year: 2010

Epidemiological data indicate that obesity is a risk factor for asthma, but the mechanistic basis for this relationship is not established. Here we review data from human subjects and animal models investigating the relationship between obesity and airway hyperresponsiveness, a characteristic feature of asthma. We discuss obesity as a state of chronic systemic inflammation resulting from, interactions between, adipocytes and adipose tissue macrophages that are recruited to obese adipose tissue. Finally, we focus on the possibility that aspects of this inflammation, particularly obesity-related changes in TNF-a, leptin, and adiponectin, may contribute to airway hyperresponsiveness in obesity. Determining how obesity promotes asthma may uncover novel therapeutic strategies that are effective in the obese asthmatic subject. Copyright © 2010 the American. Physiological Society.


Nathan D.M.,Harvard University
JAMA - Journal of the American Medical Association | Year: 2015

IMPORTANCE Chronic diseases have overtaken acute diseases, such as infections, as the major cause of premature mortality worldwide. Diabetes mellitus, a chronic degenerative metabolic disease, has reached epidemic proportions in the past 30 years, with worldwide prevalence approaching 400 million people. OBSERVATIONS AND ADVANCES The epidemic is largely secondary to an increasing sedentary lifestyle and highly prevalent overweight and obesity contributing to the development of type 2 diabetes. Clinical research efforts have developed and demonstrated effective strategies for prevention, and the annual incidence of diabetes in the United Statesmay be decreasing for the first time in 3 decades. The long-term complications of diabetes cause severe morbidity and mortality. Here too the means of reducing the burden of microvascular and cardiovascular disease have been proved. CONCLUSIONS AND RELEVANCE Improved glycemic control and better management of other identified risk factors for the complications of diabetes and more effective treatment of cardiovascular disease and microvascular complications have resulted in a more optimistic outlook for people with diabetes. This review focuses on recent advances in diagnosis and management and the remaining challenges in the prevention and treatment of diabetes mellitus. © 2015 American Medical Association. All rights reserved.


Lewton K.L.,Harvard University
Evolutionary Biology | Year: 2012

The ilium and ischiopubic bones of the pelvis arise from different regulatory pathways, and as a result, they may be modular in their organization such that features on one bone may be morphologically integrated with each other, but not with features on the other pelvic bone. Modularity at this gross level of organization can act to increase the ability of these structures to respond to selection pressures (i.e., their evolvability). Furthermore, recent work has suggested that the evolution of the human pelvis was facilitated by low levels of integration and high levels of evolvability relative to other African apes. However, the extent of morphological integration and modularity of the bones of the pelvic girdle is not well understood, especially across the entire order of primates. Therefore, the hypothesis that the ilium and ischiopubis constitute separate modules was tested using three-dimensional landmark data that were collected from 752 pelves from 35 primate species. In addition, the hypothesis that the human pelvis demonstrates greatest evolvability was tested by comparing it to all other primates. The results demonstrate that regardless of phylogeny and locomotor function, the primate pelvis as a whole is characterized by low levels of overall integration and high levels of evolvability. In addition, the results support the developmental hypothesis of separate ilium and ischiopubis modular units. Finally, all primates, including humans, apparently share a common pattern of integration, modularity, and evolvability in the pelvis. © 2011 Springer Science+Business Media, LLC.


Rando O.J.,University of Massachusetts Medical School | Winston F.,Harvard University
Genetics | Year: 2012

Understanding the mechanisms by which chromatin structure controls eukaryotic transcription has been an intense area of investigation for the past 25 years. Many of the key discoveries that created the foundation for this field came from studies of Saccharomyces cerevisiae, including the discovery of the role of chromatin in transcriptional silencing, as well as the discovery of chromatin-remodeling factors and histone modification activities. Since that time, studies in yeast have continued to contribute in leading ways. This review article summarizes the large body of yeast studies in this field. © 2012 by the Genetics Society of America.


Medvedev M.V.,Harvard University
Physical Review Letters | Year: 2014

The nature of dark matter is unknown. A number of dark matter candidates are quantum flavor-mixed particles but this property has never been accounted for in cosmology. Here we explore this possibility from the first principles via extensive N-body cosmological simulations and demonstrate that the two-component dark matter model agrees with observational data at all scales. Substantial reduction of substructure and flattening of density profiles in the centers of dark matter halos found in simulations can simultaneously resolve several outstanding puzzles of modern cosmology. The model shares the "why now?" fine-tuning caveat pertinent to all self-interacting models. Predictions for direct and indirect detection dark matter experiments are made. © 2014 American Physical Society.


Amir A.,Harvard University
Physical Review Letters | Year: 2014

Various bacteria such as the canonical gram negative Escherichia coli or the well-studied gram positive Bacillus subtilis divide symmetrically after they approximately double their volume. Their size at division is not constant, but is typically distributed over a narrow range. Here, we propose an analytically tractable model for cell size control, and calculate the cell size and interdivision time distributions, as well as the correlations between these variables. We suggest ways of extracting the model parameters from experimental data, and show that existing data for E. coli supports partial size control, and a particular explanation: a cell attempts to add a constant volume from the time of initiation of DNA replication to the next initiation event. This hypothesis accounts for the experimentally observed correlations between mother and daughter cells as well as the exponential dependence of size on growth rate. © 2014 American Physical Society.


Chen I.A.,Harvard University
Cold Spring Harbor perspectives in biology | Year: 2010

Self-assembled vesicles are essential components of primitive cells. We review the importance of vesicles during the origins of life, fundamental thermodynamics and kinetics of self-assembly, and experimental models of simple vesicles, focusing on prebiotically plausible fatty acids and their derivatives. We review recent work on interactions of simple vesicles with RNA and other studies of the transition from vesicles to protocells. Finally we discuss current challenges in understanding the biophysics of protocells, as well as conceptual questions in information transmission and self-replication.


Lopez D.,Harvard University
Cold Spring Harbor perspectives in biology | Year: 2010

The ability to form biofilms is a universal attribute of bacteria. Biofilms are multicellular communities held together by a self-produced extracellular matrix. The mechanisms that different bacteria employ to form biofilms vary, frequently depending on environmental conditions and specific strain attributes. In this review, we emphasize four well-studied model systems to give an overview of how several organisms form biofilms: Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus. Using these bacteria as examples, we discuss the key features of biofilms as well as mechanisms by which extracellular signals trigger biofilm formation.


Burton B.,Harvard University
Cold Spring Harbor perspectives in biology | Year: 2010

DNA pumps play important roles in bacteria during cell division and during the transfer of genetic material by conjugation and transformation. The FtsK/SpoIIIE proteins carry out the translocation of double-stranded DNA to ensure complete chromosome segregation during cell division. In contrast, the complex molecular machines that mediate conjugation and genetic transformation drive the transport of single stranded DNA. The transformation machine also processes this internalized DNA and mediates its recombination with the resident chromosome during and after uptake, whereas the conjugation apparatus processes DNA before transfer. This article reviews these three types of DNA pumps, with attention to what is understood of their molecular mechanisms, their energetics and their cellular localizations.


Flensberg K.,Harvard University | Flensberg K.,Copenhagen University
Physical Review Letters | Year: 2011

We demonstrate that non-Abelian rotations within the degenerate ground-state manifold of a set of Majorana fermions can be realized by the addition or removal of single electrons, and propose an implementation using Coulomb blockaded quantum dots. The exchange of electrons generates rotations similar to braiding, though not in real space. Unlike braiding operations, rotations by a continuum of angles are possible, while still being partially robust against perturbations. The quantum dots can also be used for readout of the state of the Majorana system via a charge measurement. © 2011 American Physical Society.


McClatchey A.I.,Harvard University
Journal of Cell Science | Year: 2014

The cell cortex is a dynamic and heterogeneous structure that governs cell identity and behavior. The ERM proteins (ezrin, radixin and moesin) are major architects of the cell cortex, and they link plasma membrane phospholipids and proteins to the underlying cortical actin cytoskeleton. Recent studies in several model systems have uncovered surprisingly dynamic and complex molecular activities of the ERM proteins and have provided new mechanistic insight into how they build and maintain cortical domains. Among many well-established and essential functions of ERM proteins, this Cell Science at a Glance article and accompanying poster will focus on the role of ERMs in organizing the cell cortex during cell division and apical morphogenesis. These examples highlight an emerging appreciation that the ERM proteins both locally alter the mechanical properties of the cell cortex, and control the spatial distribution and activity of key membrane complexes, establishing the ERM proteins as a nexus for the physical and functional organization of the cell cortex and making it clear that they are much more than scaffolds. © 2014.


Strominger A.,Harvard University
Journal of High Energy Physics | Year: 2014

Abstract: Asymptotic symmetries at future null infinity (I+) of Minkowski space for electrodynamics with massless charged fields, as well as nonabelian gauge theories with gauge group G, are considered at the semiclassical level. The possibility of charge/color flux through I+ suggests the symmetry group is infinite-dimensional. It is conjectured that the symmetries include a G Kac-Moody symmetry whose generators are “large” gauge transformations which approach locally holomorphic functions on the conformal two-sphere at I+ and are invariant under null translations. The Kac-Moody currents are constructed from the gauge field at the future boundary of I+. The current Ward identities include Weinberg’s soft photon theorem and its colored extension. © 2014, The Author(s).


Strominger A.,Harvard University
Journal of High Energy Physics | Year: 2014

Abstract: BMS+ transformations act nontrivially on outgoing gravitational scattering data while preserving intrinsic structure at future null infinity (I+). BMS− transformations similarly act on ingoing data at past null infinity (I−). In this paper we apply — within a suitable finite neighborhood of the Minkowski vacuum — results of Christodoulou and Klainerman to link I+ to I− and thereby identify “diagonal” elements BMS0 of BMS+ × BMS−. We argue that BMS0 is a nontrivial infinite-dimensional symmetry of both classical gravitational scattering and the quantum gravity S-matrix. It implies the conservation of net accumulated energy flux at every angle on the conformal S2 at I. The associated Ward identity is shown to relate S-matrix elements with and without soft gravitons. Finally, BMS0 is recast as a U(1) Kac-Moody symmetry and an expression for the Kac-Moody current is given in terms of a certain soft graviton operator on the boundary of I. © 2014, The Author(s).


Murugaiyan G.,Harvard University | Saha B.,National Center for Cell Science
Trends in Molecular Medicine | Year: 2013

Inflammation has a central role in cancer progression. Metastatic tumors arise at sites of chronic inflammation, and tumors or tumor-infiltrating immune cells produce inflammatory mediators. By contrast, natural killer (NK) cells and cytotoxic T cells (CTLs) help eliminate premalignant lesions and limit the rate of tumor metastasis. Interleukin (IL)-27 is an IL-12 family cytokine chiefly produced by antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages, and alone or in combination with other cytokines, IL-27 boosts antitumor immunity by contributing to the development of NK cells and CTLs - a central immnunomodulatory effect - and by exerting potent antiangiogenic and antimetastatic activities, a local antitumor effect. In this review, we argue that by virtue of its rate-limiting functions in innate and adaptive immune responses, modulating IL-27 holds considerable promise for future cancer immunotherapy. © 2012 Elsevier Ltd.


Swingle B.,Harvard University
Physical Review Letters | Year: 2013

We compute the entanglement entropy of a wide class of models that may be characterized as describing matter coupled to gauge fields. Our principle result is an entanglement sum rule that states that the entropy of the full system is the sum of the entropies of the two components. In the context of the models we consider, this result applies to the full entropy, but more generally it is a statement about the additivity of universal terms in the entropy. Our proof simultaneously extends and simplifies previous arguments, with extensions including new models at zero temperature as well as the ability to treat finite temperature crossovers. We emphasize that while the additivity is an exact statement, each term in the sum may still be difficult to compute. Our results apply to a wide variety of phases including Fermi liquids, spin liquids, and some non-Fermi liquid metals. For example, we prove that our model of an interacting Fermi liquid has exactly the log violation of the area law for entanglement entropy predicted by the Widom formula in agreement with earlier arguments. © 2013 American Physical Society.


Jedrychowski M.P.,Harvard University
Molecular & cellular proteomics : MCP | Year: 2011

Protein phosphorylation modulates a myriad of biological functions, and its regulation is vital for proper cellular activity. Mass spectrometry is the enabling tool for phosphopeptide analysis, where recent instrumentation advances in both speed and sensitivity in linear ion trap and orbitrap technologies may yield more comprehensive phosphoproteomic analyses in less time. Protein phosphorylation analysis by MS relies on structural information derived through controlled peptide fragmentation. Compared with traditional, ion-trap-based collision-induced dissociation (CID), a more recent type of fragmentation termed HCD (higher energy collisional dissociation) provides beam type CID tandem MS with detection of fragment ions at high resolution in the orbitrap mass analyzer. Here we compared HCD to traditional CID for large-scale phosphorylation analyses of murine brain under three separate experimental conditions. These included a same-precursor analysis where CID and HCD scans were performed back-to-back, separate analyses of a phosphotyrosine peptide immunoprecipitation experiment, and separate whole phosphoproteome analyses. HCD generally provided higher search engine scores with more peptides identified, thus out-performing CID for back-to-back experiments for most metrics tested. However, for phosphotyrosine IPs and in a full phosphoproteome study of mouse brain, the greater acquisition speed of CID-only analyses provided larger data sets. We reconciled our results with those in direct contradiction from Nagaraj N, D'Souza RCJ et al. (J. Proteome Res. 9:6786, 2010). We conclude, for large-scale phosphoproteomics, CID fragmentation with rapid detection in the ion trap still produced substantially richer data sets, but the back-to-back experiments demonstrated the promise of HCD and orbitrap detection for the future.


Kaelin Jr. W.G.,Harvard University | Kaelin Jr. W.G.,Howard Hughes Medical Institute | McKnight S.L.,University of Texas Southwestern Medical Center
Cell | Year: 2013

Chemical modifications of histones and DNA, such as histone methylation, histone acetylation, and DNA methylation, play critical roles in epigenetic gene regulation. Many of the enzymes that add or remove such chemical modifications are known, or might be suspected, to be sensitive to changes in intracellular metabolism. This knowledge provides a conceptual foundation for understanding how mutations in the metabolic enzymes SDH, FH, and IDH can result in cancer and, more broadly, for how alterations in metabolism and nutrition might contribute to disease. Here, we review literature pertinent to hypothetical connections between metabolic and epigenetic states in eukaryotic cells. © 2013 Elsevier Inc.


Lee J.T.,Howard Hughes Medical Institute | Lee J.T.,Harvard University | Bartolomei M.S.,University of Pennsylvania
Cell | Year: 2013

X chromosome inactivation and genomic imprinting are classic epigenetic processes that cause disease when not appropriately regulated in mammals. Whereas X chromosome inactivation evolved to solve the problem of gene dosage, the purpose of genomic imprinting remains controversial. Nevertheless, the two phenomena are united by allelic control of large gene clusters, such that only one copy of a gene is expressed in every cell. Allelic regulation poses significant challenges because it requires coordinated long-range control in cis and stable propagation over time. Long noncoding RNAs have emerged as a common theme, and their contributions to diseases of imprinting and the X chromosome have become apparent. Here, we review recent advances in basic biology, the connections to disease, and preview potential therapeutic strategies for future development. © 2013 Elsevier Inc.


Schier A.F.,Harvard University
Cell | Year: 2013

Animals are often in discrete behavioral states, but it is unclear how one specific state is generated and opposes alternative states. Flavell et al. now identify molecular and neural components in C. Elegans that are involved in the generation of dwelling and roaming states. © 2013 Elsevier Inc.


Wu H.,Harvard University
Cell | Year: 2013

Recent studies have revealed that multiple intracellular signaling proteins may assemble into structured, yet sometimes infinite, higher-order signaling machines for transmission of receptor activation information to cellular responses. These studies advance our understanding of cell signaling and implicate new molecular mechanisms in proximity-driven enzyme activation, threshold behavior, signal amplification, reduction of biological noise, and temporal and spatial control of signal transduction. © 2013 Elsevier Inc.


Basaria S.,Harvard University
Endocrinology and Metabolism Clinics of North America | Year: 2013

Aging in men is associated with a decrease in serum testosterone levels due to attrition in testicular Leydig cells and slowing of the hypothalamic GnRH pulse generator. The practicing endocrinologist is frequently consulted for consideration of testosterone therapy in older men with late-onset hypogonadism (LOH), a condition that many clinicians fail to distinguish from organic hypogonadism. Recent data using syndromic definition show that only 2% of 40-80-year-old men have LOH. Co-morbidities and obesity strongly contribute to LOH, suggesting that testosterone is a biomarker of health. Hence, prevention and treatment of these co-morbidities might attenuate age-related decline in androgen levels. © 2013 Elsevier Inc.


Razzaque M.S.,Harvard University
Kidney International | Year: 2011

Vitamin D is a multifunctional hormone that can affect many essential biological functions, ranging from the immune regulation to mineral ion metabolism. A close association between altered activity of vitamin D and vascular calcification has been reported in various human diseases, including in patients with atherosclerosis, osteoporosis, and chronic kidney disease (CKD). Vascular calcification is a progressive disorder and is a major determinant of morbidity and mortality of the affected patients. Experimental studies have shown that excessive vitamin D activities can induce vascular calcification, and such vascular pathology can be reversed by reducing vitamin D activities. The human relevance of these experimental studies is not clear, as vitamin D toxicity is relatively rare in the general population. Contrary to the relationship between vitamin D and vascular calcification, in experimental uremic models, low levels of vitamin D were shown to be associated with extensive vascular calcification, a phenomenon that is very similar to the vascular pathology seen in patients with CKD. The current treatment approach of providing vitamin D analogs to patients with CKD often poses a dilemma, as studies linked vitamin D treatment to subsequent vascular calcification. Recent genetic studies, however, have shown that vascular calcification can be prevented by reducing serum phosphate levels, even in the presence of extremely high serum 1,25-dihydroxyvitamin D and calcium levels. This article will briefly summarize the dual effects of vitamin D in vascular calcification and will provide evidence of vitamin D-dependent and-independent vascular calcification. © 2011 International Society of Nephrology.


Stone J.H.,Harvard University
Kidney International | Year: 2013

Alexander et al. give a detailed description of IgG4-related membranous glomerulonephritis (MGN). Their data delineate for the first time in IgG4-related disease (IgG4-RD) a second pattern of tissue injury occurring within the same organ. The paper highlights that MGN can occur alone or simultaneously with IgG4-related tubulointerstitial nephritis. Thus, it extends our understanding of IgG4-RD and illuminates potential pathways for new investigations into its pathophysiology. © 2012 International Society of Nephrology.


Kessler R.C.,Harvard University | Bromet E.J.,State University of New York at Stony Brook
Annual Review of Public Health | Year: 2013

Epidemiological data are reviewed on the prevalence, course, socio-demographic correlates, and societal costs of major depression throughout the world. Major depression is estimated in these surveys to be a commonly occurring disorder. Although estimates of lifetime prevalence and course vary substantially across countries for reasons that could involve both substantive and methodological processes, the cross-national data are clear in documenting meaningful lifetime prevalence with wide variation in age-of-onset and high risk of lifelong chronic-recurrent persistence. A number of sociodemographic correlates of major depression are found consistently across countries, and cross-national data also document associations with numerous adverse outcomes, including difficulties in role transitions (e.g., low education, high teen childbearing, marital disruption, unstable employment), reduced role functioning (e.g., low marital quality, low work performance, low earnings), elevated risk of onset, persistence and severity of a wide range of secondary disorders, and increased risk of early mortality due to physical disorders and suicide. © 2013 by Annual Reviews. All rights reserved.


BACKGROUND: Anatomical reconstruction techniques that can restore normal joint kinematics without increasing surgical complications could potentially improve clinical outcomes and help manage anterior cruciate ligament injuries more efficiently. HYPOTHESIS: Single-tunnel double-bundle anterior cruciate ligament reconstruction with anatomical placement of hamstring tendon graft can more closely restore normal knee anterior-posterior, medial-lateral, and internal-external kinematics than can conventional single-bundle anterior cruciate ligament reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: Kinematic responses after single-bundle anterior cruciate ligament reconstruction and single-tunnel double-bundle anterior cruciate ligament reconstruction with anatomical placement of hamstring tendon graft were compared with the intact knee in 9 fresh-frozen human cadaveric knee specimens using a robotic testing system. Kinematics of each knee were determined under an anterior tibial load (134 N), a simulated quadriceps load (400 N), and combined torques (10 N.m valgus and 5 N.m internal tibial torques) at 0 degrees , 15 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion. RESULTS: Anterior tibial translations were more closely restored to the intact knee level after single-tunnel double-bundle reconstruction with anatomical placement of hamstring tendon graft than with a single-bundle reconstruction under the 3 external loading conditions. Under simulated quadriceps load, the mean internal tibial rotations after both reconstructions were lower than that of the anterior cruciate ligament-intact knee with no significant differences between these 3 knee conditions at 0 degrees and 30 degrees of flexion (P > .05). The increased medial tibial shifts of the anterior cruciate ligament-deficient knees were restored to the intact level by both reconstruction techniques under the 3 external loading conditions. CONCLUSION: Single-tunnel double-bundle anterior cruciate ligament reconstruction with anatomical placement of hamstring tendon graft can better restore the anterior knee stability compared with a conventional single-bundle reconstruction. Both reconstruction techniques are efficient in restoring the normal medial-lateral stability but overcorrect the internal tibial rotations. CLINICAL RELEVANCE: Single-tunnel double-bundle anterior cruciate ligament reconstruction with anatomical placement of hamstring tendon graft could provide improved clinical outcomes over a conventional single-bundle reconstruction.


Ebert B.L.,Harvard University
Seminars in Oncology | Year: 2011

The 5q-syndrome is a subtype of myelodysplastic syndrome (MDS) with a defined clinical phenotype associated with heterozygous deletions of chromosome 5q. While no genes have been identified that undergo recurrent homozygous inactivation, functional studies have revealed individual genes that contribute to the clinical phenotype of MDS through haplo-insufficient gene expression. Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q-syndrome. The megakaryocytic and platelet phenotype of the 5q-syndrome has been attributed to heterozygous deletion of miR145 and miR146a. Murine models have implicated heterozygous loss of APC, EGR1, DIAPH1, and NPM1 in the pathophysiology of del(5q) MDS. These findings indicate that the phenotype of MDS patients with deletions of chromosome 5q is due to haplo-insufficiency of multiple genes. © 2011 Elsevier Inc. All rights reserved.


Wofsy S.C.,Harvard University
Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2011

The HIAPER Pole-to-Pole Observations (HIPPO) programme has completed three of five planned aircraft transects spanning the Pacific from 85° N to 67° S, with vertical profiles every approximately 2.2° of latitude. Measurements include greenhouse gases, long-lived tracers, reactive species, O2/N2 ratio, black carbon (BC), aerosols and CO 2 isotopes. Our goals are to address the problem of determining surface emissions, transport strength and patterns, and removal rates of atmospheric trace gases and aerosols at global scales and to provide strong tests of satellite data and global models. HIPPO data show dense pollution and BC at high altitudes over the Arctic, imprints of large N2O sources from tropical lands and convective storms, sources of pollution and biogenic CH4 in the Arctic, and summertime uptake of CO2 and sources for O2 at high southern latitudes. Global chemical signatures of atmospheric transport are imaged, showing remarkably sharp horizontal gradients at air mass boundaries, weak vertical gradients and inverted profiles (maxima aloft) in both hemispheres. These features challenge satellite algorithms, global models and inversion analyses to derive surface fluxes. HIPPO data can play a crucial role in identifying and resolving questions of global sources, sinks and transport of atmospheric gases and aerosols. © 2011 The Royal Society.


Hresko M.T.,Harvard University
New England Journal of Medicine | Year: 2013

A 12-year-old girl presents with her parents after a positive school screening for scoliosis. Physical examination reveals shoulder and torso asymmetry with trunk imbalance (i.e., shift from the midline). Neurologic and skin examinations are normal. How should the patient be evaluated and treated? Copyright © 2013 Massachusetts Medical Society.


Bohmer R.M.J.,Harvard University
Health Affairs | Year: 2013

In 2000 the English National Health Service (NHS) began a series of workforce redesign initiatives that increased the number of doctors and nurses serving patients, expanded existing staffroles and developed new ones, redistributed health care work, and invested in teamwork. The English workforce redesign experience offers important lessons for US policy makers. Redesigning the health care workforce is not a quick fix to control costs or improve the quality of care. A poorly planned redesign can even result in increased costs and decreased quality. Changes in skill mix and role definitions should be preceded by a detailed analysis and redesign of the work performed by health care professionals. New roles and responsibilities must be clearly defined in advance, and teamwork models that include factors common in successful redesigns such as leadership, shared objectives, and training should be promoted. The focus should be on retraining current staffinstead of hiring new workers. Finally, any workforce redesign must overcome opposition from professional bodies, individual practitioners, and regulators. England's experience suggests that progress is possible if workforce redesigns are planned carefully and implemented with skill. © 2013 Project HOPE - The People-to-People Health Foundation, Inc.


Morgan B.A.,Harvard University
Cold Spring Harbor Perspectives in Medicine | Year: 2014

The dermal papilla (DP) of the hair follicle is both a chemical and physical niche for epithelial progenitor cells that regenerate the cycling portion of the hair follicle and generate the hair shaft. Here, we review experiments that revealed the importance of the DP in regulating the characteristics of the hair shaft and frequency of hair follicle regeneration. More recent work showed that the size of this niche is dynamic and actively regulated and reduction in DP cell number per follicle is sufficient to cause hair thinning and loss. The formation of the DP during follicle neogenesis provides a context to contemplate the mechanisms that maintain DP size and the potential to exploit these processes for hair preservation or restoration. ©2014 Cold Spring Harbor Laboratory Press; all rights reserved.


Abe N.,Harvard University
Neuroscientist | Year: 2011

How do people tell a lie? One useful approach to addressing this question is to elucidate the neural substrates for deception. Recent conceptual and technical advances in functional neuroimaging have enabled exploration of the psychology of deception more precisely in terms of the specific neuroanatomical mechanisms involved. A growing body of evidence suggests that the prefrontal cortex plays a key role in deception, and some researchers have recently emphasized the importance of other brain regions, such as those responsible for emotion and reward. However, it is still unclear how these regions play a role in making effective decisions to tell a lie. To provide a framework for considering this issue, the present article reviews current accomplishments in the study of the neural basis of deception. First, evolutionary and developmental perspectives are provided to better understand how and when people can make use of deception. The ensuing section introduces several findings on pathological lying and its neural correlate. Next, recent findings in the cognitive neuroscience of deception based on functional neuroimaging and loss-of-function studies are summarized, and possible neural mechanisms underlying deception are proposed. Finally, the priority areas of future neuroscience research-human honesty and dishonesty-are discussed. © SAGE Publications 2011.


Leopold J.A.,Harvard University
Trends in Cardiovascular Medicine | Year: 2015

Vascular calcification is highly prevalent and, when present, is associated with major adverse cardiovascular events. Vascular smooth muscle cells play an integral role in mediating vessel calcification by undergoing differentiation to osteoblast-like cells and generating matrix vesicles that serve as a nidus for calcium-phosphate deposition in the vessel wall. Once believed to be a passive process, it is now recognized that vascular calcification is a complex and highly regulated process that involves activation of cellular signaling pathways, circulating inhibitors of calcification, genetic factors, and hormones. This review will examine several of the key mechanisms linking vascular smooth muscle cells to vessel calcification that may be targeted to reduce vessel wall mineralization and, thereby, reduce cardiovascular risk. © 2015 Elsevier Inc.


Daniel C.,Harvard University
Social Science and Medicine | Year: 2016

This article shows how an interaction between economic constraints and children's taste preferences shapes low-income families' food decisions. According to studies of eating behavior, children often refuse unfamiliar foods 8 to 15 times before accepting them. Using 80 interviews and 41 grocery-shopping observations with 73 primary caregivers in the Boston area in 2013-2015, I find that many low-income respondents minimize the risk of food waste by purchasing what their children like-often calorie-dense, nutrient-poor foods. High-income study participants, who have greater resources to withstand the cost of uneaten food, are more likely to repeatedly introduce foods that their children initially refuse. Several conditions moderate the relationship between children's taste aversion and respondents' risk aversion, including household-level food preferences, respondents' conceptions of adult authority, and children's experiences outside of the home. Low-income participants' risk aversion may affect children's taste acquisition and eating habits, with implications for socioeconomic disparities in diet quality. This article proposes that the cost of providing children a healthy diet may include the possible cost of foods that children waste as they acquire new tastes. © 2015 Elsevier Ltd.


Mitchell R.N.,Harvard University
Journal of Autoimmunity | Year: 2013

Allograft vasculopathy is an accelerated intimal hyperplastic lesion leading to progressive vascular stenosis; it represents the major long-term limitation to successful solid organ transplant. Although allograft vasculopathy is not formally an autoimmune disease, nor does it constitute a major cause of cardiovascular disease on a purely numerical basis, its pathogenesis provides an important window on the mechanisms by which immune injury can drive more common vascular pathologic entities. Thus, insights gleaned from vascularized solid organ transplants can shed new mechanistic (and therapeutic) light on: 1) the intimal vascular responses accompanying typical atherosclerosis and other inflammatory vessel diseases (e.g., scleroderma); 2) the pathogenesis of vascular stenosis versus aneurysm formation; 3) the sources of intimal smooth muscle cells in the healing of any vascular injury; and 4) the mechanisms by which smooth muscle cells are recruited into intimal lesions. Indeed, research on allograft vasculopathy has led to the understanding that interferon-γ plays a similar pathogenic role in a host of vascular stenosing lesions-and that Th2 cytokines can drive vascular remodeling and aneurysm formation. Moreover, circulating precursors (and not just medial smooth muscle cells) contribute to the intimal hyperplasia seen in atherosclerosis and in-stent restenosis. That non-vessel smooth muscle cells can be recruited to sites of vessel injury further suggests that chemokine and adhesion molecule interactions may be viable targets to limit vascular stenosis in a wide range of vascular lesions. This review will describe the pathogenesis of allograft vasculopathy, and will relate how understanding the underlying pathways informs our understanding of both human transplant-associated disease, as well as other human vascular pathologies. © 2013 Elsevier Ltd.


Abzhanov A.,Harvard University
Trends in Genetics | Year: 2013

In 1828, Karl Ernst von Baer formulated a series of empirically defined rules, which became widely known as the 'Law of Development' or 'von Baer's law of embryology'. This was one the most significant attempts to define the principles that connected morphological complexity and embryonic development. Understanding this relation is central to both evolutionary biology and developmental genetics. Von Baer's ideas have been both a source of inspiration to generations of biologists and a target of continuous criticism over many years. With advances in multiple fields, including paleontology, cladistics, phylogenetics, genomics, and cell and developmental biology, it is now possible to examine carefully the significance of von Baer's law and its predictions. In this review, I argue that, 185 years after von Baer's law was first formulated, its main concepts after proper refurbishing remain surprisingly relevant in revealing the fundamentals of the evolution-development connection, and suggest that their explanation should become the focus of renewed research. © 2013 Elsevier Ltd.


Bronte V.,University of Verona | Pittet M.J.,Harvard University
Immunity | Year: 2013

The spleen is the main filter for blood-borne pathogens and antigens, as well as a key organ for iron metabolism and erythrocyte homeostasis. Also, immune and hematopoietic functions have been recently unveiled for the mouse spleen, suggesting additional roles for this secondary lymphoid organ. Here we discuss the integration of the spleen in the regulation of immune responses locally and in the whole body and present the relevance of findings for our understanding of inflammatory and degenerative diseases and their treatments. We consider whether equivalent activities in humans are known, as well as initial therapeutic attempts to target the spleen for modulating innate and adaptive immunity. © 2013 Elsevier Inc.


Greenberg S.A.,Harvard University
Current Opinion in Rheumatology | Year: 2011

Purpose of review: Sporadic inclusion body myositis (sIBM) is a poorly understood immune and degenerative disease of skeletal muscle. Here, current opinion of the nature of this disease is summarized. Recent findings: Recent findings for sIBM include further characterization of muscle involvement through magnetic resonance imaging, the role of muscle as a host for immune cells, progress in the role of extranuclear TDP-43 in causing cellular injury, and the discovery of a new sIBM autoantibody. Summary: sIBM understanding continues to advance, with progress regarding the mechanism of this disease. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Background Body-mass index (BMI) and diabetes have increased worldwide, whereas global average blood pressure and cholesterol have decreased or remained unchanged in the past three decades. We quantified how much of the effects of BMI on coronary heart disease and stroke are mediated through blood pressure, cholesterol, and glucose, and how much is independent of these factors. Methods We pooled data from 97 prospective cohort studies that collectively enrolled 1·8 million participants between 1948 and 2005, and that included 57 161 coronary heart disease and 31 093 stroke events. For each cohort we excluded participants who were younger than 18 years, had a BMI of lower than 20 kg/m2, or who had a history of coronary heart disease or stroke. We estimated the hazard ratio (HR) of BMI on coronary heart disease and stroke with and without adjustment for all possible combinations of blood pressure, cholesterol, and glucose. We pooled HRs with a random-effects model and calculated the attenuation of excess risk after adjustment for mediators. Findings The HR for each 5 kg/m2 higher BMI was 1·27 (95% CI 1·23-1·31) for coronary heart disease and 1·18 (1·14-1·22) for stroke after adjustment for confounders. Additional adjustment for the three metabolic risk factors reduced the HRs to 1·15 (1·12-1·18) for coronary heart disease and 1·04 (1·01-1·08) for stroke, suggesting that 46% (95% CI 42-50) of the excess risk of BMI for coronary heart disease and 76% (65-91) for stroke is mediated by these factors. Blood pressure was the most important mediator, accounting for 31% (28-35) of the excess risk for coronary heart disease and 65% (56-75) for stroke. The percentage excess risks mediated by these three mediators did not differ significantly between Asian and western cohorts (North America, western Europe, Australia, and New Zealand). Both overweight (BMI ≥25 to <30 kg/m2) and obesity (BMI ≥30 kg/m2) were associated with a significantly increased risk of coronary heart disease and stroke, compared with normal weight (BMI ≥20 to <25 kg/m2), with 50% (44-58) of the excess risk of overweight and 44% (41-48) of the excess risk of obesity for coronary heart disease mediated by the selected three mediators. The percentages for stroke were 98% (69-155) for overweight and 69% (64-77) for obesity. Interpretation Interventions that reduce high blood pressure, cholesterol, and glucose might address about half of excess risk of coronary heart disease and three-quarters of excess risk of stroke associated with high BMI. Maintenance of optimum bodyweight is needed for the full benefits.


Stevens R.G.,University of Connecticut Health Center | Brainard G.C.,Thomas College | Blask D.E.,Tulane University | Lockley S.W.,Harvard University | Motta M.E.,Tufts Medical School
CA Cancer Journal for Clinicians | Year: 2014

Breast cancer is the leading cause of cancer death among women worldwide, and there is only a limited explanation of why. Risk is highest in the most industrialized countries but also is rising rapidly in the developing world. Known risk factors account for only a portion of the incidence in the high-risk populations, and there has been considerable speculation and many false leads on other possibly major determinants of risk, such as dietary fat. A hallmark of industrialization is the increasing use of electricity to light the night, both within the home and without. It has only recently become clear that this evolutionarily new and, thereby, unnatural exposure can disrupt human circadian rhythmicity, of which three salient features are melatonin production, sleep, and the circadian clock. A convergence of research in cells, rodents, and humans suggests that the health consequences of circadian disruption may be substantial. An innovative experimental model has shown that light at night markedly increases the growth of human breast cancer xenografts in rats. In humans, the theory that light exposure at night increases breast cancer risk leads to specific predictions that are being tested epidemiologically: evidence has accumulated on risk in shift workers, risk in blind women, and the impact of sleep duration on risk. If electric light at night does explain a portion of the breast cancer burden, then there are practical interventions that can be implemented, including more selective use of light and the adoption of recent advances in lighting technology and application. CA Cancer J Clin 2014;64:207-218. © 2013 American Cancer Society. © 2013 American Cancer Society, Inc.


Vanderweele T.J.,Harvard University
Epidemiology | Year: 2014

The overall effect of an exposure on an outcome, in the presence of a mediator with which the exposure may interact, can be decomposed into 4 components: (1) the effect of the exposure in the absence of the mediator, (2) the interactive effect when the mediator is left to what it would be in the absence of exposure, (3) a mediated interaction, and (4) a pure mediated effect. These 4 components, respectively, correspond to the portion of the effect that is due to neither mediation nor interaction, to just interaction (but not mediation), to both mediation and interaction, and to just mediation (but not interaction). This 4-way decomposition unites methods that attribute effects to interactions and methods that assess mediation. Certain combinations of these 4 components correspond to measures for mediation, whereas other combinations correspond to measures of interaction previously proposed in the literature. Prior decompositions in the literature are in essence special cases of this 4-way decomposition. The 4-way decomposition can be carried out using standard statistical models, and software is provided to estimate each of the 4 components. The 4-way decomposition provides maximum insight into how much of an effect is mediated, how much is due to interaction, how much is due to both mediation and interaction together, and how much is due to neither. Copyright © 2014 by Lippincott Williams & Wilkins.


Surgical management of tetralogy of Fallot (TOF) results in anatomic and functional abnormalities in the majority of patients. Although right ventricular volume load due to severe pulmonary regurgitation can be tolerated for many years, there is now evidence that the compensatory mechanisms of the right ventricular myocardium ultimately fail and that if the volume load is not eliminated or reduced by pulmonary valve replacement the dysfunction might be irreversible. Cardiovascular magnetic resonance (CMR) has evolved during the last 2 decades as the reference standard imaging modality to assess the anatomic and functional sequelae in patients with repaired TOF. This article reviews the pathophysiology of chronic right ventricular volume load after TOF repair and the risks and benefits of pulmonary valve replacement. The CMR techniques used to comprehensively evaluate the patient with repaired TOF are reviewed and the role of CMR in supporting clinical decisions regarding pulmonary valve replacement is discussed. © 2011 Geva; licensee BioMed Central Ltd.


Buckley C.D.,Rheumatology Research Group | Gilroy D.W.,University College London | Serhan C.N.,Harvard University
Immunity | Year: 2014

Inflammatory responses, like all biological cascades, are shaped by a delicate balance between positive and negative feedback loops. It is now clear that in addition to positive and negative checkpoints, the inflammatory cascade rather unexpectedly boasts an additional checkpoint, a family of chemicals that actively promote resolution and tissue repair without compromising host defense. Indeed, the resolution phase of inflammation is just as actively orchestrated and carefully choreographed as its induction and inhibition. In this review, we explore the immunological consequences of omega-3-derived specialized proresolving mediators (SPMs) and discuss their place within what is currently understood of the role of the arachidonic acid-derived prostaglandins, lipoxins, and their natural C15-epimers. We propose that treatment of inflammation should not be restricted to the use of inhibitors of the acute cascade (antagonism) but broadened to take account of the enormous therapeutic potential of inducers (agonists) of the resolution phase of inflammation. © 2014 Elsevier Inc.


PURPOSE OF REVIEW: To review the recent literature on the safety of nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids and traditional disease-modifying antirheumatic drugs before and during pregnancy. RECENT FINDINGS: Recent data suggest that the risk of cleft palate formation after in-utero glucocorticoid exposure is lower than previously reported. Two studies of inadvertent leflunomide exposure during early pregnancy suggest that this medication may be less teratogenic than previously thought. SUMMARY: Although NSAIDs are well tolerated for use during the first two trimesters of pregnancy, they should be avoided during a conception cycle so as not to impede implantation. After gestational week 30, these medications should be discontinued as they may cause premature closure of the ductus arteriosus. The nonfluorinated glucocorticoids, prednisone and prednisolone, can be used throughout pregnancy, although use during the first trimester may increase the risk of cleft palate formation. Protracted glucocorticoids exposure during pregnancy can cause maternal preterm premature rupture of the membranes, gestational hypertension and gestational diabetes. Methotrexate and leflunomide are teratogenic and should be avoided during pregnancy. The immunosuppressive agents, azathioprine, 6-mercaptopurine and cyclosporine A, are compatible with pregnancy. © 2014 Wolters Kluwer Health.


Liem M.,Harvard University
Aggression and Violent Behavior | Year: 2013

While there exists an abundance of research on the criminal histories of homicide offenders, little is known about their future criminal behavior. This review outlines the current state of knowledge regarding recidivism among homicide offenders. It addresses the dominant theories found within the literature in this field and the prevalence of recidivism among both general and subgroups of homicide offenders. In this literary review, several shortcomings are revealed which point to potential directions for future research. © 2012 Elsevier Ltd.


Modlin R.L.,University of California at Los Angeles | Bloom B.R.,Harvard University
Science Translational Medicine | Year: 2013

Tuberculosis (TB) remains a devastating infectious disease and, with the emergence of multidrug-resistant forms, represents a major global threat. Much of our understanding of pathogenic and immunologic mechanisms in TB has derived from studies in experimental animals. However, it is becoming increasingly clear in TB as well as in other inflammatory diseases that there are substantial differences in immunological responses of humans not found or predicted by animal studies. Thus, it is critically important to understand mechanisms of pathogenesis and immunological protection in humans. In this review, we will address the key immunological question: What are the necessary and sufficient immune responses required for protection against TB infection and disease in people - specifically protection against infection, protection against the establishment of latency or persistence, and protection against transitioning from latent infection to active disease.


Kim J.Y.,The World Bank | Farmer P.,Brigham and Womens Hospital | Porter M.E.,Harvard University
The Lancet | Year: 2013

Initiatives to address the unmet needs of those facing both poverty and serious illness have expanded significantly over the past decade. But many of them are designed in an ad-hoc manner to address one health problem among many; they are too rarely assessed; best practices spread slowly. When assessments of delivery do occur, they are often narrow studies of the cost-effectiveness of a single intervention rather than the complex set of them required to deliver value to patients and their families. We propose a framework for global health-care delivery and evaluation by considering efforts to introduce HIV/AIDS care to resource-poor settings. The framework introduces the notion of care delivery value chains that apply a systems-level analysis to the complex processes and interventions that must occur, across a health-care system and over time, to deliver high-value care for patients with HIV/AIDS and cooccurring conditions, from tuberculosis to malnutrition. To deliver value, vertical or stand-alone projects must be integrated into shared delivery infrastructure so that personnel and facilities are used wisely and economies of scale reaped. Two other integrative processes are necessary for delivering and assessing value in global health: one is the alignment of delivery with local context by incorporating knowledge of both barriers to good outcomes (from poor nutrition to a lack of water and sanitation) and broader social and economic determinants of health and wellbeing (jobs, housing, physical infrastructure). The second is the use of effective investments in care delivery to promote equitable economic development, especially for those struggling against poverty and high burdens of disease. We close by reporting our own shared experience of seeking to move towards a science of delivery by harnessing research and training to understand and improve care delivery. © 2013 Elsevier Ltd.


Gershman S.J.,Harvard University | Horvitz E.J.,Microsoft | Tenenbaum J.B.,Massachusetts Institute of Technology
Science | Year: 2015

After growing up together, and mostly growing apart in the second half of the 20th century, the fields of artificial intelligence (AI), cognitive science, and neuroscience are reconverging on a shared view of the computational foundations of intelligence that promotes valuable cross-disciplinary exchanges on questions, methods, and results. We chart advances over the past several decades that address challenges of perception and action under uncertainty through the lens of computation. Advances include the development of representations and inferential procedures for large-scale probabilistic inference and machinery for enabling reflection and decisions about tradeoffs in effort, precision, and timeliness of computations. These tools are deployed toward the goal of computational rationality: identifying decisions with highest expected utility, while taking into consideration the costs of computation in complex real-world problems in which most relevant calculations can only be approximated.We highlight key concepts with examples that show the potential for interchange between computer science, cognitive science, and neuroscience.


Murray A.W.,Harvard University
Nature Cell Biology | Year: 2011

The spindle checkpoint monitors chromosome alignment on the mitotic and meiotic spindle. When the checkpoint detects errors, it arrests progress of the cell cycle while it attempts to correct the mistakes. This perspective will present a brief history summarizing what we know about the checkpoint, and a list of questions we must answer before we understand it. © 2011 Macmillan Publishers Limited. All rights reserved.


Ussar S.,Harvard University
Science translational medicine | Year: 2011

Antibodies to receptors can block or mimic hormone action. Taking advantage of receptor isoforms, co-receptors, and other receptor modulating proteins, antibodies and other designer ligands can enhance tissue specificity and provide new approaches to the therapy of diabetes and other diseases.


Aizenberg J.,Harvard University
MRS Bulletin | Year: 2010

Nature produces a wide variety of exquisite mineralized tissues, fulfilling diverse functions. Organisms exercise a level of molecular control over the detailed nano- and microstructure of the biomaterials that is unparalleled in today's technology. Our understanding of the underlying design principles of biomaterials provides ample opportunities for developing new approaches to materials fabrication at the nanometer and micrometer scale. It is clear that valuable materials lessons can be taught by any organism. I will exemplify this point by describing new nano- and microfabrication strategies and devices that have been inspired by the studies of biomineralization in echinoderms. The topics will include self-assembly, control of crystallization, synthesis of adaptive optical structures, hybrid materials, and novel actuation systems at the nanoscale level.


Ayata C.,Harvard University
Headache | Year: 2010

More than 60 years ago Aristides Leão coined the term spreading depression (SD) to describe a transient "depression" of electrocorticographic activity that lasts up to several minutes and slowly "spreads" in all directions in cortex by way of gray matter contiguity.1 Today we know that SD is an intrinsic electrophysiological property of central nervous systems, evolutionarily preserved from locust to man.2-7 Largely based on the similarities between the symptomatology of migraine aura and the electrophysiological features of SD, a causal relationship between the two has long been hypothesized.8-10 Recently, the SD theory of migraine gained momentum by evidence emerging from both clinical and experimental studies despite being challenged by alternative mechanisms and hypotheses. Here, I will review the accumulated evidence supporting a causal relationship between SD and migraine aura and headache, and discuss the contested notion that SD may also be involved in migraine attacks without a "perceived" aura. © 2010 American Headache Society.


Swindell W.R.,Harvard University
Ageing Research Reviews | Year: 2011

Metallothionein (MT) is a low molecular weight protein with anti-apoptotic properties that has been demonstrated to scavenge free radicals in vitro. MT has not been extensively investigated within the context of aging biology. The purpose of this review, therefore, is to discuss findings on MT that are relevant to basic aging mechanisms and to draw attention to the possible role of MT in pro-longevity interventions. MT is one of just a handful of proteins that, when overexpressed, has been demonstrated to increase mouse lifespan. MT also protects against development of obesity in mice provided a high fat diet as well as diet-induced oxidative stress damage. Abundance of MT is responsive to caloric restriction (CR) and inhibition of the insulin/insulin-like signaling (IIS) pathway, and elevated MT gene expression has been observed in tissues from fasted and CR-fed mice, long-lived dwarf mice, worms maintained under CR conditions, and long-lived daf-2 mutant worms. The dysregulation of MT in these systems is likely to have tissue-specific effects on aging outcomes. Further investigation will therefore be needed to understand how MT contributes to the response of invertebrates and mice to CR and the endocrine mutations studied by aging researchers. © 2010 Elsevier B.V.


It is now recognized that trace amine associated-receptor 1 (TAAR1) plays a functional role in the regulation of brain monoamines and the mediation of action of amphetamine-like psychostimulants. Accordingly, research on TAAR1 opens the door to a new avenue of approach for medications development to treat drug addiction as well as the spectrum of neuropsychiatric disorders hallmarked by aberrant regulation of brain monoamines. This overview focuses on recent studies which reveal a role for TAAR1 in the functional regulation of monoamine transporters and the neuronal regulatory mechanisms that modulate dopaminergic activity. © 2010 International Society for Neurochemistry.


Vaillant G.E.,Harvard University
World Psychiatry | Year: 2012

Seven models for conceptualizing positive mental health are reviewed: mental health as above normal, epitomized by a DSM-IV's Global Assessment of Functioning (GAF) score of over 80; mental health as the presence of multiple human strengths rather than the absence of weaknesses; mental health conceptualized as maturity; mental health as the dominance of positive emotions; mental health as high socio-emotional intelligence; mental health as subjective well-being; mental health as resilience. Safeguards for the study of mental health are suggested, including the need to define mental health in terms that are culturally sensitive and inclusive, and the need to empirically and longitudinally validate criteria for mental health.


Vallender E.J.,Harvard University
Genome Biology | Year: 2011

Background: Complete exome resequencing has the power to greatly expand our understanding of non-human primate genomes. This includes both a better appreciation of the variation that exists in non-human primate model species, but also an improved annotation of their genomes. By developing an understanding of the variation between individuals, non-human primate models of human disease can be better developed. This effort is hindered largely by the lack of comprehensive information on specific non-human primate genetic variation and the costs of generating these data. If the tools that have been developed in humans for complete exome resequencing can be applied to closely related non-human primate species, then these difficulties can be circumvented.Results: Using a human whole exome enrichment technique, chimpanzee and rhesus macaque samples were captured alongside a human sample and sequenced using standard next-generation methodologies. The results from the three species were then compared for efficacy. The chimpanzee sample showed similar coverage levels and distributions following exome capture based on the human genome as the human sample. The rhesus macaque sample showed significant coverage in protein-coding sequence but significantly less in untranslated regions. Both chimpanzee and rhesus macaque showed significant numbers of frameshift mutations compared to self-genomes and suggest a need for further annotation.Conclusions: Current whole exome resequencing technologies can successfully be used to identify coding-region variation in non-human primates extending into old world monkeys. In addition to identifying variation, whole exome resequencing can aid in better annotation of non-human primate genomes. © 2011 Vallender; licensee BioMed Central Ltd.


Martinon F.,Harvard University
Immunological Reviews | Year: 2010

Gout is an arthritis characterized by elevated uric acid in the bloodstream. In this condition, crystals of uric acid are formed and accumulate in the synovial fluids. Crystal deposition leads to acute inflammation, which is associated with the spontaneous resolution of the disease. Recent studies have led to significant advances in the understanding of the basic biology of crystal-mediated inflammation. Uric acid has been identified as a danger signal that triggers a cytosolic sensor, the inflammasome. This signaling platform is required for the activation of interleukin-1, a cytokine that is critical to the initiation of acute inflammation in gout. Importantly, both molecular and pathological evidence support the notion that gout is a prototypical member of the growing family of autoinflammatory diseases. This review discusses the role of the inflammasome in gout and the emerging new therapeutic strategies aimed at controlling inflammation in crystal arthritis. © 2009 John Wiley & Sons A/S.


Snow C.E.,Harvard University
Science | Year: 2010

A major challenge to students learning science is the academic language in which science is written. Academic language is designed to be concise, precise, and authoritative. To achieve these goals, it uses sophisticated words and complex grammatical constructions that can disrupt reading comprehension and block learning. Students need help in learning academic vocabulary and how to process academic language if they are to become independent learners of science.


The primary objective was to assess whether prospectively observed quality of parent-child interaction in infancy and middle childhood contributed to the prediction of borderline symptoms and recurrent suicidality/self-injury in late adolescence. Adolescents (mean 19.9 years) from 56 families participating in a longitudinal study since infancy (retention rate 74%) were assessed on the SCID-II for symptoms of borderline personality disorder (BPD), including suicidality/self-injury. Early clinical risk was indexed by clinical referral to parent-infant services. Attachment security and parent-child interaction were assessed from videotape at 18 months and 8 years. Severity of childhood abuse was rated from interview and self-report measures. Maternal withdrawal in infancy was a significant predictor of both borderline symptoms and suicidality/self-injury in late adolescence. Disorganized controlling child behavior at age 8 contributed independently to the prediction of borderline symptoms. The effect of maternal withdrawal was independent of, and additive to, variability explained by severity of childhood abuse. Borderline symptoms and suicidality/self-injury may be preceded developmentally by disturbed interactions as early as 18 months of age. A parent-child transactional model is proposed to account for the findings. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.


Tanzi R.E.,Harvard University
Journal of Alzheimer's Disease | Year: 2013

The rich and colorful history of gene discovery in Alzheimer's disease (AD) over the past three decades is as complex and heterogeneous as the disease, itself. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 are fully penetrant for early-onset (<60 years) familial AD, which represents <5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, influence susceptibility for common (>95%) late-onset AD. These four genes account for 30-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of additional highly confirmed AD candidate genes. Here, I review the past, present, and future of attempts to elucidate the complex and heterogeneous genetic underpinnings of AD along with some of the unique events that made these discoveries possible. © 2013 - IOS Press and the authors. All rights reserved.


We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Haig D.,Harvard University
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Human offspring are weaned earlier than the offspring of other great apes but take longer to reach nutritional independence. An analysis of human disorders of imprinted genes suggests genes of paternal origin, expressed in infants, have been selected to favor more intense suckling than genes of maternal origin. The same analysis suggests that genes of maternal origin may favor slower childhood growth but earlier sexual maturation. These observations are consistent with a hypothesis in which slow maturation was an adaptation of offspring that reduced maternal fitness, whereas early weaning was an adaptation of mothers that reduced the fitness of individual offspring.


Clougherty J.E.,Harvard University
Environmental Health Perspectives | Year: 2010

Objective: Epidemiologic studies of air pollution effects on respiratory health report significant modification by sex, although results are not uniform. Importantly, it remains unclear whether modifications are attributable to socially derived gendered exposures, to sex-linked physiological differences, or to some interplay thereof. Gender analysis, which aims to disaggregate social from biological differences between males and females, may help to elucidate these possible sources of effect modification. Data sources and Data extraction: A PubMed literature search was performed in July 2009, using the terms "respiratory" and any of "sex" or "gender" or "men and women" or "boys and girls" and either "PM 2.5" (particulate matter ≤ 2.5 μm in aerodynamic diameter) or "NO2" (nitrogen dioxide). I reviewed the identified studies, and others cited therein, to summarize current evidence of effect modification, with attention to authors' interpretation of observed differences. Owing to broad differences in exposure mixes, outcomes, and analytic techniques, with few studies examining any given combination thereof, meta-analysis was not deemed appropriate at this time. Data synthesis: More studies of adults report stronger effects among women, particularly for older persons or where using residential exposure assessment. Studies of children suggest stronger effects among boys in early life and among girls in later childhood. Conclusions: The qualitative review describes possible sources of difference in air pollution response between women and men, which may vary by life stage, coexposures, hormonal status, or other factors. The sources of observed effect modifications remain unclear, although gender analytic approaches may help to disentangle gender and sex differences in pollution response. A framework for incorporating gender analysis into environmental epidemiology is offered, along with several potentially useful methods from gender analysis.


Saboo S.S.,Harvard University
AJR. American journal of roentgenology | Year: 2014

The purpose of this article is to describe the evaluation of congenital coronary artery fistulas (CAFs) with MDCT angiography with ECG gating (MDCTA), including the clinical manifestations, scanning techniques, differential diagnosis, and other imaging methods that may be used. Congenital CAFs are rare coronary artery anomalies of termination. MDCTA is a first-line modality for pretreatment planning, and imaging findings should be recognized because CAFs may be detected incidentally.


Struhl K.,Harvard University
eLife | Year: 2014

In colorectal cancer cells, a non-epigenetic transcriptional pathway that is mediated by an oncogene maintains DNA methylation of tumour suppressor genes. © Struhl.


Mello N.K.,Harvard University
Hormones and Behavior | Year: 2010

Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (2 min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine's sustained positive effects (<20 min), ratings of "high" and "rush" began to decrease within one or two puffs of a high-nicotine cigarette while nicotine levels were increasing. Peak nicotine levels increased progressively after each of three successive cigarettes smoked at 60 min intervals, but the magnitude of the subjective effects ratings and peak ACTH and cortisol levels diminished. Only DHEA increased consistently after successive cigarettes. The possible influence of neuroactive hormones on nicotine dependence and cocaine abuse and the implications for treatment of these addictive disorders are discussed. © 2009 Elsevier Inc.


Gunawardena J.,Harvard University
PLoS ONE | Year: 2012

Cellular physiology is implemented by formidably complex biochemical systems with highly nonlinear dynamics, presenting a challenge for both experiment and theory. Time-scale separation has been one of the few theoretical methods for distilling general principles from such complexity. It has provided essential insights in areas such as enzyme kinetics, allosteric enzymes, G-protein coupled receptors, ion channels, gene regulation and post-translational modification. In each case, internal molecular complexity has been eliminated, leading to rational algebraic expressions among the remaining components. This has yielded familiar formulas such as those of Michaelis-Menten in enzyme kinetics, Monod-Wyman-Changeux in allostery and Ackers-Johnson-Shea in gene regulation. Here we show that these calculations are all instances of a single graph-theoretic framework. Despite the biochemical nonlinearity to which it is applied, this framework is entirely linear, yet requires no approximation. We show that elimination of internal complexity is feasible when the relevant graph is strongly connected. The framework provides a new methodology with the potential to subdue combinatorial explosion at the molecular level. © 2012 Jeremy Gunawardena.


McCunney R.J.,Massachusetts Institute of Technology | Li J.,Harvard University
Chest | Year: 2014

The National Lung Cancer Screening Trial (NLST) demonstrated that screening with low-dose CT (LDCT) scan reduced lung cancer and overall mortality by 20% and 7%, respectively. The LDCT scanning involves an approximate 2-mSv dose, wherea full-chest CT scanning, the major diagnostic study used to follow up nodules, may involve a dose of 8 mSv. Radiation associated with CT scanning and other diagnostic studies to follow up nodules may present an independent risk of lung cancer. On the basis of the NLST, we estimated the incidence and prevalence of nodules detected in screening programs. We followed the Fleischner guidelines for follow-up of nodules to assess cumulative radiation exposure over 20- and 30-year periods. We then evaluated nuclear worker cohort studies and atomic bomb survivor studies to assess the risk of lung cancer from radiation associated with long-term lung cancer screening programs. The fi ndings indicate that a 55-year-old lung screening participant may experience a cumulative radiation exposure of up to 280 mSv over a 20-year period and 420 mSv over 30 years. These exposures exceed those of nuclear workers and atomic bomb survivors. This assessment suggests that long-term (20-30 years) LDCT screening programs are associated with nontrivial cumulative radiation doses. Current lung cancer screening protocols, if conducted over 20- to 30-year periods, can independently increase the risk of lung cancer beyond cigarette smoking as a result of cumulative radiation exposure. Radiation exposures from LDCT screening and follow-up diagnostic procedures exceed lifetime radiation exposures among nuclear power workers and atomic bomb survivors. © 2014 American College of Chest Physicians.


Birt-Hogg-Dube (BHD) is a tumor suppressor gene syndrome associated with fibrofolliculomas, cystic lung disease, and chromophobe renal cell carcinoma. In seeking to elucidate the pathogenesis of BHD, we discovered a physical interaction between folliculin (FLCN), the protein product of the BHD gene, and p0071, an armadillo repeat containing protein that localizes to the cytoplasm and to adherens junctions. Adherens junctions are one of the three cell-cell junctions that are essential to the establishment and maintenance of the cellular architecture of all epithelial tissues. Surprisingly, we found that downregulation of FLCN leads to increased cell-cell adhesion in functional cell-based assays and disruption of cell polarity in a three-dimensional lumen-forming assay, both of which are phenocopied by downregulation of p0071. These data indicate that the FLCN-p0071 protein complex is a negative regulator of cell-cell adhesion. We also found that FLCN positively regulates RhoA activity and Rho-associated kinase activity, consistent with the only known function of p0071. Finally, to examine the role of Flcn loss on cell-cell adhesion in vivo, we utilized keratin-14 cre-recombinase (K14-cre) to inactivate Flcn in the mouse epidermis. The K14-Cre-Bhd(flox/flox) mice have striking delays in eyelid opening, wavy fur, hair loss, and epidermal hyperplasia with increased levels of mammalian target of rapamycin complex 1 (mTORC1) activity. These data support a model in which dysregulation of the FLCN-p0071 interaction leads to alterations in cell adhesion, cell polarity, and RhoA signaling, with broad implications for the role of cell-cell adhesion molecules in the pathogenesis of human disease, including emphysema and renal cell carcinoma.


Rehm H.L.,Harvard University | Rehm H.L.,HealthCare Partners
Nature Reviews Genetics | Year: 2013

With the declining cost of sequencing and the ongoing discovery of disease genes, it is now possible to examine hundreds of genes in a single disease-targeted test. Although exome- and genome-sequencing approaches are beginning to compete, disease-targeted testing retains certain advantages and still holds a firm place in the diagnostic evaluation. Here I examine the current state of clinical disease-targeted sequencing and evaluate the benefits and challenges of incorporating sequencing tests into patient care. © 2013 Macmillan Publishers Limited. All rights reserved.


Simon J.A.,University of Minnesota | Kingston R.E.,Harvard University
Molecular Cell | Year: 2013

Chromatin modification by Polycomb proteins provides an essential strategy for gene silencing in higher eukaryotes. Polycomb repressive complexes (PRCs) silence key developmental regulators and are centrally integrated in the transcriptional circuitry of stem cells. PRC2 trimethylates histone H3 on lysine 27 (H3K27me3), and PRC1-type complexes ubiquitylate histone H2A and compact polynucleosomes. How PRCs are deployed to select and silence genomic targets is the subject of intense investigation. We review advances on targeting, modulation, and functions of PRC1 and PRC2 and progress on defining the transcriptional steps they impact. Recent findings emphasize PRC1 targeting independent of H3K27me3, nonenzymatic PRC1-mediated compaction, and connections between PRCs and noncoding RNAs. Systematic analyses of Polycomb complexes and associated histone modifications during DNA replication and mitosis have also emerged. The stage is now set to reveal fundamental epigenetic mechanisms that determine how Polycomb target genes are silenced and how Polycomb silence is preserved through cell-cycle progression. © 2013 Elsevier Inc.


Kacanek D.,Harvard University
Journal of acquired immune deficiency syndromes (1999) | Year: 2013

We longitudinally examined the effect of intimate partner violence (IPV) on condom and diaphragm nonadherence among women in the Methods for Improving Reproductive Health in Africa study, a phase III HIV prevention trial in southern Africa. Recent IPV (fear of violence, emotional abuse, physical violence, or forced sex, in past 3 months), condom nonadherence, and diaphragm nonadherence were assessed at baseline, 12 month, and exit visits (up to 24 months). The association between IPV and (1) condom nonadherence or (2) diaphragm nonadherence across visits was modeled using Generalized Estimating Equations adjusting for potential confounders. Of 4505 participants, 55% reported recent IPV during their trial participation. Women reported fearing violence (41%), emotional abuse (38%), being physically assaulted (16%), and forced sex (15%) by their regular male partner. IPV was associated with condom nonadherence in both study arms [adjusted odds ratio (AOR): 1.41, 95% confidence interval (CI): 1.24 to 1.61 (control arm) and AOR: 1.47, 95% CI: 1.28 to 1.69, (intervention arm)] and with diaphragm nonadherence (AOR 1.24, 95% CI: 1.06 to 1.45) adjusting for age, study sites, number of sex partners, and knowledge of male partner infidelity. Modeling effects of each form of IPV separately on nonadherence outcomes yielded similar results. Prevalence of recent IPV was high and associated with condom and diaphragm nonadherence during the trial. Counseling in prevention trials should proactively address IPV, for its own sake, and in product and risk-reduction counseling. Strategies to encourage men's positive involvement in product use and prevent IPV perpetration should be considered.


Hughes K.S.,Harvard University
Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2013

To determine whether there is a benefit to adjuvant radiation therapy after breast-conserving surgery and tamoxifen in women age ≥ 70 years with early-stage breast cancer. Between July 1994 and February 1999, 636 women (age ≥ 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) -positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women). Primary end points were time to local or regional recurrence, frequency of mastectomy, breast cancer-specific survival, time to distant metastasis, and overall survival (OS). Results: Median follow-up for treated patients is now 12.6 years. At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences. There were no significant differences in time to mastectomy, time to distant metastasis, breast cancer-specific survival, or OS between the two groups. Ten-year OS was 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%) in the TamRT and Tam groups, respectively. With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age ≥ 70 years with ER-positive early-stage breast cancer.


Pearson A.,Harvard University | Ingalls A.E.,University of Washington
Annual Review of Earth and Planetary Sciences | Year: 2013

Archaea are abundant in marine and terrestrial aquatic environments, sediments, and soils. They inhabit at least an 85°C temperature range from the polar ocean to hydrothermal springs. Many Archaea produce membrane lipids called glycerol dialkyl glycerol tetraethers (GDGTs). Experiments on pure and enrichment cultures as well as an empirical correlation for marine sediments (the TEX86 index) together show positive relationships between temperature and the number of cyclopentane or cyclohexane rings in GDGTs. The resulting TEX86 paleotemperature proxy has been applied across a wide range of geologic history and depositional settings. The exact relationship between TEX86 and temperature, however, remains poorly understood. Environmental systems and cultures have different temperature dependencies, and the ecological niche(s) of aquatic Archaea are still a subject of active investigation. Here we review some of the remaining questions about GDGT paleotemperature proxies. Better answers to these challenging problems will help refine future paleoceanographic applications. © Copyright ©2013 by Annual Reviews. All rights reserved.


Schacter D.L.,Harvard University
Dialogues in Clinical Neuroscience | Year: 2012

Human memory is not a literal reproduction of the past, but instead relies on constructive processes that are sometimes prone to error and distortion. Understanding of constructive memory has accelerated during recent years as a result of research that has linked together its cognitive and neural bases. This article focuses on three aspects of constructive memory that have been the target of recent research: (i) the idea that certain kinds of memory distortions reflect the operation of adaptive cognitive processes that contribute to the efficient functioning of memory; (ii) the role of a constructive memory system in imagining or simulating possible future events; and (iii) differences between true and false memories that have been revealed by functional neuroimaging techniques. The article delineates the theoretical implications of relevant research, and also considers some clinical and applied implications. © 2012, LLS SAS.


Januzzi Jr. J.L.,Harvard University
Journal of Cardiovascular Translational Research | Year: 2013

ST2 is a member of the interleukin (IL)-1 receptor family discovered in a classical translational science fashion, and exists in two forms, a trans-membrane receptor (ST2L) as well as a soluble decoy receptor (sST2). The ligand of ST2 is IL-33, which is involved in reducing fibrosis and hypertrophy in mechanically strained tissues. In in vitro and in vivo models, ST2L transduces the effects of IL-33, while excess sST2 or abnormalities in ST2 signaling leads to cardiac hypertrophy, fibrosis, and ventricular dysfunction. Clinically, in patients with symptomatic heart failure (HF), elevated concentrations of sST2 are strongly associated with severity of the diagnosis, and powerfully predict increased risk of complications, independent of other established or emerging biomarkers. sST2 testing has also been shown to predict onset of symptomatic HF in patients with acute myocardial infarction, while in community-based subjects, sST2 values independently predict future HF, cardiovascular disease events, and mortality. © 2013 Springer Science+Business Media New York.


Population-based HIV testing surveys have become central to deriving estimates of national HIV prevalence in sub-Saharan Africa. However, limited participation in these surveys can lead to selection bias. We control for selection bias in national HIV prevalence estimates using a novel approach, which unlike conventional imputation can account for selection on unobserved factors. For 12 Demographic and Health Surveys conducted from 2001 to 2009 (N=138 300), we predict HIV status among those missing a valid HIV test with Heckman-type selection models, which allow for correlation between infection status and participation in survey HIV testing. We compare these estimates with conventional ones and introduce a simulation procedure that incorporates regression model parameter uncertainty into confidence intervals. Selection model point estimates of national HIV prevalence were greater than unadjusted estimates for 10 of 12 surveys for men and 11 of 12 surveys for women, and were also greater than the majority of estimates obtained from conventional imputation, with significantly higher HIV prevalence estimates for men in Cote d'Ivoire 2005, Mali 2006 and Zambia 2007. Accounting for selective non-participation yielded 95% confidence intervals around HIV prevalence estimates that are wider than those obtained with conventional imputation by an average factor of 4.5. Our analysis indicates that national HIV prevalence estimates for many countries in sub-Saharan African are more uncertain than previously thought, and may be underestimated in several cases, underscoring the need for increasing participation in HIV surveys. Heckman-type selection models should be included in the set of tools used for routine estimation of HIV prevalence.


Khalil R.A.,Harvard University
Biochemical Pharmacology | Year: 2013

Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and 'timing' could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD. © 2012 Elsevier B.V. All rights reserved.


Mathis D.,Harvard University
Cell Metabolism | Year: 2013

Chronic, low-grade inflammation of visceral adipose tissue, and systemically, is a critical link between recent strikingly parallel rises in the incidence of obesity and type 2 diabetes. Macrophages have been recognized for some time to be critical participants in obesity-induced inflammation of adipose tissue. Of late, a score of other cell types of the innate and adaptive arms of the immune system have been suggested to play a positive or negative role in adipose tissue infiltrates. This piece reviews the existing data on these new participants; discusses experimental uncertainties, inconsistencies, and complexities; and puts forward a minimalist synthetic scheme. © 2013 Elsevier Inc.


Physicochemical properties preclude ideal biomolecules and perfect biological functions. This inherent imperfectness leads to the generation of damage by every biological process, at all levels, from small molecules to cells. The damage is too numerous to be repaired, is partially invisible to natural selection, and manifests as aging. I propose that the inherent imperfectness of biological systems is the true root of the aging process. Because each biomolecule generates specific forms of damage, the cumulative damage is largely non-random and is indirectly encoded in the genome. I consider this concept in light of other proposed theories of aging and integrate these disparate ideas into a single model. I also discuss the evolutionary significance of damage accumulation and strategies for reducing damage. Finally, I suggest ways to test this integrated model of aging. © 2013 Elsevier Ltd.


Radisavljevic Z.,Harvard University
Journal of Cellular Physiology | Year: 2013

Angiogenesis get full robustness in metastatic cancer, relapsed leukemia or lymphoma when complex positive feedback loop signaling systems become integrative. A cancer hypoxic microenvironment generates positive loops inducing formation of the vascular functional shunts. AKT is an upstream angiogenic locus of integrative robustness and fragility activated by the positive loops. AKT controls two downstream nodes the mTOR and NOS in nodal organization of the signaling genes. AKT phosphorylation is regulated by a balance of an oxidant/antioxidant. Targeting AKT locus represents new principle to control integrative angiogenic robustness by the locus chemotherapy. © 2012 Wiley Periodicals, Inc.


The recent study by Alexander et al validates the effectiveness of the Afirma test, and suggests a potential ancillary role for this unique test when appropriately applied in the evaluation of thyroid nodules classified by fine-needle aspiration as indeterminate. © 2013 American Cancer Society.


Bhattacharyya N.,Harvard University
Laryngoscope | Year: 2014

Objectives/Hypothesis Determine rates and reasons for revisits after adult ambulatory sinonasal surgery. Study Design Cross-sectional analysis of multi-state ambulatory surgery and hospital databases. Methods Ambulatory adult sinonasal procedures were extracted from the State Ambulatory Surgery Databases for New York, Florida, Iowa, and California for 2010. Cases were linked to the State Emergency Department Databases and the State Inpatient Databases for visit encounters occurring 0 to 14 days after the procedure. The number of revisits (including readmissions) was determined as well as the reason for revisit. The overall rate of and intervention rate for postprocedural bleeding were determined. Results A total of 35,678 ambulatory sinonasal cases were extracted (mean age, 47.5 years). Overall, 5.0% of patients had a revisit after surgery (18.9% revisited the ambulatory surgery center, 67.0% the emergency department, and 14.1% to inpatient admission). The primary diagnoses at the first revisit were bleeding (23.0%), acute pain (3.7%), and fever/dehydration (3.8%). Overall, 0.8% of patients incurred a second revisit. Among all cases, 1.2% and 0.3% presented with a bleeding diagnosis at a first and second revisit, respectively. Among revisits, 1.0% and 17.9% underwent a procedure to control bleeding at the first and second revisits, respectively. Three deaths were noted for an overall 14-day mortality rate of 0.0084%. Conclusion There is a nonnegligible revisit rate after ambulatory sinonasal surgery. The most common reasons for revisit include bleeding, but also acute pain and fever/dehydration. These particular complications should be targeted for prevention to reduce postoperative revisit rates. Level of Evidence 2b. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.


Mair W.,Harvard University
Cell Metabolism | Year: 2013

AMPK is a cellular energy sensor conserved across eukaryotes that in C. elegans prolongs life span and mimics dietary restriction. Stenesen and colleagues (2012) activate AMPK both directly and indirectly by altering AMP biosynthesis to slow aging in Drosophila, highlighting AMPK as a conserved life span modulator that links energy sensing to longevity. © 2013 Elsevier Inc.


Burgess A.E.,Harvard University
Seminars in Nuclear Medicine | Year: 2011

Most academic radiologists will be familiar with receiver operating characteristic (ROC) studies. Fundamental studies of human observer performance are now usually performed by forced-choice methods. Both methods are based on signal detection theory. The ROC method gives an operating curve of true-positive versus false-positive probabilities. The area under the curve, A Z, can be used a summary performance measure. In the forced-choice method, observers are given 2 or more images with one containing the signal. The observer's task is to select the option most likely to contain the signal. The percentage of correct responses, PC, is a summary performance measure. Precise comparison of the 2 methods is limited to very controlled experiments in which signals (simulated lesions for example) are carefully designed and detection or discrimination is limited by true random noise. Under these conditions, theory predicts a simple relationship between summary measures and human results are consistent with theory. There will be a description of forced-choice experimental methods and data analysis. There has also been considerable work on development of theoretic observer models. Human experiment results have used to evaluate the models. Models that correlate well with human performance in turn can be used for preliminary design of new imaging systems and for selection of image quality metrics for comparing equipment performance, this article will provide a summary of work during the last 30 years on evaluating human signal detection capabilities, observer models and image quality metrics. © 2011 Elsevier Inc.


Haig D.,Harvard University
Annual Review of Cell and Developmental Biology | Year: 2013

Seeds are complex structures that unite diploid maternal tissues with filial tissues that may be haploid (gametophyte), diploid (embryo), or triploid (endosperm). Maternal tissues are predicted to favor smaller seeds than are favored by filial tissues, and filial genes of maternal origin are predicted to favor smaller seeds than are favored by filial genes of paternal origin. Consistent with these predictions, seed size is determined by an interplay between growth of maternal integuments, which limits seed size, and of filial endosperm, which promotes larger seeds. Within endosperm, genes of paternal origin favor delayed cellularization of endosperm and larger seeds, whereas genes of maternal origin favor early cellularization and smaller seeds. The ratio of maternal and paternal gene products in endosperm contributes to the failure of crosses between different ploidy levels of the same species and crosses between species. Maternally expressed small-interfering RNAs (siRNAs) are predicted to associate with growth-enhancing genes. © 2013 by Annual Reviews. All rights reserved.


Struhl K.,Harvard University | Segal E.,Weizmann Institute of Science
Nature Structural and Molecular Biology | Year: 2013

Nucleosome positioning is critical for gene expression and most DNA-related processes. Here we review the dominant patterns of nucleosome positioning that have been observed and summarize the current understanding of their underlying determinants. The genome-wide pattern of nucleosome positioning is determined by the combination of DNA sequence, ATP-dependent nucleosome remodeling enzymes and transcription factors that include activators, components of the preinitiation complex and elongating RNA polymerase II. These determinants influence each other such that the resulting nucleosome positioning patterns are likely to differ among genes and among cells in a population, with consequent effects on gene expression. Copyright © 2013 Nature America, Inc.


Radisavljevic Z.,Harvard University
Journal of Cellular Physiology | Year: 2013

A positive feedback loops induce extreme robustness in metastatic cancer, relapsed leukemia, myeloma or lymphoma. The loops are generated by the signaling interactome networks of autocrine and paracrine elements from cancer hypoxic microenvironment. The elements of the networks are signaling proteins synthesized in hypoxic microenvironment such as the vascular endothelial growth factor, HIF-1α, hepatocyte growth factor, and molecules nitric oxide and H2O2. The signals from upstream or rebound downstream pathways are amplified by the short or wide positive feedback loops, hyperstimulating AKT-inducing cancer extreme robustness. Targeting the phosphorylated AKT locus by an oxidant/antioxidant modulation induces collapse of positive feedback loops and establishment of negative feedback loops leading to stability of the system and disappearance of cancer extreme robustness. This is a new principle for the conversion of cancer positive loops into negative feedback loops by the locus chemotherapy. © 2012 Wiley Periodicals, Inc.


Wolfe M.S.,Harvard University
Journal of Neurochemistry | Year: 2012

γ-Secretase is a membrane embedded aspartyl protease complex with presenilin as the catalytic component. Along with β-secretase, this enzyme produces the amyloid β-protein of Alzheimer's disease (AD) from the amyloid β-protein precursor. Because of its key role in the pathogenesis of AD, γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. The therapeutic potential of these inhibitors is virtually negated by the fact that γ-secretase is an essential part of the Notch signaling pathway, rendering the compounds unacceptably toxic upon chronic exposure. However, these compounds have served as useful chemical tools for biological investigations. In contrast, γ-secretase modulators continue to be of keen interest as possible AD therapeutics. These modulators either shift amyloid β-protein production to shorter, less pathogenic peptides or inhibit the proteolysis of amyloid β-protein precursor selectively compared to that of Notch. The various chemical types of inhibitors and modulators will be discussed, along with their use as probes for basic biology and their potential as AD therapeutics. © 2011 International Society for Neurochemistry.


Liu C.,Microsoft | Sun D.,Harvard University
IEEE Transactions on Pattern Analysis and Machine Intelligence | Year: 2014

Although multiframe super resolution has been extensively studied in past decades, super resolving real-world video sequences still remains challenging. In existing systems, either the motion models are oversimplified or important factors such as blur kernel and noise level are assumed to be known. Such models cannot capture the intrinsic characteristics that may differ from one sequence to another. In this paper, we propose a Bayesian approach to adaptive video super resolution via simultaneously estimating underlying motion, blur kernel, and noise level while reconstructing the original high-resolution frames. As a result, our system not only produces very promising super resolution results outperforming the state of the art, but also adapts to a variety of noise levels and blur kernels. To further analyze the effect of noise and blur kernel, we perform a two-step analysis using the Cramer-Rao bounds. We study how blur kernel and noise influence motion estimation with aliasing signals, how noise affects super resolution with perfect motion, and finally how blur kernel and noise influence super resolution with unknown motion. Our analysis results confirm empirical observations, in particular that an intermediate size blur kernel achieves the optimal image reconstruction results. © 1979-2012 IEEE.


Santos E.J.G.,Harvard University
Journal of Physical Chemistry C | Year: 2013

Electric field control of magnetism has become increasingly important for the next generation of graphene-based spintronic devices. We predict that the magnetic moment induced by chemisorbed H atoms on the top layer of a few-layer graphene system is tunable by an external electric field. Through accurate first-principles electronic structure calculations, we show that this magnetoelectric effect is negligible in one-layer graphene, but becomes pronounced in bilayer and trilayer graphene, saturating in magnitude in quadrilayer graphene. The effect is due to shifting of the Dirac cone of the pure graphene layers relative to the bands of the hydrogenated layer, induced by the external field. The calculated magnetoelectric coefficient (α) has values comparable to those found for ferromagnetic films or perovskite interfaces. The value of α was also used to identify a half-metallic state at low gate bias, which suggests a new class of spin-polarized materials based on hydrogenated multilayer graphene. Our results point to an experimentally feasible way to create a magnetoelectric coupling in graphene using the interplay between covalent functionalization and electric fields. © 2013 American Chemical Society.


Tuberculosis is the leading cause of death in South Africa by death notification, but accurate diagnosis of tuberculosis is challenging in this setting of high HIV prevalence. We conducted limited autopsies on young adults dying in a single public hospital in the province of KwaZulu-Natal between October 2008 and August 2009 in order to estimate the magnitude of deaths attributable to tuberculosis. We studied a representative sample of 240 adult inpatients (aged 20-45 years) dying after admission to Edendale Hospital. Limited autopsies included collection of respiratory tract secretions and tissue by needle core biopsies of lung, liver, and spleen. Specimens were examined by fluorescent microscopy for acid-fast bacilli and cultured in liquid media; cultures positive for M. tuberculosis were tested for drug susceptibility to first- and second-line antibiotics. Ninety-four percent of our study cohort was HIV seropositive and 50% of decedents had culture-positive tuberculosis at the time of death. Fifty percent of the participants were on treatment for tuberculosis at the time of death and 58% of these treated individuals remained culture positive at the time of death. Of the 50% not receiving tuberculosis treatment, 42% were culture positive. Seventeen percent of all positive cultures were resistant to both isoniazid and rifampin (i.e., multidrug resistant); 16% of patients dying during the initiation phase of their first ever course of tuberculosis treatment were infected with multidrug-resistant bacilli. Our findings reveal the immense toll of tuberculosis among HIV-positive individuals in KwaZulu-Natal. The majority of decedents who remained culture positive despite receiving tuberculosis treatment were infected with pan-susceptible M. tuberculosis, suggesting that the diagnosis of tuberculosis was made too late to alter the fatal course of the infection. There is also a significant burden of undetected multidrug-resistant tuberculosis among HIV-coinfected individuals dying in this setting. New public health approaches that improve early diagnosis of tuberculosis and accelerate the initiation of treatment are urgently needed in this setting. Please see later in the article for the Editors' Summary.


Shakhnovich E.,Harvard University
Nature Materials | Year: 2011

The discovery of deep knots in proteins created a significant challenge for protein-folding researchers. They conducted investigations to determine whether knotted proteins were able to fold spontaneously or were there dedicated chaperones that tied the knots. This problem was solved by Sophie Jackson and a team of researchers who demonstrated spontaneous refolding of a knotted protein, known as YibK. The researchers performed folding simulations that confirmed the spontaneous folding scenario of the protein. The apparent ease with which YibK and its computational counterpart actually folded and the apparent topological difficulty involved in folding a knotted protein, led to suggestions that evolution had to optimize the folding pathways of knotted proteins for such reliable folding to occur.


Laboratory survival experiments have shown that dietary restriction (DR) can increase median and maximum lifespan. This paper provides a meta-analysis of laboratory experiments that have evaluated the effects of DR on lifespan in rats and mice (1934-present). In rats, DR increased median lifespan by 14-45% in half of all experiments, but in mice the effects of DR have been much weaker (4-27%). The least favorable effects of DR on lifespan have been observed among inbred rather than non-inbred mouse strains. In fact, some inbred mouse strains do not necessarily live longer with DR, including DBA/2 male mice and several strains from the ILSXISS recombinant inbred panel. Shortening of lifespan with DR has also been observed and confirmed for ILSXISS strain 114. Importantly, all rodent studies may be biased by the effects of laboratory breeding, since one study has shown that median lifespan is not improved by DR in wild-derived mice. These findings suggest that the set of genetic backgrounds studied in rodent DR experiments should be diversified. This will broaden the scope of genotypes studied in aging research, but may also be critical for translation of findings from rodents to historically outbred and genetically heterogeneous primate species. © 2011 Elsevier B.V.


Although advances in the reduction of maternal mortality have been made, up to 273,000 women will die this year from obstetric etiologies. Obstructed labor (OL), most commonly treated with Caesarean delivery, has been identified as a major contributor to global maternal morbidity and mortality. We used economic and epidemiological modeling to estimate the cost per disability-adjusted life-year (DALY) averted and benefit-cost ratio of treating OL with Caesarean delivery for 49 countries identified as providing an insufficient number of Caesarean deliveries to meet demand. Using publicly available data and explicit economic assumptions, we estimated that the cost per DALY (3,0,0) averted for providing Caesarean delivery for OL ranged widely, from $251 per DALY averted in Madagascar to $3,462 in Oman. The median cost per DALY averted was $304. Benefit-cost ratios also varied, from 0.6 in Zimbabwe to 69.9 in Gabon. The median benefit-cost ratio calculated was 6.0. The main limitation of this study is an assumption that lack of surgical capacity is the main factor responsible for DALYs from OL. Using the World Health Organization's cost-effectiveness standards, investing in Caesarean delivery can be considered "highly cost-effective" for 48 of the 49 countries included in this study. Furthermore, in 46 of the 49 included countries, the benefit-cost ratio was greater than 1.0, implying that investment in Caesarean delivery is a viable economic proposition. While Caesarean delivery alone is not sufficient for combating OL, it is necessary, cost-effective by WHO standards, and ultimately economically favorable in the vast majority of countries included in this study.


Schmidt A.G.,Harvard University
PLoS pathogens | Year: 2010

The mechanism of membrane fusion by "class II" viral fusion proteins follows a pathway that involves large-scale domain rearrangements of the envelope glycoprotein (E) and a transition from dimers to trimers. The rearrangement is believed to proceed by an outward rotation of the E ectodomain after loss of the dimer interface, followed by a reassociation into extended trimers. The approximately 55-aa-residue, membrane proximal "stem" can then zip up along domain II, bringing together the transmembrane segments of the C-terminus and the fusion loops at the tip of domain II. We find that peptides derived from the stem of dengue-virus E bind stem-less E trimer, which models a conformational intermediate. In vitro assays demonstrate that these peptides specifically block viral fusion. The peptides inhibit infectivity with potency proportional to their affinity for the conformational intermediate, even when free peptide is removed from a preincubated inoculum before infecting cells. We conclude that peptides bind virions before attachment and are carried with virions into endosomes, the compartment in which acidification initiates fusion. Binding depends on particle dynamics, as there is no inhibition of infectivity if preincubation and separation are at 4 degrees C rather than 37 degrees C. We propose a two-step model for the mechanism of fusion inhibition. Targeting a viral entry pathway can be an effective way to block infection. Our data, which support and extend proposed mechanisms for how the E conformational change promotes membrane fusion, suggest strategies for inhibiting flavivirus entry.


Witztum J.L.,University of California at San Diego | Lichtman A.H.,Harvard University
Annual Review of Pathology: Mechanisms of Disease | Year: 2014

Both the chronic development of atherosclerotic lesions and the acute changes in lesion phenotype that lead to clinical cardiovascular events are significantly influenced by the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall. The rapid pace of discovery of mechanisms of immunologic recognition, effector functions, and regulation has significantly influenced the study of atherosclerosis, and our new knowledge is beginning to affect how we treat this ubiquitous disease. In this review, we discuss recent advances in our understanding of how innate and adaptive immunity contribute to atherosclerosis, as well as therapeutic opportunities that arise from this knowledge. © 2014 by Annual Reviews. All rights reserved.


Kopans D.B.,Harvard University
American Journal of Roentgenology | Year: 2014

OBJECTIVE. The purpose of this article is to describe the development of digital breast tomosynthesis (DBT) and to describe its advantages over 2D mammography for breast cancer screening. CONCLUSION. Mammographic screening has dramatically reduced breast cancer deaths, but it does not depict all cancer early enough to result in a cure. In addition, because of the recall rates associated with mammography, efforts are underway to reduce access to screening. Use of DBT improves sensitivity and specificity, and there is no longer a need to obtain full-exposure 2D mammograms. DBT will replace standard 2D mammography for breast cancer screening. © American Roentgen Ray Society.


Tritos N.A.,Harvard University
Discovery medicine | Year: 2012

Cushing's syndrome (CS) is a heterogeneous disorder of diverse etiologies, leading to cortisol excess. Endogenous CS is caused by tumors secreting adrenocorticotropin (ACTH) (either eutopically or ectopically), cortisol, or very rarely corticotropin-releasing hormone (CRH). Definitive therapy of endogenous CS optimally involves tumor resection. Indications for medical therapy include acutely ill patients in preparation for surgery, those for whom surgery is not indicated (such as patients with unknown tumor location or unresectable lesions, and patients unfit for surgery for medical reasons), or patients who remain hypercortisolemic postoperatively. In the current article, the published literature has been reviewed to summarize data on medical therapies used in CS. Several agents are either used "off label" or being studied as potential therapies for CS. Medications suppressing adrenal steroidogenesis currently in use include ketoconazole, metyrapone, mitotane, or etomidate. In addition, the investigational agent LCI699 is under study. Centrally acting agents, which suppress ACTH secretion, include cabergoline, octreotide, as well as the investigational agents pasireotide, bexarotene, and lapatinib, which are being studied in patients with pituitary tumors. Mifepristone, a type 2 glucocorticoid receptor antagonist, was recently approved by the FDA as a new therapy for CS. Although not definitive at present, medical therapies have an important role in the management of CS patients. It is anticipated that understanding the pathogenesis of these tumors at a molecular level may spawn the development of rationally designed, highly efficacious medical therapies for CS in the future.


Manson J.E.,Harvard University
Metabolism: Clinical and Experimental | Year: 2013

Menopausal estrogen therapy has a complex balance of benefits and risks and is no longer routinely recommended for the majority of women during or after the transition to menopause. Recent findings from the Women's Health Initiative (WHI) and other studies suggest that a woman's clinical and biological characteristics may modify her health outcomes on hormone therapy (HT) and that some women may be more appropriate candidates for therapy than others. An emerging body of evidence suggests that it may be possible to identify women who are more likely to have favorable outcomes and less likely to have adverse events on HT, as well as to tailor the optimal dose, formulation, and route of delivery of treatment, by the use of individual risk stratification and a personalized approach. Several clinical characteristics that have been proposed for this purpose include a woman's age, time since menopause, symptom severity, baseline vascular health, risk for breast cancer, biomarker levels, and genetic predisposition. The underlying rationale for personalized medicine, that each person has a unique biologic profile that can help to guide the choice of therapy, applies well to HT decision making and holds promise for improved treatment efficacy and safety. This report, which focuses on vascular health, reviews the evidence on the role of such markers in tailoring the use of hormone therapy to appropriate candidates, with the ultimate goal of developing a personalized risk:benefit prediction model that takes into account clinical and genetic factors, patient-centered outcomes including sense of well being and quality of life, and other variables. The proposed personalized approach to HT decision making has the potential to improve the quality of health care.


Haigis K.M.,Harvard University | Sweet-Cordero A.,Stanford University
Nature Genetics | Year: 2011

Expression of oncogenes in otherwise normal cells often leads to the activation of anti-oncogenic pathways through a poorly understood process described as 'oncogenic stress'. A new study implicates the Jnk pathway signaling in the activation of p53 in response to both K-Ras and Neu oncogene expression. © 2011 Nature America, Inc. All rights reserved.


Hemoglobin A1c (HbA1c), a time-integrated marker of glycemic control, predicts risk of coronary heart disease (CHD) among diabetics. Few studies have examined HbA1c and risk of CHD among women and men without clinically elevated levels or previously diagnosed diabetes. We conducted parallel nested case-control studies among women (Nurses' Health Study) and men (Health Professionals Follow-up Study). During 14 and 10 years of follow-up, 468 women and 454 men developed incident nonfatal myocardial infarction (MI) and fatal CHD. Controls were matched 2:1 based on age, smoking, and date of blood draw. For these analyses, participants with a history of diabetes or HbA1c levels ≥6.5% at baseline were excluded. Compared with HbA1c of 5.0% to <5.5%, those with an HbA1c of 6.0% to <6.5% had a multivariable-adjusted relative risk (RR) of CHD of 1.90 (95% CI 1.11 to 3.25) in women and 1.81 (95% CI 1.09 to 3.03) in men. The pooled RR of CHD was 1.29 (95% CI 1.11 to 1.50) for every 0.5%-increment increase in HbA1c levels and 1.67 (95% CI 1.23 to 2.25) for every 1%-increment increase, with the risk plateauing around 5.0%. Furthermore, participants with HbA1c levels between 6.0% and <6.5% and C-reactive protein levels >3.0 mg/L had a 2.5-fold higher risk of CHD compared with participants in the lowest categories of both biomarkers. Our findings suggest that HbA1c is associated with CHD risk among apparently healthy, nondiabetic women and men and may be an important early clinical marker of disease risk.


Baehring J.M.,Yale University | Batchelor T.T.,Harvard University
Cancer Journal (United States) | Year: 2012

Invasion of cranial nerves and peripheral nerve roots, plexus, or nerves by non-Hodgkin lymphoma is denoted as neurolymphomatosis (NL). Four clinical patterns are recognized. Most commonly, NL presents as a painful polyneuropathy or polyradiculopathy, followed by cranial neuropathy, painless polyneuropathy, and peripheral mononeuropathy. Diagnosis of NL is challenging and requires integration of clinical information, imaging findings, and histopathologic examination of involved nerves or nonneural tissue and cerebrospinal fluid analysis. In the rare cases of primary NL, the diagnosis is often delayed. Successful therapy is contingent upon recognition of the disease and its exact neuroanatomic localization without delay. Treatment options include systemic chemotherapy and localized irradiation of bulky disease sites. Concomitant involvement of cerebrospinal fluid and systemic disease sites requires more complex regimens. © 2012 by Lippincott Williams & Wilkins.


Sajjad A.,Harvard University
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2016

We conduct a model-independent effective theory analysis of hypercharged fields with various spin structures towards understanding the diboson excess found in LHC run I, as well as possible future anomalies involving WZ and WH modes. Within the assumption of no additional physics beyond the standard model up to the scale of the possible diboson resonance, we show that a hypercharged scalar and a spin 2 particle do not have tree-level WZ and WH decay channels up to dimension 5 operators, and cannot therefore account for the anomaly, whereas a hypercharged vector is a viable candidate provided we also introduce a Z′ in order to satisfy electroweak precision constraints. We calculate bounds on the Z′ mass consistent with the ATLAS/CMS diboson signals as well as electroweak precision data, taking into account both LHC run I and II data. © 2016 American Physical Society.


Kagan J.C.,Harvard University
Trends in Immunology | Year: 2012

Innate immune activation by microbial detection receptors is a complex process involving at least 100 proteins and multiple signaling pathways. Although there continues to be a need to identify additional regulators of host-microbe interactions, a larger conceptual challenge is our lack of understanding of how the known regulators interact in space and time. This review offers a framework to explain the long appreciated (but poorly understood) observation that innate immune signaling pathways are activated from multiple organelles. Using the Toll-like receptors (TLRs) and the retinoic acid-inducible gene 1 protein (RIG-I)-like receptors (RLRs) as examples, I propose that the receptors do not necessarily define the sites of signaling. Rather, a structurally unrelated class of proteins called 'sorting adaptors' functions in this capacity. © 2012 Elsevier Ltd.


Kupper T.S.,Harvard University
Journal of Investigative Dermatology | Year: 2012

Memory is the hallmark of the adaptive immune system, and the observation that infectious diseases often lead to lifelong immunity in individuals who survive a first infection became the genesis for the development of vaccines. Immunization, which is the iatrogenic engineering of a protective memory immune response to a pathogen, became a standard part of medical care in the twentieth century, and has had an almost incalculable positive effect on human health and wellness. Vaccines to many, but by no means all, infectious diseases have been developed and are in common use. Smallpox vaccine, arguably the most effective vaccine in human history, was (and still is) delivered through disrupted epidermis in a process called scarification. Virtually all vaccines today are delivered by means of a hypodermic needle and syringe into muscle, in a process that bypasses the epidermis and dermis and their attendant innate and adaptive immune attributes. This article discusses vaccines in the context of the newly appreciated paradigm of tissue-resident memory T cells, and specifically discusses the role of these cells in skin and other epithelial interfaces with the environment in the maintenance of protective immunity. © 2012 The Society for Investigative Dermatology.


Swearingen B.,Harvard University
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Transsphenoidal surgeryhasanimportantrole inthemanagementof pituitarytumorsandremainsthe primary treatment for most adenomas, with the exception of prolactinomas. This update will review the recent neurosurgical literature; modifications to the traditional microscopic approach, including the potential utility of endoscopy and intraoperative magnetic resonance imaging, are discussed. The value of experienced surgical judgment and expertise remains clear, over and above the possible advantages of current technology. Preliminary dataonthe relative cost-effectiveness of surgery vs. medical treatment suggest that surgical approaches compare favorably. It will be important to incorporate future technological advances in surgical technique with new medical therapies in a combined multidisciplinary approach for improved treatment algorithms. Copyright © 2012 by The Endocrine Society.


Brooks A.W.,Harvard University
Journal of Experimental Psychology: General | Year: 2014

Individuals often feel anxious in anticipation of tasks such as speaking in public or meeting with a boss. I find that an overwhelming majority of people believe trying to calm down is the best way to cope with pre-performance anxiety. However, across several studies involving karaoke singing, public speaking, and math performance, I investigate an alternative strategy: reappraising anxiety as excitement. Compared with those who attempt to calm down, individuals who reappraise their anxious arousal as excitement feel more excited and perform better. Individuals can reappraise anxiety as excitement using minimal strategies such as self-talk (e.g., saying "I am excited" out loud) or simple messages (e.g., "get excited"), which lead them to feel more excited, adopt an opportunity mind-set (as opposed to a threat mind-set), and improve their subsequent performance. These findings suggest the importance of arousal congruency during the emotional reappraisal process. © 2013 American Psychological Association.


Mendoza M.C.,Harvard University
Seminars in Cell and Developmental Biology | Year: 2013

The WAVE2 regulatory complex (WRC) induces actin polymerization by activating the actin nucleator Arp2/3. Polymerizing actin pushes against the cell membrane and induces dramatic edge protrusions. In order to properly control such changes in cell morphology and function, cells have evolved multiple methods to tightly regulate WRC and Arp2/3 activity in space and time. Of these mechanisms, phosphorylation plays a fundamental role in transmitting extracellular and intracellular signals to the WRC and the actin cytoskeleton. This review discusses the phosphorylation-based regulatory inputs into the WRC. Signaling pathways that respond to growth factors, chemokines, hormones, and extracellular matrix converge upon the WAVE and ABI components of the WRC. The Abl, Src, ERK, and PKA kinases promote complex activation through a WRC conformation change that permits interaction with the Arp2/3 complex and through WRC translocation to the cell edge. The neuron-specific CDK5 and constitutively active CK2 kinases inhibit WRC activation. These regulatory signals are integrated in space and time as they coalesce upon the WRC. The combination of WRC phosphorylation events and WRC activity is controlled by stimulus, cell type, and cell cycle-specific pathway activation and via pathway cross-inhibition and cross-activation. © 2013 Elsevier Ltd.


Alam H.B.,Harvard University
British Journal of Surgery | Year: 2012

Background: Hypothermia is commonly used for organ and tissue preservation in multiple clinical settings, but its role in the management of injured patients remains controversial. There is no doubt that temperature modulation is a powerful tool, and hypothermia has been shown to protect cells during ischaemia and reperfusion, decrease organ damage and improve survival. Yet hypothermia is a double-edged sword: unless carefully managed, its induction can be associated with a number of complications. Methods: A literature review was performed to include important papers that address the impact of hypothermia on key biological processes, and explore the potential therapeutic role of hypothermia in trauma/haemorrhage models. Results: No clinical studies have been conducted to test the therapeutic benefits of hypothermia in injured patients. However, numerous well designed animal studies support this concept. Despite excellent preclinical data, there are several potential barriers to translating hypothermia into clinical practice. Conclusion: Therapeutic hypothermia is a promising life-saving strategy. Appropriate patient selection requires a thorough understanding of how temperature modulation affects various biological mechanisms. Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.


Cell migration, phagocytosis and cytokinesis are mechanically intensive cellular processes that are mediated by the dynamic assembly and contractility of the actin cytoskeleton. GAPs (GTPase-activating proteins) control activities of the Rho family proteins including Cdc42, Rac1 and RhoA, which are prominent upstream regulators of the actin cytoskeleton. The present review concerns a class of Rho GAPs, FilGAP (ARHGAP24 gene product) and its close relatives (ARHGAP22 and AHRGAP25 gene products). FilGAP is a GAP for Rac1 and a binding partner of FLNa (filamin A), a widely expressed F-actin (filamentous actin)-cross-linking protein that binds many different proteins that are important in cell regulation. Phosphorylation of FilGAP serine/threonine residues and binding to FLNa modulate FilGAP's GAP activity and, as a result, its ability to regulate cell protrusion and spreading. FLNa binds to FilGAP at F-actin-enriched sites, such as at the leading edge of the cell where Rac1 activity is controlled to inhibit actin assembly. FilGAP then dissociates from FLNa in actin networks by myosin-dependent mechanical deformation of FLNa's FilGAP-binding site to relocate at the plasma membrane by binding to polyphosphoinositides. Since actomyosin contraction is activated downstream of RhoA-ROCK (Rho-kinase), RhoA activity regulates Rac1 through FilGAP by signalling to the force-generating system. FilGAP and the ARHGAP22 gene product also act as mediators between RhoA and Rac1 pathways, which lead to amoeboid and mesenchymal modes of cell movements respectively. Therefore FilGAP and its close relatives are key regulators that promote the reciprocal inhibitory relationship between RhoA and Rac1 in cell shape changes and the mesenchymal-amoeboid transition in tumour cells. © The Authors Journal compilation © 2013 Biochemical Society.


Sau J.D.,Harvard University | Sarma S.D.,University of Maryland University College
Nature Communications | Year: 2012

Semiconducting nanowires in proximity to superconductors are promising experimental systems for realizing the elusive Majorana fermions, which, because of their non-Abelian anyonic braiding statistics, may ultimately be used as building blocks for topological quantum computers. A serious challenge in the experimental realization of the Majorana fermions is the suppression of topological superconductivity by disorder together with the tunability of carrier density for semiconductors in close proximity to superconductors. Here we show that Majorana fermions that are protected by a disorder robust topological gap can occur at the ends of a chain of gate-tunable quantum dots connected by s-wave superconductors. Such an array of quantum dots provides the simplest realization of Majorana fermions in systems as simple as a few quantum dot array. The proposed system provides a very practical and easily realizable experimental platform for the observation of non-Abelian Majorana modes. © 2012 Macmillan Publishers Limited. All rights reserved.