Cambridge, MA, United States
Cambridge, MA, United States

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.

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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.

Boudsocq M.,French National Institute for Agricultural Research | Sheen J.,Harvard University
Trends in Plant Science | Year: 2013

Ca2+ has long been recognized as a conserved second messenger and principal mediator in plant immune and stress responses. How Ca2+ signals are sensed and relayed into diverse primary and global signaling events is still largely unknown. Comprehensive analyses of the plant-specific multigene family of Ca2+-dependent protein kinases (CDPKs) are unraveling the molecular, cellular and genetic mechanisms of Ca2+ signaling. CDPKs, which exhibit overlapping and distinct expression patterns, sub-cellular localizations, substrate specificities and Ca2+ sensitivities, play versatile roles in the activation and repression of enzymes, channels and transcription factors. Here, we review the recent advances on the multifaceted functions of CDPKs in the complex immune and stress signaling networks, including oxidative burst, stomatal movements, hormonal signaling and gene regulation. © 2012 Elsevier Ltd.

Patra K.C.,Harvard University | Hay N.,University of Illinois at Chicago | Hay N.,Jesse Brown Medical Center
Trends in Biochemical Sciences | Year: 2014

The pentose phosphate pathway (PPP), which branches from glycolysis at the first committed step of glucose metabolism, is required for the synthesis of ribonucleotides and is a major source of NADPH. NADPH is required for and consumed during fatty acid synthesis and the scavenging of reactive oxygen species (ROS). Therefore, the PPP plays a pivotal role in helping glycolytic cancer cells to meet their anabolic demands and combat oxidative stress. Recently, several neoplastic lesions were shown to have evolved to facilitate the flux of glucose into the PPP. This review summarizes the fundamental functions of the PPP, its regulation in cancer cells, and its importance in cancer cell metabolism and survival. © 2014 Elsevier Ltd.

Mayadas T.N.,Harvard University | Cullere X.,Harvard University | Lowell C.A.,University of California at San Francisco
Annual Review of Pathology: Mechanisms of Disease | Year: 2014

Neutrophils and neutrophil-like cells are the major pathogen-fighting immune cells in organisms ranging from slime molds to mammals. Central to their function is their ability to be recruited to sites of infection, to recognize and phagocytose microbes, and then to kill pathogens through a combination of cytotoxic mechanisms. These include the production of reactive oxygen species, the release of antimicrobial peptides, and the recently discovered expulsion of their nuclear contents to form neutrophil extracellular traps. Here we discuss these primordial neutrophil functions, which also play key roles in tissue injury, by providing details of neutrophil cytotoxic functions and congenital disorders of neutrophils. In addition, we present more recent evidence that interactions between neutrophils and adaptive immune cells establish a feed-forward mechanism that amplifies pathologic inflammation. These newly appreciated contributions of neutrophils are described in the setting of several inflammatory and autoimmune diseases. © 2014 by Annual Reviews. 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.

Farrell J.A.,Harvard University | O'Farrell P.H.,University of California at San Francisco
Annual Review of Genetics | Year: 2014

Many, if not most, embryos begin development with extremely short cell cycles that exhibit unusually rapid DNA replication and no gap phases. The commitment to the cell cycle in the early embryo appears to preclude many other cellular processes that only emerge as the cell cycle slows just prior to gastrulation at a major embryonic transition known as the mid-blastula transition (MBT). As reviewed here, genetic and molecular studies in Drosophila have identified changes that extend S phase and introduce a postreplicative gap phase, G2, to slow the cell cycle. Although many mysteries remain about the upstream regulators of these changes, we review the core mechanisms of the change in cell cycle regulation and discuss advances in our understanding of how these might be timed and triggered. Finally, we consider how the elements of this program may be conserved or changed in other organisms. © 2014 by Annual Reviews. All rights reserved.

Weinberger A.D.,Harvard University | Weinberger L.S.,Gladstone | Weinberger L.S.,University of California at San Francisco
Cell | Year: 2013

Classic studies proposed that stochastic variability ("noise") can drive biological fate switching, enhancing evolutionary success. Now, Ho et al. report that HIV's reactivation from dormant (latently infected) patient cells - the major barrier to an HIV cure - is inherently stochastic. Eradicating an incompletely inducible (probabilistic) viral phenotype will require inventive approaches. © 2013 Elsevier Inc.

Yao Y.,Harvard University | Hoffman A.J.,University of Notre Dame | Gmachl C.F.,Princeton University
Nature Photonics | Year: 2012

Mid-infrared quantum cascade lasers are semiconductor injection lasers whose active core implements a multiple-quantum-well structure. Relying on a designed staircase of intersubband transitions allows free choice of emission wavelength and, in contrast with diode lasers, a low transparency point that is similar to a classical, atomic four-level laser system. In recent years, this design flexibility has expanded the achievable wavelength range of quantum cascade lasers to ∼3-25 μm and the terahertz regime, and provided exemplary improvements in overall performance. Quantum cascade lasers are rapidly becoming practical mid-infrared sources for a variety of applications such as trace-chemical sensing, health monitoring and infrared countermeasures. In this Review we focus on the two major areas of recent improvement: power and power efficiency, and spectral performance. © 2012 Macmillan Publishers Limited. All rights reserved.

Hata A.,University of California at San Francisco | Lieberman J.,Harvard University
Science Signaling | Year: 2015

MicroRNAs (miRNAs) are small noncoding RNAs that suppress the abundance of partially complementary mRNAs and inhibit their translation. Each miRNA can regulate hundreds ofmRNAs, sometimes strongly but often weakly, to mediate a diverse array of biological functions, including proliferation, cell signaling, differentiation, stress responses and DNA repair, cell adhesion and motility, inflammation, cell survival, senescence, and apoptosis, all intimately related to cancer initiation, treatment response, and metastasis. The expression and activity of miRNAs are spatially and temporally controlled. Global miRNA expression is reduced in many cancers. In addition, the expression and processing of cancer-related miRNAs that act as oncogenes ("oncomiRs") or tumor suppressors are often dysregulated in cancer. In this review, we summarize emerging knowledge about how miRNA biogenesis and gene silencing are altered to promote cancer.

Demetrius L.A.,Harvard University | Demetrius L.A.,Max Planck Institute for Molecular Genetics
Physics Reports | Year: 2013

Boltzmann's statistical thermodynamics is a mathematical theory which relates the macroscopic properties of aggregates of interacting molecules with the laws of their interaction. The theory is based on the concept thermodynamic entropy, a statistical measure of the extent to which energy is spread throughout macroscopic matter. Macroscopic evolution of material aggregates is quantitatively explained in terms of the principle: Thermodynamic entropy increases as the composition of the aggregate changes under molecular collision.Darwin's theory of evolution is a qualitative theory of the origin of species and the adaptation of populations to their environment. A central concept in the theory is fitness, a qualitative measure of the capacity of an organism to contribute to the ancestry of future generations. Macroscopic evolution of populations of living organisms can be qualitatively explained in terms of a neo-Darwinian principle: Fitness increases as the composition of the population changes under variation and natural selection.Directionality theory is a quantitative model of the Darwinian argument of evolution by variation and selection. This mathematical theory is based on the concept evolutionary entropy, a statistical measure which describes the rate at which an organism appropriates energy from the environment and reinvests this energy into survivorship and reproduction. According to directionality theory, microevolutionary dynamics, that is evolution by mutation and natural selection, can be quantitatively explained in terms of a directionality principle: Evolutionary entropy increases when the resources are diverse and of constant abundance; but decreases when the resource is singular and of variable abundance.This report reviews the analytical and empirical support for directionality theory, and invokes the microevolutionary dynamics of variation and selection to delineate the principles which govern macroevolutionary dynamics of speciation and extinction. We also elucidate the relation between thermodynamic entropy, which pertains to the extent of energy spreading and sharing within inanimate matter, and evolutionary entropy, which refers to the rate of energy appropriation from the environment and allocation within living systems. We show that the entropic principle of thermodynamics is the limit as R→. 0, M→. ∞, (where R denote the resource production rate, and M denote population size) of the entropic principle of evolution.We exploit this relation between the thermodynamic and evolutionary tenets to propose a physico-chemical model of the transition from inanimate matter which is under thermodynamic selection, to living systems which are subject to evolutionary selection. © 2013 Elsevier B.V.

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.

Bettigole S.E.,New York Medical College | Bettigole S.E.,Harvard University | Glimcher L.H.,New York Medical College
Annual Review of Immunology | Year: 2015

Immune responses occur in the midst of a variety of cellular stresses that can severely perturb endoplasmic reticulum (ER) function. The unfolded protein response is a three-pronged signaling axis dedicated to preserving ER homeostasis. In this review, we highlight many important and emerging functional roles for ER stress in immunity, focusing on how the bidirectional cross talk between immunological processes and basic cell biology leads to pleiotropic signaling outcomes and enhanced sensitivity to inflammatory stimuli. We also discuss how dysregulated ER stress responses can provoke many diseases, including autoimmunity, firmly positioning the unfolded protein response as a major therapeutic target in human disease. © 2015 by Annual Reviews. All rights reserved.

Carmeliet P.,Vesalius Research Center | Jain R.K.,Harvard University
Nature Reviews Drug Discovery | Year: 2011

Despite having an abundant number of vessels, tumours are usually hypoxic and nutrient-deprived because their vessels malfunction. Such abnormal milieu can fuel disease progression and resistance to treatment. Traditional anti-angiogenesis strategies attempt to reduce the tumour vascular supply, but their success is restricted by insufficient efficacy or development of resistance. Preclinical and initial clinical evidence reveal that normalization of the vascular abnormalities is emerging as a complementary therapeutic paradigm for cancer and other vascular disorders, which affect more than half a billion people worldwide. Here, we discuss the mechanisms, benefits, limitations and possible clinical translation of vessel normalization for cancer and other angiogenic disorders. © 2011 Macmillan Publishers Limited. All rights reserved.

Napetschnig J.,New York Medical College | Wu H.,New York Medical College | Wu H.,Harvard University
Annual Review of Biophysics | Year: 2013

NF-κB (nuclear factor kappa B) family transcription factors are master regulators of immune and lammatory processes in response to both injury and ection. In the latent state, NF-κBs are sequestered in the cytosol by their inhibitor IκB (inhibitor of NF-κB) proteins. Upon stimulations of innate immune receptors such as Toll-like receptors and cytokine receptors such as those in the TNF (tumor necrosis factor) receptor erfamily, a series of membrane proximal events lead to the activation of the IKK (IκB kinase). Phosphorylation of IκBs results in their proteasomal degradation and the release of NF-κB for nuclear translocation and activation of gene transcription. Here, we review the plethora of structural studies in these NF-κB activation pathways, including the TRAF (TNF receptor-associated factor) proteins, IKK, NF-κB, ubiquitin ligases, and deubiquitinating enzymes. Although these structures only provide snapshots of isolated processes, an emerging picture is that these signaling cascades coalesce into large oligomeric signaling complexes, or signalosomes, for signal propagation. Copyright © 2013 by Annual Reviews.

Gino F.,Harvard University | Mogilner C.,University of Pennsylvania
Psychological Science | Year: 2014

Money, a resource that absorbs much daily attention, seems to be involved in much unethical behavior, which suggests that money itself may corrupt. This research examined a way to offset such potentially deleterious effects-by focusing on time, a resource that tends to receive less attention than money but is equally ubiquitous in daily life. Across four experiments, we examined whether shifting focus onto time can salvage individuals' ethicality. We found that implicitly activating the construct of time, rather than money, leads individuals to behave more ethically by cheating less. We further found that priming time reduces cheating by making people reflect on who they are. Implications for the use of time primes in discouraging dishonesty are discussed. © The Author(s) 2013.

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.

Kamisawa T.,Tokyo Metropolitan Komagome Hospital | Zen Y.,Kobe University | Pillai S.,Harvard University | Stone J.H.,Harvard University
The Lancet | Year: 2015

IgG4-related disease is a protean condition that mimics many malignant, infectious, and inflammatory disorders. This multi-organ immune-mediated condition links many disorders previously regarded as isolated, single-organ diseases without any known underlying systemic condition. It was recognised as a unified entity only 10 years ago. Histopathology is the key to diagnosis. The three central pathology features of IgG4-related disease are lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. The extent of fibrosis is an important determinant of responsiveness to immunosuppressive therapies. IgG4-related disease generally responds to glucocorticoids in its inflammatory stage, but recurrent or refractory cases are common. Important mechanistic insights have been derived from studies of patients treated by B-cell depletion. Greater awareness of this disease is needed to ensure earlier diagnoses, which can prevent severe organ damage, disabling tissue fibrosis, and even death. Identification of specific antigens and T-cell clones that drive the disease will be the first steps to elucidate the pathogenesis of IgG4-related disease.

Xu J.,Harvard University | Smale S.T.,University of California at Los Angeles
Cell | Year: 2012

In this issue and in a recent issue of Cell, Vahedi et al. and Samstein et al. provide new insights into the strategies used to establish an enhancer landscape during development of cell lineages. They report that enhancer landscapes characterizing T cell lineages are pre-established and strongly influenced by environmental stimuli. © 2012 Elsevier Inc.

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.

Fehon R.G.,University of Chicago | McClatchey A.I.,Harvard University | Bretscher A.,Cornell University
Nature Reviews Molecular Cell Biology | Year: 2010

Specialized membrane domains are an important feature of almost all cells. In particular, they are essential to tissues that have a highly organized cell cortex, such as the intestinal brush border epithelium. The ERM proteins (ezrin, radixin and moesin) have a crucial role in organizing membrane domains through their ability to interact with transmembrane proteins and the cytoskeleton. In doing so, they can provide structural links to strengthen the cell cortex and regulate the activities of signal transduction pathways. Recent studies examining the structure and in vivo functions of ERMs have greatly advanced our understanding of the importance of membrane-cytoskeleton interactions. © 2010 Macmillan Publishers Limited. All rights reserved.

Kosuri S.,University of California at Los Angeles | Church G.M.,Wyss Institute for Biologically Inspired Engineering | Church G.M.,Harvard University
Nature Methods | Year: 2014

For over 60 years, the synthetic production of new DNA sequences has helped researchers understand and engineer biology. Here we summarize methods and caveats for the de novo synthesis of DNA, with particular emphasis on recent technologies that allow for large-scale and low-cost production. In addition, we discuss emerging applications enabled by large-scale de novo DNA constructs, as well as the challenges and opportunities that lie ahead. © 2014 Nature America, Inc.

Jiang J.,University of California at Los Angeles | Pentelute B.L.,Massachusetts Institute of Technology | Collier R.J.,Harvard University | Hong Zhou Z.,University of California at Los Angeles
Nature | Year: 2015

Anthrax toxin, comprising protective antigen, lethal factor, and oedema factor, is the major virulence factor of Bacillus anthracis, an agent that causes high mortality in humans and animals. Protective antigen forms oligomeric prepores that undergo conversion to membrane-spanning pores by endosomal acidification, and these pores translocate the enzymes lethal factor and oedema factor into the cytosol of target cells. Protective antigen is not only a vaccine component and therapeutic target for anthrax infections but also an excellent model system for understanding the mechanism of protein translocation. On the basis of biochemical and electrophysiological results, researchers have proposed that a phi (Î ▪)-clamp composed of phenylalanine (Phe)427 residues of protective antigen catalyses protein translocation via a charge-state-dependent Brownian ratchet. Although atomic structures of protective antigen prepores are available, how protective antigen senses low pH, converts to active pore, and translocates lethal factor and oedema factor are not well defined without an atomic model of its pore. Here, by cryo-electron microscopy with direct electron counting, we determine the protective antigen pore structure at 2.9-Å resolution. The structure reveals the long-sought-after catalytic Î ▪-clamp and the membrane-spanning translocation channel, and supports the Brownian ratchet model for protein translocation. Comparisons of four structures reveal conformational changes in prepore to pore conversion that support a multi-step mechanism by which low pH is sensed and the membrane-spanning channel is formed. © 2015 Macmillan Publishers Limited. All rights reserved.

Parson E.A.,University of California at Los Angeles | Keith D.W.,Harvard University
Science | Year: 2013

Can scientific self-regulation control small-scale research, or is governmental regulation needed?

Agency: GTR | Branch: EPSRC | Program: | Phase: Research Grant | Award Amount: 432.76K | Year: 2014

The connectome, the comprehensive map of neural connections in the human brain, is unique in every individual. Even identical twins differ at the level of neural connectivity. Mapping the human connectome and its variability across individuals is essential in getting insight into the unknown cognitive aspects of brain function, but also into identifying dysfunctional features of the diseased brain. For these reasons, understanding the human brain, its organisation and ultimately its function, is amongst the key scientific challenges of the 21st century. Magnetic resonance imaging (MRI) has revolutionised neuroscience by uniquely allowing both brain anatomy and function to be probed in living humans. Even if MRI allows only macroscopic features to be recovered (at the level of relatively large tissue regions, rather than individual neuronal cells), its non-invasive and in-vivo application has opened tremendous possibilities for brain research. Diffusion-weighted MRI (dMRI) is a particular modality that uniquely allows the mapping of fibre bundles, the underlying connection pathways that mediate information flow between different brain regions. The connection mapping is performed indirectly by processing dMRI images via computational algorithms referred to as tractography. Tractography has already provided fundamental new insights into brain anatomy. The importance of brain connectivity to our understanding of the brain along, with the great potential revealed by tractography algorithms have led to large initiatives from both sides of the Atlantic. These utilise dMRI to collect state-of-the-art datasets of the healthy adult and the developing brain and map the structural connectome through tractography. They include the $30M NIH Human Connectome Project, the 15M Euros ERC Developing Human Connectome Project and the £30M UK funded Biobank Imaging. However, without state-of-the-art analysis methods, and new ways of analysing dMRI data, researchers will fai to get the most out of this vast wealth of upcoming data. In this project, we propose new frameworks for tractography methods centred on neuroanatomy. We particularly focus on problems arising from ambiguous mapping of complex geometries (which are very common in the brain) to the dMRI measurements. These pose significant limits to the accuracy of existing approaches. We propose wholesale changes through computational and algorithmic solutions that will allow connections to be measured in-vivo with unprecedented detail, whole brain organization to be studied at a much finer scale and anatomical features -invisible to existing techniques- to be revealed. These advances will open new possibilities for neuroanatomical studies, but also set the foundations for new basic research in MRI processing and connectivity mapping. We will illustrate their potential using compelling demonstrator applications from basic and clinical neuroscience, including the assessment of benefits from using the new technology in assisting neurosurgical planning.

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.

Hensch T.K.,Harvard University | Hensch T.K.,Boston Childrens Hospital
Cell | Year: 2014

Experience shapes brain function throughout life to varying degrees. In a recent issue of Nature, Donato et al. identify reversible shifts in focal parvalbumin cell state during adult learning, placing it on a mechanistic continuum with developmental critical periods. A disinhibitory microcircuit controls the plasticity switch to modulate memory formation. © 2014 Elsevier Inc.

Rogers K.W.,Harvard University | Schier A.F.,Harvard University | Schier A.F.,Harvard Stem Cell Institute
Annual Review of Cell and Developmental Biology | Year: 2011

Morphogens are long-range signaling molecules that pattern developing tissues in a concentration-dependent manner. The graded activity of morphogens within tissues exposes cells to different signal levels and leads to region-specific transcriptional responses and cell fates. In its simplest incarnation, a morphogen signal forms a gradient by diffusion from a local source and clearance in surrounding tissues. Responding cells often transduce morphogen levels in a linear fashion, which results in the graded activation of transcriptional effectors. The concentration-dependent expression of morphogen target genes is achieved by their different binding affinities for transcriptional effectors as well as inputs from other transcriptional regulators. Morphogen distribution and interpretation are the result of complex interactions between the morphogen and responding tissues. The response to a morphogen is dependent not simply on morphogen concentration but also on the duration of morphogen exposure and the state of the target cells. In this review, we describe the morphogen concept and discuss the mechanisms that underlie the generation, modulation, and interpretation of morphogen gradients. © 2011 by Annual Reviews. All rights reserved.

Stuckey D.W.,Harvard University | Shah K.,Harvard University | Shah K.,Harvard Stem Cell Institute
Nature Reviews Cancer | Year: 2014

Stem cell-based therapies are emerging as a promising strategy to tackle cancer. Multiple stem cell types have been shown to exhibit inherent tropism towards tumours. Moreover, when engineered to express therapeutic agents, these pathotropic delivery vehicles can effectively target sites of malignancy. This perspective considers the current status of stem cell-based treatments for cancer and provides a rationale for translating the most promising preclinical studies into the clinic. © 2014 Macmillan Publishers Limited. All rights reserved.

Lipton J.O.,Boston Childrens Hospital | Lipton J.O.,Harvard University | Sahin M.,Boston Childrens Hospital
Neuron | Year: 2014

The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders. The mTOR signaling pathway, which regulates protein synthesis and cell growth, is crucial for the normal development and function of the nervous system. Lipton and Sahin review the contributions of this pathway to neurological disorders including tuberous sclerosis, autism, epilepsy, and neurodegenerative diseases. © 2014 Elsevier Inc.

Goldhaber S.Z.,Harvard University | Bounameaux H.,University of Geneva
The Lancet | Year: 2012

Pulmonary embolism is the third most common cause of death from cardiovascular disease after heart attack and stroke. Sequelae occurring after venous thrombo embolism include chronic thromboembolic pulmonary hypertension and post-thrombotic syndrome. Venous thromboembolism and atherothrombosis share common risk factors and the common pathophysiological characteristics of inflammation, hypercoagulability, and endothelial injury. Clinical probability assessment helps to identify patients with low clinical probability for whom the diagnosis of venous thromboembolism can be excluded solely with a negative result from a plasma D-dimer test. The diagnosis is usually confirmed with compression ultrasound showing deep vein thrombosis or with chest CT showing pulmonary embolism. Most patients with venous thromboembolism will respond to anticoagulation, which is the foundation of treatment. Patients with pulmonary embolism should undergo risk stratification to establish whether they will benefit from the addition of advanced treatment, such as thrombolysis or embolectomy. Several novel oral anticoagulant drugs are in development. These drugs, which could replace vitamin K antagonists and heparins in many patients, are prescribed in fixed doses and do not need any coagulation monitoring in the laboratory. Although rigorous clinical trials have reported the effectiveness and safety of pharmacological prevention with low, fixed doses of anticoagulant drugs, prophylaxis remains underused in patients admitted to hospital at moderate risk and high risk for venous thromboembolism. In this Seminar, we discuss pulmonary embolism and deep vein thrombosis of the legs.

Kourembanas S.,Boston Childrens Hospital | Kourembanas S.,Harvard University
Annual Review of Physiology | Year: 2015

Mesenchymal stem cells (MSCs), whose mechanism of action is predominantly paracrine, are being widely tested for the treatment of a variety of human diseases. No one factor has been proven sufficient to mediate the therapeutic effects of MSCs. However, exosomes-membrane vesicles secreted by many cells, including MSCs-are appealing candidates as vectors of their efficacy. Exosomes can transport and deliver a large cargo of proteins, lipids, and nucleic acids and can modify cell and organ function. In addition to their key role as vehicles of intercellular communication, exosomes are increasingly recognized as biomarkers and prognosticators of disease. Moreover, they have the potential to be used as vehicles of gene and drug delivery for clinical application. This article reviews the biogenesis of exosomes, their molecular composition, and their role as messengers of intercellular communication, focusing on their potential as therapeutic vectors for stem cell therapy. Copyright © 2015 by Annual Reviews. All rights reserved.

Springer T.A.,Boston Childrens Hospital | Springer T.A.,Harvard University
Blood | Year: 2014

When blood vessels are cut, the forces in the bloodstream increase and change character. The dark side of these forces causes hemorrhage and death. However, von Willebrand factor (VWF), with help from our circulatory system and platelets, harnesses the same forces to form a hemostatic plug. Force and VWF function are so closely intertwined that, like members of the Jedi Order in the movie Star Wars who learn to use "the Force" to do good, VWF may be considered the Jedi knight of the bloodstream. The long length of VWF enables responsiveness to flow. The shape of VWF is predicted to alter from irregularly coiled to extended threadlike in the transition from shear to elongational flow at sites of hemostasis and thrombosis. Elongational force propagated through the length of VWF in its thread-like shape exposes its monomers for multimeric binding to platelets and subendothelium and likely also increases affinity of the A1 domain for platelets. Specialized domains concatenate and compact VWF during biosynthesis. A2 domain unfolding by hydrodynamic force enables postsecretion regulatio nof VWF length. Mutations in VWF in von Willebrand disease contribute to and are illuminated byVWFbiology. I attempt to integrate classic studies on the physiology of hemostatic plug formation intomodernmolecularunderstanding, and point out what remains to be learned. © 2014 by The American Society of Hematology.

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.

Sale S.,Harvard University | Lafkas D.,University Pierre and Marie Curie | Artavanis-Tsakonas S.,Harvard University
Nature Cell Biology | Year: 2013

Notch signalling is implicated in stem and progenitor cell fate control in numerous organs. Using conditional in vivo genetic labelling we traced the fate of cells expressing the Notch2 receptor paralogue and uncovered the existence of two previously unrecognized mammary epithelial cell lineages that we term S (Small) and L (Large). S cells appear in a bead-on-a-string formation and are embedded between the luminal and basal/myoepithelial layers in a unique reiterative pattern, whereas single or paired L cells appear among ductal and alveolar cells. Long-term lineage tracing and functional studies indicate that S and L cells regulate ipsi- and contralateral spatial placement of tertiary branches and formation of alveolar clusters. Our findings revise present models of mammary epithelial cell hierarchy, reveal a hitherto undescribed mechanism regulating branching morphogenesis and may have important implications for identification of the cell-of-origin of distinct breast cancer subtypes. © 2013 Macmillan Publishers Limited. All rights reserved.

Van Tyne D.,Massachusetts Eye and Ear Infirmary | Gilmore M.S.,Harvard University
Annual Review of Microbiology | Year: 2014

The enterococci are an ancient genus that evolved along with the tree of life. These intrinsically rugged bacteria are highly adapted members of the intestinal consortia of a range of hosts that spans the animal kingdom. Enterococci are also leading opportunistic hospital pathogens, causing infections that are often resistant to treatment with most antibiotics. Despite the importance of enterococci as hospital pathogens, the vast majority live outside of humans, and nearly all of their evolutionary history took place before the appearance of modern humans. Because hospital infections represent evolutionary end points, traits that exacerbate human infection are unlikely to have evolved for that purpose. However, clusters of traits have converged in specific lineages that are well adapted to colonize the antibiotic-perturbed gastrointestinal tracts of patients and that thrive in the hospital environment. Here we discuss these traits in an evolutionary context, as well as how comparative genomics is providing new insights into the evolution of the enterococci. Copyright © 2014 by Annual Reviews. All rights reserved.

Hsu V.W.,Harvard University | Prekeris R.,University of Colorado at Denver
Current Opinion in Cell Biology | Year: 2010

The recycling endosome (RE) has long been considered as a sub-compartment of the early endosome that recycles internalized cargoes to the plasma membrane. The RE is now appreciated to participate in a more complex set of intracellular itineraries. Key cargo molecules and transport factors that act in these pathways are being identified. These advancements are beginning to reveal complexities in pathways involving the RE, and also suggest ways of further delineating functional domains of this compartment. © 2010 Elsevier Ltd.

Dibble C.C.,Beth Israel Deaconess Medical Center | Dibble C.C.,Harvard University | Manning B.D.,Harvard University
Nature Cell Biology | Year: 2013

Flux through metabolic pathways is inherently sensitive to the levels of specific substrates and products, but cellular metabolism is also managed by integrated control mechanisms that sense the nutrient and energy status of a cell or organism. The mechanistic target of rapamycin complex 1 (mTORC1), a protein kinase complex ubiquitous to eukaryotic cells, has emerged as a critical signalling node that links nutrient sensing to the coordinated regulation of cellular metabolism. Here, we discuss the role of mTORC1 as a conduit between cellular growth conditions and the anabolic processes that promote cell growth. The emerging network of signalling pathways through which mTORC1 integrates systemic signals (secreted growth factors) with local signals (cellular nutrients-amino acids, glucose and oxygen-and energy, ATP) is detailed. Our expanding understanding of the regulatory network upstream of mTORC1 provides molecular insights into the integrated sensing mechanisms by which diverse cellular signals converge to control cell physiology. © 2013 Macmillan Publishers Limited. All rights reserved.

Rosen E.D.,Beth Israel Deaconess Medical Center | Rosen E.D.,Harvard University | Rosen E.D.,The Broad Institute of MIT and Harvard | Spiegelman B.M.,Harvard University | Spiegelman B.M.,Dana-Farber Cancer Institute
Cell | Year: 2014

There has been an upsurge of interest in the adipocyte coincident with the onset of the obesity epidemic and the realization that adipose tissue plays a major role in the regulation of metabolic function. The past few years, in particular, have seen significant changes in the way that we classify adipocytes and how we view adipose development and differentiation. We have new perspective on the roles played by adipocytes in a variety of homeostatic processes and on the mechanisms used by adipocytes to communicate with other tissues. Finally, there has been significant progress in understanding how these relationships are altered during metabolic disease and how they might be manipulated to restore metabolic health. © 2014 Elsevier Inc.

Mitchell S.L.,Beth Israel Deaconess Medical Center | Mitchell S.L.,Harvard University
New England Journal of Medicine | Year: 2015

An 89-year-old male nursing home resident with a 10-year history of Alzheimer's disease presents with a temperature of 38.3° C, a productive cough, and a respiratory rate of 28 breaths per minute. Nurses report that for the past 6 months he has been coughing at breakfast and having trouble swallowing. He has profound memory deficits, no longer recognizes his daughter (who is his health care proxy), is bedbound, is able to mumble a couple of words, and is unable to perform any activities of daily living. The nurse asks whether he should be hospitalized. How should this patient be evaluated and treated? Copyright © 2015 Massachusetts Medical Society.

Marcantonio E.R.,Beth Israel Deaconess Medical Center | Marcantonio E.R.,Harvard University
JAMA - Journal of the American Medical Association | Year: 2012

Delirium (acute confusion) complicates 15% to 50% of major operations in older adults and is associated with other major postoperative complications, prolonged length of stay, poor functional recovery, institutionalization, dementia, and death. Importantly, delirium may be predictable and preventable through proactive intervention. Yet clinicians fail to recognize and address postoperative delirium in up to 80%of cases. Using the case of MsR, a 76-year-old woman who developed delirium first after colectomy with complications and again after routine surgery, the diagnosis, prevention, and treatment of delirium in the postoperative setting is reviewed. The risk of postoperative delirium can be quantified by the sum of predisposing and precipitating factors. Successful strategies for prevention and treatment of delirium include proactive multifactorial intervention targeted to reversible risk factors, limiting use of sedating medications (especially benzodiazepines), effective management of postoperative pain, and, perhaps, judicious use of antipsychotics. ©2012 American Medical Association. All rights reserved.

Cheifetz A.S.,Beth Israel Deaconess Medical Center | Cheifetz A.S.,Harvard University
JAMA - Journal of the American Medical Association | Year: 2013

Importance: Treatment of Crohn disease is rapidly evolving, with the induction of novel biologic therapies and newer, often more intensive treatment approaches. Knowing how to treat individual patients in this quickly changing milieu can be a challenge. Objective: To review the diagnosis and management of moderate to severe Crohn disease, with a focus on newer treatments and goals of care. Evidence Review: MEDLINE was searched from 2000 to 2011. Additional citations were procured from references of select research and review articles. Evidence was graded using the American Heart Association level-of-evidence guidelines. Results: Although mesalamines are still often used to treat Crohn disease, the evidence for their efficacy is lacking. Corticosteroids can be effectively used to induce remission in moderate to severe Crohn disease, but they do not maintain remission. The mainstays of treatment are immunomodulators and biologics, particularly anti-tumor necrosis factor. Conclusion and Relevance: Immunomodulators and biologics are now the preferred treatment options for Crohn disease. ©2013 American Medical Association. All rights reserved.

Hayes J.H.,Dana-Farber Cancer Institute | Barry M.J.,Harvard University
JAMA - Journal of the American Medical Association | Year: 2014

IMPORTANCE: Prostate cancer screening with the prostate-specific antigen (PSA) test remains controversial. OBJECTIVE: To review evidence from randomized trials and related modeling studies examining the effect of PSA screening vs no screening on prostate cancer-specific mortality and to suggest an approach balancing potential benefits and harms. EVIDENCE ACQUISITION: MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials were searched from January 1, 2010, to April 3, 2013, for PSA screening trials to update a previous systematic review. Another search was performed in EMBASE and MEDLINE to identify modeling studies extending the results of the 2 large randomized trials identified. The American Heart Association Evidence-Based Scoring System was used to rate level of evidence. RESULTS: Two trials - the Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC) - dominate the evidence regarding PSA screening. The former trial demonstrated an increase in cancer incidence in the screening group (relative risk [RR], 1.12; 95% CI, 1.07-1.17) but no cancer-specific mortality benefit to PSA screening after 13-year follow-up (RR, 1.09; 95% CI, 0.87-1.36). The ERSPC demonstrated an increase in cancer incidence with screening (RR, 1.63; 95% CI, 1.57-1.69) and an improvement in the risk of prostate cancer-specific death after 11 years (RR, 0.79; 95% CI, 0.68-0.91). The ERSPC documented that 37 additional men needed to receive a diagnosis through screening for every 1 fewer prostate cancer death after 11 years of follow-up among men aged 55 to 69 years (level B evidence for prostate cancer mortality reduction). Harms associated with screening include false-positive results and complications of biopsy and treatment. Modeling studies suggest that this high ratio of additional men receiving diagnoses to prostate cancer deaths prevented will decrease during a longer follow-up (level B evidence). CONCLUSIONS AND RELEVANCE: Available evidence favors clinician discussion of the pros and cons of PSA screening with average-risk men aged 55 to 69 years. Only men who express a definite preference for screening should have PSA testing. Other strategies to mitigate the potential harms of screening include considering biennial screening, a higher PSA threshold for biopsy, and conservative therapy for men receiving a new diagnosis of prostate cancer. Copyright 2014 American Medical Association. All rights reserved.

Peteet J.R.,Dana-Farber Cancer Institute | Peteet J.R.,Harvard University | Balboni M.J.,Dana-Farber Cancer Institute
CA Cancer Journal for Clinicians | Year: 2013

Despite the difficulty in clearly defining and measuring spirituality, a growing literature describes its importance in oncology and survivorship. Religious/spiritual beliefs influence patients' decision-making with respect to both complementary therapies and aggressive care at the end of life. Measures of spirituality and spiritual well-being correlate with quality of life in cancer patients, cancer survivors, and caregivers. Spiritual needs, reflective of existential concerns in several domains, are a source of significant distress, and care for these needs has been correlated with better psychological and spiritual adjustment as well as with less aggressive care at the end of life. Studies show that while clinicians such as nurses and physicians regard some spiritual care as an appropriate aspect of their role, patients report that they provide it infrequently. Many clinicians report that their religious/spiritual beliefs influence their practice, and practices such as mindfulness have been shown to enhance clinician self-care and equanimity. Challenges remain in the areas of conceptualizing and measuring spirituality, developing and implementing training for spiritual care, and coordinating and partnering with chaplains and religious communities. © 2013 American Cancer Society, Inc.

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.

Feinberg E.H.,Harvard University | Meister M.,Harvard University | Meister M.,California Institute of Technology
Nature | Year: 2015

More than twenty types of retinal ganglion cells conduct visual information from the eye to the rest of the brain. Each retinal ganglion cell type tessellates the retina in a regular mosaic, so that every point in visual space is processed for visual primitives such as contrast and motion. This information flows to two principal brain centres: the visual cortex and the superior colliculus. The superior colliculus plays an evolutionarily conserved role in visual behaviours, but its functional architecture is poorly understood. Here we report on population recordings of visual responses from neurons in the mouse superior colliculus. Many neurons respond preferentially to lines of a certain orientation or movement axis. We show that cells with similar orientation preferences form large patches that span the vertical thickness of the retinorecipient layers. This organization is strikingly different from the randomly interspersed orientation preferences in the mouse's visual cortex; instead, it resembles the orientation columns observed in the visual cortices of large mammals. Notably, adjacent superior colliculus orientation columns have only limited receptive field overlap. This is in contrast to the organization of visual cortex, where each point in the visual field activates neurons with all preferred orientations. Instead, the superior colliculus favours specific contour orientations within ∼30regions of the visual field, a finding with implications for behavioural responses mediated by this brain centre. © 2015, Macmillan Publishers Limited. All rights reserved.

D'Andrea A.D.,Dana-Farber Cancer Institute | D'Andrea A.D.,Harvard University
New England Journal of Medicine | Year: 2010

Fanconi's anemia is a rare disorder that arises from defective repair of damaged DNA. Of the 13 Fanconi's anemia genes, 3 are breast cancer- susceptibility genes. One is identical to BRCA2. Cells from patients with the D1 subtype of Fanconi's anemia and their family members carry biallelic mutations in BRCA2, and heterozygote members of kindreds with the D1 subtype have an increased risk of breast and ovarian cancer. Studies of a rare disorder can thus illuminate a common disorder. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

Pietrobon D.,University of Padua | Pietrobon D.,CNR Institute of Neuroscience | Moskowitz M.A.,Harvard University
Annual Review of Physiology | Year: 2013

Migraine is a collection of perplexing neurological conditions in which the brain and its associated tissues have been implicated as major players during an attack. Once considered exclusively a disorder of blood vessels, compelling evidence has led to the realization that migraine represents a highly choreographed interaction between major inputs from both the peripheral and central nervous systems, with the trigeminovascular system and the cerebral cortex among the main players. Advances in in vivo and in vitro technologies have informed us about the significance to migraine of events such as cortical spreading depression and activation of the trigeminovascular system and its constituent neuropeptides, as well as about the importance of neuronal and glial ion channels and transporters that contribute to the putative cortical excitatory/inhibitory imbalance that renders migraineurs susceptible to an attack. This review focuses on emerging concepts that drive the science of migraine in both a mechanistic direction and a therapeutic direction. Copyright © 2013 by Annual Reviews. All rights reserved.

Hagan C.L.,Harvard University | Silhavy T.J.,Princeton University | Kahne D.,Harvard University
Annual Review of Biochemistry | Year: 2011

β-barrel membrane proteins perform important functions in the outer membranes (OMs) of Gram-negative bacteria and of the mitochondria and chloroplasts of eukaryotes. The protein complexes that assemble these proteins in their respective membranes have been identified and shown to contain a component that has been conserved from bacteria to humans. βα-barrel proteins are handled differently from α-helical membrane proteins in the cell in order to efficiently transport them to their final locations in unfolded but folding-competent states. The mechanism by which the assembly complex then binds, folds, and inserts β-barrels into the membrane is not well understood, but recent structural, biochemical, and genetic studies have begun to elucidate elements of how the complex provides a facilitated pathway for β-barrel assembly. Ultimately, studies of the mechanism of β-barrel assembly and comparison to the better-understood process of αÎ ±-helical membrane protein assembly will reveal whether there are general principles that guide the folding and insertion of all membrane proteins. © 2011 by Annual Reviews. All rights reserved.

Joesch M.,Harvard University | Meister M.,California Institute of Technology
Nature | Year: 2016

In bright light, cone-photoreceptors are active and colour vision derives from a comparison of signals in cones with different visual pigments. This comparison begins in the retina, where certain retinal ganglion cells have 'colour-opponent' visual responses-excited by light of one colour and suppressed by another colour. In dim light, rod-photoreceptors are active, but colour vision is impossible because they all use the same visual pigment. Instead, the rod signals are thought to splice into retinal circuits at various points, in synergy with the cone signals. Here we report a new circuit for colour vision that challenges these expectations. A genetically identified type of mouse retinal ganglion cell called JAMB (J-RGC), was found to have colour-opponent responses, OFF to ultraviolet (UV) light and ON to green light. Although the mouse retina contains a green-sensitive cone, the ON response instead originates in rods. Rods and cones both contribute to the response over several decades of light intensity. Remarkably, the rod signal in this circuit is antagonistic to that from cones. For rodents, this UV-green channel may play a role in social communication, as suggested by spectral measurements from the environment. In the human retina, all of the components for this circuit exist as well, and its function can explain certain experiences of colour in dim lights, such as a 'blue shift' in twilight. The discovery of this genetically defined pathway will enable new targeted studies of colour processing in the brain. © 2016 Macmillan Publishers Limited.

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.

Goss P.E.,Harvard University | Chambers A.F.,University of Western Ontario
Nature Reviews Cancer | Year: 2010

The increasing number of cancer survivors is cause for celebration, but this expanding population has highlighted the problem of tumour dormancy, which can lead to relapse. As we start to understand more about the biology of dormant cancer cells, we can begin to address how best to treat this form of disease. Preclinical models and initial clinical trials, as exemplified in patients with breast cancer, are paving the way to address how best to treat long-term cancer survivors to minimize the risk of cancer recurrence. © 2010 Macmillan Publishers Limited. All rights reserved.

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.

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.

Hayes J.,St James's 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.

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.

Hsu P.D.,The Broad Institute of MIT and Harvard | Hsu P.D.,Massachusetts Institute of Technology | Hsu P.D.,Harvard University | Lander E.S.,The Broad Institute of MIT and Harvard | And 2 more authors.
Cell | Year: 2014

Recent advances in genome engineering technologies based on the CRISPR-associated RNA-guided endonuclease Cas9 are enabling the systematic interrogation of mammalian genome function. Analogous to the search function in modern word processors, Cas9 can be guided to specific locations within complex genomes by a short RNA search string. Using this system, DNA sequences within the endogenous genome and their functional outputs are now easily edited or modulated in virtually any organism of choice. Cas9-mediated genetic perturbation is simple and scalable, empowering researchers to elucidate the functional organization of the genome at the systems level and establish causal linkages between genetic variations and biological phenotypes. In this Review, we describe the development and applications of Cas9 for a variety of research or translational applications while highlighting challenges as well as future directions. Derived from a remarkable microbial defense system, Cas9 is driving innovative applications from basic biology to biotechnology and medicine. © 2014 Elsevier Inc.

Baron R.,Harvard University | Kneissel M.,Novartis
Nature Medicine | Year: 2013

Low bone mass and strength lead to fragility fractures, for example, in elderly individuals affected by osteoporosis or children with osteogenesis imperfecta. A decade ago, rare human mutations affecting bone negatively (osteoporosis-pseudoglioma syndrome) or positively (high-bone mass phenotype, sclerosteosis and Van Buchem disease) have been identified and found to all reside in components of the canonical WNT signaling machinery. Mouse genetics confirmed the importance of canonical Wnt signaling in the regulation of bone homeostasis, with activation of the pathway leading to increased, and inhibition leading to decreased, bone mass and strength. The importance of WNT signaling for bone has also been highlighted since then in the general population in numerous genome-wide association studies. The pathway is now the target for therapeutic intervention to restore bone strength in millions of patients at risk for fracture. This paper reviews our current understanding of the mechanisms by which WNT signalng regulates bone homeostasis. © 2013 Nature America, Inc. All rights reserved.

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.

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.

Li E.,Novartis | Zhang Y.,Harvard University
Cold Spring Harbor Perspectives in Biology | Year: 2014

DNA methylation is one of the best characterized epigenetic modifications. In mammals it is involved in various biological processes including the silencing of transposable elements, regulation of gene expression, genomic imprinting, and X-chromosome inactivation. This article describes how DNA methylation serves as a cellular memory system and how it is dynamically regulated through the action of the DNA methyltransferase (DNMT) and ten eleven translocation (TET) enzymes. Its role in the regulation of gene expression, through its interplay with histone modifications, is also described, and its implication in human diseases discussed. The exciting areas of investigation that will likely become the focus of research in the coming years are outlined in the summary. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.

Kouchaki M.,Harvard University | Smith I.H.,University of Utah
Psychological Science | Year: 2014

Are people more moral in the morning than in the afternoon? We propose that the normal, unremarkable experiences associated with everyday living can deplete one's capacity to resist moral temptations. In a series of four experiments, both undergraduate students and a sample of U.S. adults engaged in less unethical behavior (e.g., less lying and cheating) on tasks performed in the morning than on the same tasks performed in the afternoon. This morning morality effect was mediated by decreases in moral awareness and self-control in the afternoon. Furthermore, the effect of time of day on unethical behavior was found to be stronger for people with a lower propensity to morally disengage. These findings highlight a simple yet pervasive factor (i.e., the time of day) that has important implications for moral behavior. © The Author(s) 2013.

Carroll M.,Harvard University | Isenman D.,University of Toronto
Immunity | Year: 2012

The complement system of innate immunity is important in regulating humoral immunity largely through the complement receptor CR2, which forms a coreceptor on B cells during antigen-induced activation. However, CR2 also retains antigens on follicular dendritic cells (FDCs). Display of antigen on FDCs is critical for clonal selection and affinity maturation of activated B cells. This review will discuss the role of complement in adaptive immunity in general with a focus on the interplay between CR2-associated antigen on B cells with CR2 expressed on FDCs. This latter interaction provides an opportunity for memory B cells to sample antigen over prolonged periods. The cocrystal structure of CR2 with its ligand C3d provides insight into how the complement system regulates access of antigen by B cells with implications for therapeutic manipulations to modulate aberrant B cell responses in the case of autoimmunity. © 2012 Elsevier Inc.

Dwivedi N.,Harvard University | Radic M.,University of Tennessee Health Science Center
Annals of the Rheumatic Diseases | Year: 2014

Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins thus are crucial questions for understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death called NETosis deserves attention because it requires the post-translational modification of histones and results in the extracellular release of chromatin. NETosis received its name from NET, the acronym given to Neutrophil Extracellular Trap. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4). The deiminated chromatin may function to capture or 'trap' bacterial pathogens, thus generating an extracellular complex of deiminated histones and bacterial cell adjuvants. The complex of bacterial antigens and deiminated chromatin may be internalised by host phagocytes during acute inflammatory conditions, as arise during bacterial infections or chronic autoinflammatory disorders. The uptake and processing of deiminated chromatin together with bacterial adjuvants by phagocytes may induce the presentation of modified histone epitopes and co-stimulation, thus yielding a powerful stimulus to break tolerance. Autoantibodies to deiminated histones are prevalent in Felty's syndrome patients and are present in systemic lupus erythematosus (SLE) and patients with rheumatoid arthritis (RA). These observations clearly implicate histone deimination as an epigenetic mark that can act as an autoantibody stimulant.

Cook N.R.,Harvard University | Appel L.J.,Welch Center for Prevention | Whelton P.K.,Tulane University
Circulation | Year: 2014

BACKGROUND-: Recent studies have raised the possibility of adverse effects of low sodium, particularly <2300 mg/d, on cardiovascular disease; however, these paradoxical findings might have resulted from suboptimal measurement of sodium and potential biases related to indication or reverse causation. METHODS AND RESULTS-: Phases 1 and 2 of the Trials of Hypertension Prevention (TOHP) collected multiple 24-hour urine specimens among prehypertensive individuals. During extended posttrial surveillance, 193 cardiovascular events or cardiovascular disease deaths occurred among 2275 participants not in a sodium reduction intervention with 10 (TOHP II) or 15 (TOHP I) years of posttrial follow-up. Median sodium excretion was 3630 mg/d, with 1.4% of the participants having intake <1500 mg/d and 10% <2300 mg/d, consistent with national levels. Compared with those with sodium excretion of 3600 to <4800 mg/d, risk for those with sodium <2300 mg/d was 32% lower after multivariable adjustment (hazard ratio, 0.68; 95% confidence interval, 0.34-1.37; P for trend=0.13). There was a linear 17% increase in risk per 1000 mg/d increase in sodium (P=0.05). Spline curves supported a linear association of sodium with cardiovascular events, which continued to decrease from 3600 to 2300 and 1500 mg/d, although the data were sparse at the lowest levels. Controlling for creatinine levels had little effect on these results. CONCLUSIONS-: Results from the TOHP studies, which overcome the major methodological challenges of prior studies, are consistent with overall health benefits of reducing sodium intake to the 1500 to 2300 mg/d range in the majority of the population, in agreement with current dietary guidelines. © 2014 American Heart Association, Inc.

Wolfe B.E.,Tufts University | Dutton R.J.,Harvard University
Cell | Year: 2015

Microbial communities of fermented foods have provided humans with tools for preservation and flavor development for thousands of years. These simple, reproducible, accessible, culturable, and easy-to-manipulate systems also provide opportunities for dissecting the mechanisms of microbial community formation. Fermented foods can be valuable models for processes in less tractable microbiota. ©2015 Elsevier Inc.

Arteaga C.L.,Vanderbilt University | Engelman J.A.,Harvard University
Cancer Cell | Year: 2014

ERBB receptors were linked to human cancer pathogenesis approximately three decades ago. Biomedical investigators have since developed substantial understanding of the biology underlying the dependence of cancers on aberrant ERBB receptor signaling. An array of cancer-associated genetic alterations in ERBB receptors has also been identified. These findings have led to the discovery and development of mechanism-based therapies targeting ERBB receptors that have improved outcome for many cancer patients. In this Perspective, we discuss current paradigms of targeting ERBB receptors with cancer therapeutics and our understanding of mechanisms of action and resistance to these drugs. As current strategies still have limitations, we also discuss challenges and opportunities that lie ahead as basic scientists and clinical investigators work toward more breakthroughs. © 2014 Elsevier Inc.

Meroz Y.,Harvard University | Sokolov I.M.,Humboldt University of Berlin
Physics Reports | Year: 2015

Subdiffusive processes have become a field of great interest in the last decades, due to amounting experimental evidence of subdiffusive behavior in complex systems, and especially in biological systems. Different physical scenarios leading to subdiffusion differ in the details of the dynamics. These differences are what allow to theoretically reconstruct the underlying physics from the results of observations, and will be the topic of this review. We review the main statistical analyses available today to distinguish between these scenarios, categorizing them according to the relevant characteristics. We collect the available tools and statistical tests, presenting them within a broader perspective. We also consider possible complications such as the subordination of subdiffusive mechanisms. Due to the advances in single particle tracking experiments in recent years, we focus on the relevant case of where the available experimental data is scant, at the level of single trajectories. © 2015 Elsevier B.V.

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