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News Article | May 15, 2017
Site: www.prnewswire.com

Although immune system activation by viruses has long been linked to cognitive problems, the underlying mechanisms have been poorly understood. In the new report, researchers found that virus-associated immune activation causes a loss of connections between nerve cells within brain circuits in the cortex, the brain region responsible for learning. Such mice then do worse on established tests of learning ability. The observed changes in nerve connections were triggered, not in the brain, but out in the body (the periphery) where viral infection first makes contact with CX3CR1highLY6Clow monocytes in the bloodstream, say the authors. "This study in animals resonates with what we see in the clinic, where patients with acute or chronic infectious diseases often have weaker performance on motor skills and experience memory decline," says Guang Yang, PhD, assistant professor in the Department of Anesthesiology, Perioperative Care, and Pain Medicine at NYU Langone. "Our results suggest that existing anti-inflammatory treatments that target TNFα may protect against brain dysfunction during peripheral infection." The study results revolve around dendrites, which are offshoots of nerve cells that pick up electrical signals from the previous cell in a nerve pathway and pass it along. Nerve networks form memories by changing the physical wiring of dendrite branches (spines) to increase the strength of connections (synapses). Previous studies have shown that motor skill learning causes an increase in dendritic spine formation in the motor cortex, and that the extent of new spine formation correlates with the animals' performance improvement as it learns. In the current study, experiments found that, once exposed to a mimic (mimetic) of viral infection called poly(I:C), mice eliminated more than twice the percentage of dendritic spines as did mice whose immune systems were not activated, suggesting the disruption of synaptic networks. Furthermore, in mice being trained to run on a rotating rod, which requires muscle coordination (motor) learning, those exposed to poly(I:C) formed significantly fewer dendritic spines. Researchers also measured the levels of pro-inflammatory signaling proteins (cytokines) in mice at several time points after the injection of poly(I:C), and found a larger, longer-lasting increase in levels of TNFα than in other cytokines. Given their findings, the team guessed that the impact of systemic immune response on brain cell connections was executed through TNFα signaling.  Indeed, mice engineered to lack TNFα signals in white blood cells saw neither a drop in dendritic spine formation nor in motor learning ability when exposed to the viral mimetic. Moving forward, Guang and colleagues will be looking for drugs or treatments that specifically target CX3CR1highLY6Clow monocytes to see it they can prevent "undesirable signals to the brain after viral infection." They may also study whether or not existing anti-TNF drugs, such as infliximab, which is used to treat rheumatoid arthritis, could be used to prevent virus-driven cognitive disturbance. Along with Yang, NYU Langone study authors were Juan Mauricio Garré, Hernandez Moura-Silva, and Juan Lafaille in Departments of Anesthesiology, Pathology and Medicine, and in the Skirball Institute of Biomolecular Medicine. This work was supported by a Whitehall Foundation Research Grant, and by National Institutes of Health grants R01 GM107469 and R21 AG048410. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/certain-immune-reactions-to-viruses-cause-learning-problems-300457523.html


News Article | November 14, 2016
Site: www.eurekalert.org

In living beings, from roundworms to humans, some cells may ball up unwanted contents on their surfaces for other cells to "eat." This is the finding of a study led by researchers at NYU Langone Medical Center and published online November 14 in Nature Cell Biology. The results raise the possibility that cellular cannibalism may be more widespread than once thought, and may even shed light on certain brain disorders. The work was done in the worm species C. elegans, which is famous for its role in past discoveries of vital mechanisms also at work in human cells. Specifically, the study found that, as an embryo develops into a worm, cells that pass on genes to the next generation (primordial germ cells or PGCs) form outer lobes, or "balls," that are digested by nearby cells that form the worm's gut. By forming lobes destined to be clipped off and digested, germ cells may be discarding large amounts of material that would otherwise interfere with reproduction, say the study authors. "These findings define a new way in which cells dramatically change their contents via cannibalism, and, in doing so, may reveal a new set of genetic causes for diseases when this mechanism goes awry," says Jeremy Nance, PhD, associate professor in the Department of Cell Biology at NYU Langone. The study poses the question of whether this ability to quickly edit cell contents is vital to the function of many cell types in many organisms, including humans. A 2012 paper led by a separate research team, for instance, proposed that immune cells in the brain prune nerve connections by "eating" bulbs on nearby nerve cell extensions to edit brain circuitry. Some experts have asked whether some forms of autism may be caused by faulty cellular cannibalism. If these mechanisms exist, how widespread are they? In worms, as in humans, certain cells in a portion of the embryo, called the endoderm, migrate and become the cells that form the gut. In both species, cells that go on to form the sexual organs, and the cells that will become sperm and eggs, migrate alongside pre-gut cells to end up in their final location at the bottom of the gut. It was while studying this partnership between co-migrating cell types that the research team first observed one cell type eating part of another. Researchers also found that the lobes put forth for removal by PGCs contained large numbers of mitochondria, the cell powerhouses that convert blood sugar into molecules that serve as cellular energy currency. One theory for why this occurs is that mitochondria, as a side effect of making energy, also produce highly-reactive free radicals that can damage DNA in a process called oxidative stress. This is a problem for any cell, but more so for the gamete or germ cell, which carries the copy of genetic information that will serve as the template for the offspring. Any random change there could have devastating consequences, not just for one cell, but for future generations. The study results raise the question of whether germ cells trade lower energy production, by getting rid of mitochondria via cell cannibalism, for greater DNA protection. Researchers will also seek to determine if genetic risk for some forms of sterility proceeds from the failure of cannibalistic mechanisms to protect gametes from oxidative stress. Specifically, the research team found that lobe cannibalism is carefully choreographed by biochemical signals, with all lobes forming during the same developmental time window and bitten off in a set order. Furthermore, progenitor gamete cells in worms always form lobes full of mitochondria, but the lobes are only cut off if partnering endodermal cells are present. Moving forward, the research team will seek to identify the signals by which PGC lobes embed specifically into endodermal cells, and those that tell endodermal cells to eat lobes. The work may also help the field to determine whether similar cellular remodeling events shape brain circuitry, say the authors. Along with Nance, study authors were Yusuff Abdu and Chelsea Maniscalco in the Skirball Institute of Biomolecular Medicine, along with John Heddleston and Teng-Leong Chew from the Advanced Imaging Center at the Howard Hughes Medical Institute in Ashburn, Virginia. The study was funded by grants from the National Institutes of Health, and sequencing of genomic DNA samples was performed at the NYULMC Genome Technology Center, which is partially supported by a grant (P30CA016087) from the Perlmutter Cancer Center.


Ye J.,University of Pennsylvania | Kumanova M.,University of Pennsylvania | Hart L.S.,University of Pennsylvania | Sloane K.,University of Pennsylvania | And 6 more authors.
EMBO Journal | Year: 2010

The transcription factor ATF4 regulates the expression of genes involved in amino acid metabolism, redox homeostasis and ER stress responses, and it is overexpressed in human solid tumours, suggesting that it has an important function in tumour progression. Here, we report that inhibition of ATF4 expression blocked proliferation and survival of transformed cells, despite an initial activation of cytoprotective macroautophagy. Knockdown of ATF4 significantly reduced the levels of asparagine synthetase (ASNS) and overexpression of ASNS or supplementation of asparagine in trans, reversed the proliferation block and increased survival in ATF4 knockdown cells. Both amino acid and glucose deprivation, stresses found in solid tumours, activated the upstream eukaryotic initiation factor 2α (eIF2α) kinase GCN2 to upregulate ATF4 target genes involved in amino acid synthesis and transport. GCN2 activation/overexpression and increased phospho-eIF2α were observed in human and mouse tumours compared with normal tissues and abrogation of ATF4 or GCN2 expression significantly inhibited tumour growth in vivo. We conclude that the GCN2-eIF2α-ATF4 pathway is critical for maintaining metabolic homeostasis in tumour cells, making it a novel and attractive target for anti-tumour approaches. © 2010 European Molecular Biology Organization.


Christie D.A.,University of Western Ontario | Kirchhof M.G.,University of Western Ontario | Vardhana S.,Skirball Institute of Biomolecular Medicine | Dustin M.L.,Skirball Institute of Biomolecular Medicine | And 2 more authors.
PLoS ONE | Year: 2012

Stomatin-like protein 2 (SLP-2) is a member of the stomatin - prohibitin - flotillin - HflC/K (SPFH) superfamily. Recent evidence indicates that SLP-2 is involved in the organization of cardiolipin-enriched microdomains in mitochondrial membranes and the regulation of mitochondrial biogenesis and function. In T cells, this role translates into enhanced T cell activation. Although the major pool of SLP-2 is associated with mitochondria, we show here that there is an additional pool of SLP-2 associated with the plasma membrane of T cells. Both plasma membrane-associated and mitochondria-associated pools of SLP-2 coalesce at the immunological synapse (IS) upon T cell activation. SLP-2 is not required for formation of IS nor for the re-localization of mitochondria to the IS because SLP-2-deficient T cells showed normal re-localization of these organelles in response to T cell activation. Interestingly, upon T cell activation, we found the surface pool of SLP-2 mostly excluded from the central supramolecular activation complex, and enriched in the peripheral area of the IS where signalling TCR microclusters are located. Based on these results, we propose that SLP-2 facilitates the compartmentalization not only of mitochondrial membranes but also of the plasma membrane into functional microdomains. In this latter location, SLP-2 may facilitate the optimal assembly of TCR signalosome components. Our data also suggest that there may be a net exchange of membrane material between mitochondria and plasma membrane, explaining the presence of some mitochondrial proteins in the plasma membrane. © 2012 Christie et al.


Mulligan C.,U.S. National Institutes of Health | Fitzgerald G.A.,U.S. National Institutes of Health | Wang D.-N.,Skirball Institute of Biomolecular Medicine | Wang D.-N.,New York University | Mindell J.A.,U.S. National Institutes of Health
Journal of General Physiology | Year: 2014

The SLC13 transporter family, whose members play key physiological roles in the regulation of fatty acid synthesis, adiposity, insulin resistance, and other processes, catalyzes the transport of Krebs cycle intermediates and sulfate across the plasma membrane of mammalian cells. SLC13 transporters are part of the divalent anion:Na+ symporter (DASS) family that includes several well-characterized bacterial members. Despite sharing significant sequence similarity, the functional characteristics of DASS family members differ with regard to their substrate and coupling ion dependence. The publication of a high resolution structure of dimer VcINDY, a bacterial DASS family member, provides crucial structural insight into this transporter family. However, marrying this structural insight to the current functional understanding of this family also demands a comprehensive analysis of the transporter's functional properties. To this end, we purified VcINDY, reconstituted it into liposomes, and determined its basic functional characteristics. Our data demonstrate that VcINDY is a high affinity, Na+-dependent transporter with a preference for C4- and C5-dicarboxylates. Transport of the model substrate, succinate, is highly pH dependent, consistent with VcINDY strongly preferring the substrate's dianionic form. VcINDY transport is electrogenic with succinate coupled to the transport of three or more Na+ ions. In contrast to succinate, citrate, bound in the VcINDY crystal structure (in an inward-facing conformation), seems to interact only weakly with the transporter in vitro. These transport properties together provide a functional framework for future experimental and computational examinations of the VcINDY transport mechanism.


Zito E.,Skirball Institute of Biomolecular Medicine | Chin K.-T.,Skirball Institute of Biomolecular Medicine | Blais J.,Skirball Institute of Biomolecular Medicine | Harding H.P.,Skirball Institute of Biomolecular Medicine | And 2 more authors.
Journal of Cell Biology | Year: 2010

Mammals have two genes encoding homologues of the endoplasmic reticulum (ER) disulfide oxidase ERO1 (ER oxidoreductin 1). ERO1-β is greatly enriched in the endocrine pancreas. We report in this study that homozygosity for a disrupting allele of Ero1lb selectively compromises oxidative folding of proinsulin and promotes glucose intolerance in mutant mice. Surprisingly, concomitant disruption of Ero1l, encoding the other ERO1 isoform, ERO1-α, does not exacerbate the ERO1-β deficiency phenotype. Although immunoglobulinproducing cells normally express both isoforms of ERO1, disulfide bond formation and immunoglobulin secretion proceed at nearly normal pace in the double mutant. Moreover, although the more reducing environment of their ER protects cultured ERO1-β knockdown Min6 cells from the toxicity of a misfolding-prone mutant Ins2Akita, the diabetic phenotype and islet destruction promoted by Ins2Akita are enhanced in ERO1-β compound mutant mice. These findings point to an unexpectedly selective function for ERO1-β in oxidative protein folding in insulinproducing cells that is required for glucose homeostasis in vivo. © 2010 Zito et al.


News Article | October 31, 2016
Site: www.eurekalert.org

The brain's interpretation of sound is influenced by cues from other senses, explaining more precisely how we interpret what we hear at a particular moment, according to a report published in Nature Neuroscience online Oct. 31. In the new study in mice, researchers at NYU Langone Medical Center found that nerve cells dedicated to hearing also rely on surrounding context to properly interpret and react to familiar sounds. "What the brain 'hears' depends on what is 'seen' in addition to specific sounds, as the brain calculates how to respond," says study senior investigator and neuroscientist Robert Froemke, PhD, an assistant professor at NYU Langone and its Skirball Institute of Biomolecular Medicine. Froemke says his team's latest findings reveal that while mammals recognize sounds in the auditory cortex of their brains, the signaling levels of nerve cells in this brain region are simultaneously being strengthened or weakened in response to surrounding context. "Our study shows how the same sound can mean different things inside the brain depending on the situation," says Froemke. "We know, for instance, that people learn to respond without alarm to the honk of a car horn if heard from the safety of their homes, but are startled to hear the same honk while crossing a busy street." If further experiments find similar activity in human brains, the researchers say their work may lead to precise explanations of situation-specific behaviors, such as anxiety brought on during math exams; sudden post-traumatic stress among combat veterans hearing a car backfire; and the ability of people with dementia to better remember certain events when they hear a familiar voice or see a friend's face. To map how the same sense can be perceived differently in the brain, the NYU Langone team, led by postdoctoral fellow Kishore Kuchibhotla, PhD, monitored nerve circuit activity in mice when the animals expected, and did not expect, to get a water reward through a straw-like tube (that they see) after the ringing of a familiar musical note. When mice were exposed to specific auditory cues, researchers observed patterns based on a basic divide in the nature of nerve cells. Each nerve cell "decides" whether a message travels onward in a nerve pathway. Nerve cells that emit chemicals which tell the next cell in line to amplify a message are excitatory; those that stop messages are inhibitory. Combinations of the two strike a counterbalance critical to the function of the nervous system, with inhibitory cells sculpting "noise" from excitatory cells into the arrangements behind thought and memory. Furthermore, the processing of incoming sensory information is achieved in part by adjusting signaling levels through each type of nerve cell. Theories hold that the brain may attach more importance to a given signal by turning up or down excitatory signals, or by doing the same with inhibitory nerve cells. In the current study, researchers found to their surprise that most of the nerve cells in auditory cortex neurons that stimulate brain activity (excitatory) had signaled less (had "weaker" activity) when the mice expected and got a reward. Meanwhile, and to the contrary, a second set of remaining "excitatory" neurons saw greater signaling activity when mice expected a reward based on exposure to the two sensory cues and got one. Further tests showed that the activation of specific inhibitory neurons -- parvalbumin, somatostatin, and vasointestinal peptide -- was responsible for these changes and was in turn controlled by the chemical messenger, or neurotransmitter, acetylcholine. Chemically shutting down acetylcholine activity cut in half the number of times mice successfully went after their water reward when prompted by a ring tone. Some studies in humans have linked acetylcholine depletion to higher rates of Alzheimer's disease. Froemke, who is also a faculty scholar at the Howard Hughes Medical Institute, says the team next plans to assess how the hormones noradrenaline and dopamine affect auditory cortex neurons under different situations. "If we can sort out the many interactions between these chemicals and brain activity based on sensory perception and context, then we can possibly target specific excitatory and inhibitory neurological pathways to rebalance and influence behaviors," says Froemke. Funding support for the study was provided by National Institute on Deafness and Other Communication Disorders grants R01 DC009635, R01 DC012557, and R01 DC05014; National Institute of Development Administration grant T32 DA007254; a Sloan Research Fellowship; a Klingenstein Fellowship; and the Charles H. Revson Senior Fellowship in Biomedical Sciences. In addition to Froemke and Kuchibhotla, other NYU Langone researchers involved in the study are Jonathan Gill, MS; Grace Lindsay, BS; Eleni Papadoyannis; Rachel Field, BS; and Tom Hindmarsh Sten. Additional research support was provided by Kenneth Miller, PhD, at Columbia University, also in New York City.


News Article | November 1, 2016
Site: www.sciencedaily.com

The brain's interpretation of sound is influenced by cues from other senses, explaining more precisely how we interpret what we hear at a particular moment, according to a report published in Nature Neuroscience online Oct. 31. In the new study in mice, researchers at NYU Langone Medical Center found that nerve cells dedicated to hearing also rely on surrounding context to properly interpret and react to familiar sounds. "What the brain 'hears' depends on what is 'seen' in addition to specific sounds, as the brain calculates how to respond," says study senior investigator and neuroscientist Robert Froemke, PhD, an assistant professor at NYU Langone and its Skirball Institute of Biomolecular Medicine. Froemke says his team's latest findings reveal that while mammals recognize sounds in the auditory cortex of their brains, the signaling levels of nerve cells in this brain region are simultaneously being strengthened or weakened in response to surrounding context. "Our study shows how the same sound can mean different things inside the brain depending on the situation," says Froemke. "We know, for instance, that people learn to respond without alarm to the honk of a car horn if heard from the safety of their homes, but are startled to hear the same honk while crossing a busy street." If further experiments find similar activity in human brains, the researchers say their work may lead to precise explanations of situation-specific behaviors, such as anxiety brought on during math exams; sudden post-traumatic stress among combat veterans hearing a car backfire; and the ability of people with dementia to better remember certain events when they hear a familiar voice or see a friend's face. To map how the same sense can be perceived differently in the brain, the NYU Langone team, led by postdoctoral fellow Kishore Kuchibhotla, PhD, monitored nerve circuit activity in mice when the animals expected, and did not expect, to get a water reward through a straw-like tube (that they see) after the ringing of a familiar musical note. When mice were exposed to specific auditory cues, researchers observed patterns based on a basic divide in the nature of nerve cells. Each nerve cell "decides" whether a message travels onward in a nerve pathway. Nerve cells that emit chemicals which tell the next cell in line to amplify a message are excitatory; those that stop messages are inhibitory. Combinations of the two strike a counterbalance critical to the function of the nervous system, with inhibitory cells sculpting "noise" from excitatory cells into the arrangements behind thought and memory. Furthermore, the processing of incoming sensory information is achieved in part by adjusting signaling levels through each type of nerve cell. Theories hold that the brain may attach more importance to a given signal by turning up or down excitatory signals, or by doing the same with inhibitory nerve cells. In the current study, researchers found to their surprise that most of the nerve cells in auditory cortex neurons that stimulate brain activity (excitatory) had signaled less (had "weaker" activity) when the mice expected and got a reward. Meanwhile, and to the contrary, a second set of remaining "excitatory" neurons saw greater signaling activity when mice expected a reward based on exposure to the two sensory cues and got one. Further tests showed that the activation of specific inhibitory neurons -- parvalbumin, somatostatin, and vasointestinal peptide -- was responsible for these changes and was in turn controlled by the chemical messenger, or neurotransmitter, acetylcholine. Chemically shutting down acetylcholine activity cut in half the number of times mice successfully went after their water reward when prompted by a ring tone. Some studies in humans have linked acetylcholine depletion to higher rates of Alzheimer's disease. Froemke, who is also a faculty scholar at the Howard Hughes Medical Institute, says the team next plans to assess how the hormones noradrenaline and dopamine affect auditory cortex neurons under different situations. "If we can sort out the many interactions between these chemicals and brain activity based on sensory perception and context, then we can possibly target specific excitatory and inhibitory neurological pathways to rebalance and influence behaviors," says Froemke.


Mcintyre D.C.,Duke University | Mcintyre D.C.,Skirball Institute of Biomolecular Medicine | Lyons D.C.,Duke University | Martik M.,Duke University | Mcclay D.R.,Duke University
Genesis | Year: 2014

Summary: It is a challenge to understand how the information encoded in DNA is used to build a three-dimensional structure. To explore how this works the assembly of a relatively simple skeleton has been examined at multiple control levels. The skeleton of the sea urchin embryo consists of a number of calcite rods produced by 64 skeletogenic cells. The ectoderm supplies spatial cues for patterning, essentially telling the skeletogenic cells where to position themselves and providing the factors for skeletal growth. Here, we describe the information known about how this works. First the ectoderm must be patterned so that the signaling cues are released from precise positions. The skeletogenic cells respond by initiating skeletogenesis immediately beneath two regions (one on the right and the other on the left side). Growth of the skeletal rods requires additional signaling from defined ectodermal locations, and the skeletogenic cells respond to produce a membrane-bound template in which the calcite crystal grows. Important in this process are three signals, fibroblast growth factor, vascular endothelial growth factor, and Wnt5. Each is necessary for explicit tasks in skeleton production. genesis 52:173-185. © 2014 Wiley Periodicals, Inc.


Kumari S.,Skirball Institute of Biomolecular Medicine | Curado S.,Skirball Institute of Biomolecular Medicine | Mayya V.,Skirball Institute of Biomolecular Medicine | Dustin M.L.,Skirball Institute of Biomolecular Medicine
Biochimica et Biophysica Acta - Biomembranes | Year: 2014

T cells constitute a crucial arm of the adaptive immune system and their optimal function is required for a healthy immune response. After the initial step of T cell-receptor (TCR) triggering by antigenic peptide complexes on antigen presenting cell (APC), the T cell exhibits extensive cytoskeletal remodeling. This cytoskeletal remodeling leads to the formation of an "immunological synapse" [1] characterized by regulated clustering, segregation and movement of receptors at the interface. Synapse formation regulates T cell activation and response to antigenic peptides and proceeds via feedback between actin cytoskeleton and TCR signaling. Actin polymerization participates in various events during the synapse formation, maturation, and eventually its disassembly. There is increasing knowledge about the actin effectors that couple TCR activation to actin rearrangements [2,3], and how defects in these effectors translate into impairment of T cell activation. In this review we aim to summarize and integrate parts of what is currently known about this feedback process. In addition, in light of recent advancements in our understanding of TCR triggering and translocation at the synapse, we speculate on the organizational and functional diversity of microfilament architecture in the T cell. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé. © 2013 Elsevier B.V.

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