The rockefeller university

Objective: Paraneoplastic neurologic disorders (PND) are autoimmune diseases associated with cancer and ectopic expression of a neuronal antigen in a peripheral tumor. Patients with PND harbor high-titer antibodies and T cells in their serum and cerebrospinal fluid (CSF) that are specific to the tumor antigen, and treatment with the immunosuppressant FK506 (tacrolimus) decreases CSF white blood cell counts. The objective of this study was to determine the effect of FK506 on CSF chemokine levels in PND patients. Methods: CSF samples before and after FK506 treatment were tested by multiplex assay for the presence of 27 cytokines. Follow-up in vitro experiments aimed to determine whether T cells secrete CXCL10 in response to cognate antigen. Results: Here we report that PND patients harbor high levels of the chemokine CXCL10 in their CSF. CXCL10 is a cytokine that recruits CXCR3(+) cells such as activated T cells, and we found that FK506 treatment specifically decreased CSF CXCL10 from among 27 cytokines tested. In vitro, CXCL10 was only produced during antigen-specific cognate interactions between T cells and antigen-presenting cells (APCs) when interferon-gamma (IFN gamma) receptors were present on the T cell. Interpretation: These results support a model in which antigen-specific T cell stimulation by PND APCs triggers IFN gamma, followed by CXCL10 production and further lymphocyte recruitment, suggesting that treatments targeting T cells or CXCL10 in the central nervous system (CNS) may interrupt a destructive positive feedback loop present in CNS inflammation.

Measurements of the ZZ production cross sections in proton-proton collisions at center-of-mass energies of 7 and 8 TeV are presented. Candidate events for the leptonic decay mode ZZ -> 2l2 nu. where l denotes an electron or a muon, are reconstructed and selected from data corresponding to an integrated luminosity of 5.1 (19.6) fb(-1) at 7 (8) TeV collected with the CMS experiment. The measured cross sections, sigma(pp -> ZZ) = 5.1(1.4)(+1.5) (stat)(-1.1)(+1.4) (syst) +/- 0.1 (lumi) pb at 7 TeV, and 7.2(-0.8)(+0.8) (stat)(1.5)(+1.9) (syst) +/- 0.2 (lumi) pb at 8 TeV, are in good agreement with the standard model predictions with next-to-leading-order accuracy. The selected data are analyzed to search for anomalous triple gauge couplings involving the ZZ final state. In the absence of any deviation from the standard model predictions, limits are set on the relevant parameters. These limits are then combined with the previously published CMS results for ZZ in 4l final states, yielding the most stringent constraints on the anomalous couplings.

Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors. We found that altered ACF binding after chronic stress was correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress. Together, our findings identify the ACF chromatin-remodeling complex as a critical component in the development of susceptibility to depression and in regulating stress-related behaviors.

Studies investigating the causes of autism spectrum disorder (ASD) point to genetic, as well as epigenetic, mechanisms of the disease. Identification of epigenetic processes that contribute to ASD development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here, we identify the bromodomain and extraterminal domain-containing proteins (BETs) as epigenetic regulators of genes involved in ASD-like behaviors in mice. We found that the pharmacological suppression of BET proteins in the brain of young mice, by the novel, highly specific, brain-permeable inhibitor I-BET858 leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome. Many of the I-BET858-affected genes have been linked to ASD in humans, thus suggesting the key role of the BET-controlled gene network in the disorder. Our studies suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD.

Gut bacteria are known to affect immune cell development, but most intestinal lymphocytes have no direct contact with luminal bacteria. Two studies by Atarashi et al. and Sano et al. shed light on how bacterial adhesion can cue intestinal epithelial cells to direct differentiation of gut T cells.

Electrophysiological recordings have enabled identification of physiologically distinct yet behaviorally similar states of mammalian sleep. In contrast, sleep in nonmammals has generally been identified behaviorally and therefore regarded as a physiologically uniform state characterized by quiescence of feeding and locomotion, reduced responsiveness, and rapid reversibility. The nematode Caenorhabditis elegans displays sleep-like quiescent behavior under two conditions: developmentally timed quiescence (DTQ) occurs during larval transitions, and stress-induced quiescence (SIQ) occurs in response to exposure to cellular stressors. Behaviorally, DTQ and SIQ appear identical. Here, we use optogenetic manipulations of neuronal and muscular activity, pharmacology, and genetic perturbations to uncover circuit and molecular mechanisms of DTQ and SIQ. We find that locomotion quiescence induced by DTQ- and SIQ-associated neuropeptides occurs via their action on the nervous system, although their neuronal target(s) and/or molecular mechanisms likely differ. Feeding quiescence during DTQ results from a loss of pharyngeal muscle excitability, whereas feeding quiescence during SIQ results from a loss of excitability in the nervous system. Together these results indicate that, as in mammals, quiescence is subserved by different mechanisms during distinct sleep-like states in C. elegans.

Hirsutella sinensis mycelium (HSM), the anamorph of Cordyceps sinensis, is a traditional Chinese medicine that has been shown to possess various pharmacological properties. We previously reported that this fungus suppresses interleukin-1 beta and IL-18 secretion by inhibiting both canonical and non-canonical inflammasomes in human macrophages. However, whether HSM may be used to prevent lung fibrosis and the mechanism underlying this activity remain unclear. Our results show that pretreatment with HSM inhibits TGF-beta 1-induced expression of fibronectin and alpha-SMA in lung fibroblasts. HSM also restores superoxide dismutase expression in TGF-beta 1-treated lung fibroblasts and inhibits reactive oxygen species production in lung epithelial cells. Furthermore, HSM pretreatment markedly reduces bleomycin-induced lung injury and fibrosis in mice. Accordingly, HSM reduces inflammatory cell accumulation in bronchoalveolar lavage fluid and proinflammatory cytokines levels in lung tissues. The HSM extract also significantly reduces TGF-beta 1 in lung tissues, and this effect is accompanied by decreased collagen 3 alpha 1 and alpha-SMA levels. Moreover, HSM reduces expression of the NLRP3 inflammasome and P2X(7)R in lung tissues, whereas it enhances expression of superoxide dismutase. These findings suggest that HSM may be used for the treatment of pulmonary inflammation and fibrosis.

We analyzed global transcriptome changes during synchronized cell division in the green alga Chlamydomonas reinhardtii. The Chlamydomonas cell cycle consists of a long G1 phase, followed by an S/M phase with multiple rapid, alternating rounds of DNA replication and segregation. We found that the S/M period is associated with strong induction of; 2300 genes, many with conserved roles in DNA replication or cell division. Other genes, including many involved in photosynthesis, are reciprocally downregulated in S/M, suggesting a gene expression split correlating with the temporal separation between G1 and S/M. The Chlamydomonas cell cycle is synchronized by light-dark cycles, so in principle, these transcriptional changes could be directly responsive to light or to metabolic cues. Alternatively, cell-cycle-periodic transcription may be directly regulated by cyclin-dependent kinases. To distinguish between these possibilities, we analyzed transcriptional profiles of mutants in the kinases CDKA and CDKB, as well as other mutants with distinct cell cycle blocks. Initial cell-cycle-periodic expression changes are largely CDK independent, but later regulation (induction and repression) is under differential control by CDKA and CDKB. Deviation from the wild-type transcriptional program in diverse cell cycle mutants will be an informative phenotype for further characterization of the Chlamydomonas cell cycle.

Background: Follicular helper T (T-FH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. T-FH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of T-FH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. Objective: We sought to determine the signaling pathways and cellular interactions required for the development and function of T-FH cells in human subjects. Methods: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cT(FH)) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. Results: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cT(FH) cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cT(FH) cell differentiation toward a phenotype characterized by overexpression of IFN-gamma and programmed death 1. IFN-gamma inhibited cT(FH) cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. Conclusion: Specific mutations affect the quantity and quality of cT(FH) cells, highlighting the need to assess T-FH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-gamma functions in vivo to restrain T-FH cell-induced B-cell differentiation. These findings shed new light on T-FH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

In development, cells organize into biological tissues through cell growth, migration, and differentiation. Globally, this process is dictated by a genetically encoded program in which secreted morphogens and cell-cell interactions prompt the adoption of unique cell fates. Yet, at its lowest level, development is achieved through the modification of cell cell adhesion and actomyosin-based contractility, which set the level of tension within cells and dictate how they pack together into tissues. The regulation of tension within individual cells and across large groups of cells is a major driving force of tissue organization and the basis of all cell shape change and cell movement in development.