The rockefeller university

Persistence of replication-competent viral reservoirs during infection remains a barrier to HIV cure, despite the ability of combination antiretroviral therapy (cART) to effectively suppress viral replication. Simian-tropic HIV (stHIV) is a minimally chimeric HIV-1 that is comprised of 94% HIV-1 sequence, contains HIV-1 drug and immunologic targets, and is capable of replicating to high levels and causing authentic HIV-like pathogenesis leading to clinical AIDS in pigtail macaques. Suppression of stHIV replication by cART provides a model for study of viral reservoirs and HIV-specific intervention strategies targeting them. Accurate measurement of reservoir size is crucial for evaluating the effect of any such intervention strategies. Although there are a variety of assays that allow for indirect monitoring of viral reservoir size ex vivo, they each quantify a different aspect of viral reservoirs, and are characterized by conceptual and/or technical limitations. Measurement of viral protein in ex vivo cell culture assays captures the immunologically relevant viral-antigen producing component of the reservoir. This study demonstrates the utility of an ultrasensitive digital HIV Gag p24 immunoassay, which enabled earlier, and more sensitive detection of viral protein in culture supernatants from stimulated CD4+ T cells from stHIV-infected pigtail macaques receiving cART compared with conventional enzyme-linked immunosorbent assay. Protein measurements were highly correlated with cell-free stHIV RNA, as measured by quantitative reverse transcription polymerase chain reaction. This ultrasensitive p24 assay can be used to complement other reservoir measurement tools to assess ongoing replication and reactivation of infectious virus from reservoirs in stHIV-infected pigtail macaques.

High-precision HERA data corresponding to a luminosity of around 1 fb(-1) have been used in the framework of eeqq contact interactions (CI) to set limits on possible high-energy contributions beyond the Standard Model to electron-quark scattering. Measurements of the inclusive deep inelastic cross sections in neutral and charged current ep scattering were considered. The analysis of the ep data has been based on simultaneous fits of parton distribution functions including contributions of CI couplings to ep scattering. Several general CI models and scenarios with heavy leptoquarks were considered. Improvements in the description of the inclusive HERA data were obtained for a few models. Since a statistically significant deviation from the Standard Model cannot be established, limits in the TeV range were set on all models considered.

A clue to hippocampal function has been the discovery of place cells, leading to the 'spatial map' theory. Although the firing attributes of place cells are well documented, little is known about the organization of the spatial map. Unit recording studies, thus far, have reported a low coherence between neighboring cells and geometric space, leading to the prevalent view that the spatial map is not topographically organized. However, the number of simultaneously recorded units is severely limited, rendering construction of the spatial map nearly impossible. To visualize the functional organization of place cells, we used the activity-dependent immediate early gene Zif268 in combination with behavioral, pharmacological and electrophysiological methods, in mice and rats exploring an environment. Here, we show that in animals confined to a small part of a maze, principal cells in the CA1/CA3 subfields of the dorsal hippocampus immunoreactive (IR) for Zif268 adhere to a 'cluster type' organization. Unit recordings confirmed that the Zif268 IR clusters correspond to active place cells, while blockade of NMDAR (which alters place fields) disrupted the Zif268 IR clusters. Contrary to the prevalent view that the spatial map consists of a non-topographic neural network, our results provide evidence for a 'cluster type' functional organization of hippocampal neurons encoding for space.

Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory musculoskeletal condition with complex pathophysiology. In recent years, understanding of the pathogenesis of PsA has improved substantially. Several genetic and inflammatory factors have been identified and studied as targets for new biologic disease-modifying therapies. This review presents findings from a detailed literature assessment conducted to identify genes and biomarkers associated with PsA and its most common comorbidities. This literature assessment identifies genes and biomarkers that may be predictive of the onset and severity of PsA, places them in the context of our understanding of PsA pathogenesis, and explores potential connections between the pathways involved in PsA and current biologic therapeutics used to treat PsA. Knowledge of the genetics and inflammatory factors associated with disease pathogenesis can support the targeted development of new biologic therapies and biomarkers for PsA.

Performance on cognitive tasks during learning is used to measure knowledge, yet it remains controversial since such testing is susceptible to contextual factors. To what extent does performance during learning depend on the testing context, rather than underlying knowledge? We trained mice, rats and ferrets on a range of tasks to examine how testing context impacts the acquisition of knowledge versus its expression. We interleaved reinforced trials with probe trials in which we omitted reinforcement. Across tasks, each animal species performed remarkably better in probe trials during learning and inter-animal variability was strikingly reduced. Reinforcement feedback is thus critical for learning-related behavioral improvements but, paradoxically masks the expression of underlying knowledge. We capture these results with a network model in which learning occurs during reinforced trials while context modulates only the read-out parameters. Probing learning by omitting reinforcement thus uncovers latent knowledge and identifies context- not "smartness"- as the major source of individual variability.

Regular exercise and dietary supplements with antioxidants each have the potential to improve cognitive function and attenuate cognitive decline, and, in some cases, they enhance each other. Our current results reveal that low-intensity exercise (mild exercise, ME) and the natural antioxidant carotenoid astaxanthin (AX) each have equivalent beneficial effects on hippocampal neurogenesis and memory function. We found that the enhancement by ME combined with AX in potentiating hippocampus-based plasticity and cognition is mediated by leptin (LEP) made and acting in the hippocampus. In assessing the combined effects upon wild-type (WT) mice undergoing ME with or without an AX diet for four weeks, we found that, when administrated alone, ME and AX separately enhanced neurogenesis and spatial memory, and when combined they were at least additive in their effects. DNA microarray and bioinformatics analyses revealed not only the up-regulation of an antioxidant gene, ABHD3, but also that the up-regulation of LEP gene expression in the hippocampus of WT mice with ME alone is further enhanced by AX. Together, they also increased hippocampal LEP (h-LEP) protein levels and enhanced spatial memory mediated through AKT/STAT3 signaling. AX treatment also has direct action on human neuroblastoma cell lines to increase cell viability associated with increased LEP expression. In LEP-deficient mice (ob/ob), chronic infusion of LEP into the lateral ventricles restored the synergy. Collectively, our findings suggest that not only h-LEP but also exogenous LEP mediates effects of ME on neural functions underlying memory, which is further enhanced by the antioxidant AX.

Cellular antiviral programs encode molecules capable of targeting multiple steps in the virus lifecycle. Zinc-finger antiviral protein (ZAP) is a central and general regulator of antiviral activity that targets pathogen mRNA stability and translation. ZAP is diffusely cytoplasmic, but upon infection ZAP is targeted to particular cytoplasmic structures, termed stress granules (SGs). However, it remains unclear if ZAP's antiviral activity correlates with SG localization, and what molecular cues are required to induce this localization event. Here, we use Sindbis virus (SINV) as a model infection and find that ZAP's localization to SGs can be transient. Sometimes no apparent viral infection follows ZAP SG localization but ZAP SG localization always precedes accumulation of SINV non-structural protein, suggesting virus replication processes trigger SG formation and ZAP recruitment. Data from single-molecule RNA FISH corroborates this finding as the majority of cells with ZAP localization in SGs contain low levels of viral RNA. Furthermore, ZAP recruitment to SGs occurred in ZAP-expressing cells when co-cultured with cells replicating full-length SINV, but not when co-cultured with cells replicating a SINV replicon. ZAP recruitment to SGs is functionally important as a panel of alanine ZAP mutants indicate that the anti-SINV activity is correlated with ZAP's ability to localize to SGs. As ZAP is a central component of the cellular antiviral programs, these data provide further evidence that SGs are an important cytoplasmic antiviral hub. These findings provide insight into how antiviral components are regulated upon virus infection to inhibit virus spread.

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The coronary vasculature is crucial for normal heart function, yet much remains to be learned about its development, especially the maturation of coronary arterial endothelium. Here, we show that endothelial inactivation of ADAM10, a key regulator of Notch signaling, leads to defects in coronary arterial differentiation, as evidenced by dysregulated genes related to Notch signaling and arterial identity. Moreover, transcriptome analysis indicated reduced EGFR signaling in A10EC coronary endothelium. Further analysis revealed that A10EC mice have enlarged dysfunctional hearts with abnormal myocardial compaction, and increased expression of venous and immature endothelium markers. These findings provide the first evidence for a potential role for endothelial ADAM10 in cardioprotective homeostatic EGFR signaling and implicate ADAM10/Notch signaling in coronary arterial cell specification, which is vital for normal heart development and function. The ADAM10/Notch signaling pathway thus emerges as a potential therapeutic target for improving the regenerative capacity and maturation of the coronary vasculature.