The rockefeller university

Features from outside the classical receptive field (CRF) can modulate the stimulus-driven activity of single cells in the primary visual cortex. This modulation, mediated by horizontal and feedback networks, has been extensively described as a variation of firing rate and is considered the basis of processing features as, for example, motion contrast. However, surround influences have also been identified in pairwise spiking or local field coherence. Yet, evidence about co-existence and integration of different neural signatures remains elusive. To compare multiple signatures, we recorded spiking and LFP activity evoked by stimuli exhibiting a motion contrast in the CRFs surround in anesthetized cat primary visual cortex. We chose natural-like scenes over gratings to avoid predominance of simple visual features, which could be easily represented by a rate code. We analyzed firing rates and phase-locking to low-gamma frequency in single cells and neuronal assemblies. Motion contrast was reflected in all measures but in semi-independent populations. Whereas activation of assemblies accompanied single neuron rates, their phase relations were modulated differently. Interestingly, only assembly phase relations mirrored the direction of movement of the surround and were selectively affected by thermal deactivation of visual interhemispheric connections. We argue that motion contrast can be reflected in complementary and superimposed neuronal signatures that can represent different surround features in independent neuronal populations.

Patients undergoing methadone maintenance treatment self-report enhanced preferences for, and excessive consumption of, foods rich in sugar. However, it is unclear whether these are direct pharmacological effects of methadone or the consequences of metabolic dysfunctions induced by addiction to illicit opiates. Hence, the current study in drug-naive male Sprague-Dawley rats explored the effects of steady-state methadone delivered by osmotic mini-pumps (13 days; 0, 10, 30 mg/kg/day) on consumption of rat chow and a palatable, sweet, liquid high fructose corn syrup solution. Six days after the removal of the pumps, mRNA expression of genes involved in responses to stress and rewards were quantified: pro-opiomelanocortin in the hypothalamus, mu-opioid receptor in the nucleus accumbens, and dopamine D2 receptor in the dorsal striatum. Taste reactivity and locomotion tests were also performed throughout the study. It was found that methadone increased caloric intake from high fructose corn syrup and reduced caloric intake from chow, effects that could not be directly ascribed to changes in high fructose corn syrup taste reactivity or motor functions. However, the changes in caloric intake displayed significant tolerance, and mRNA expression analysis suggested that methadone attenuated the effect of high fructose corn syrup on pro-opiomelanocortin mRNA, and possibly on dopamine D2 receptor mRNA. These findings in rats suggest that the pharmacological effect of methadone, administered to achieve steady-state maintenance, may not be the primary cause of dietary alterations reported by patients maintained on methadone.

In social insects, natural selection operates at the level of the colony, rather than the individual, but our understanding of how colony-level phenotypes arise and vary between species is lacking. Here, we test how colony-level phenotypes vary within the fire ants by measuring the composition of colonies of the tropical fire ant, Solenopsis geminata, over a wide range of sizes at multiple times throughout the year. Similar to the well-studied fire ant species S. invicta, we find that S. geminata colony composition varies strongly with colony size, such that as colonies grow they produce increasingly large workers as well as queens and males. However, major production increases more rapidly with colony size in S. geminata than in S. invicta, which may explain our observation that S. geminata also possesses a smaller maximum colony size. Unlike S. geminata or S. invicta in the USA, we find no evidence for seasonal variation in colony composition in S. geminata in Costa Rica. Solenopsis geminata colonies from Costa Rica also exhibit continuous variation in queen number, from one to two to hundreds. Overall, this research describes how colony-level features vary within the fire ants, providing basic data that can be used to study the mechanisms underlying the development and evolution of colony-level phenotypes in social insects.

A search for new physics is presented in final states with two oppositely charged leptons (electrons or muons), jets identified as originating from b quarks, and missing transverse momentum (p(T)(miss)). The search uses proton-proton collision data at root s = 13 TeV amounting to 35.9 fb(-1) of integrated luminosity collected using the CMS detector in 2016. Hypothetical signal events are efficiently separated from the dominant t (t) over bar background with requirements on p(T)(miss) and transverse-mass variables. No significant deviation is observed from the expected background. Exclusion limits are set in the context of simplified supersymmetric models with pair-produced top squarks. For top squarks, decaying exclusively to a top quark and a neutralino, exclusion limits are placed at 95% confidence level on the mass of the lightest top squark up to 800 GeVand on the lightest neutralino up to 360 GeV. These results, combined with searches in the single-lepton and all-jet final states, raise the exclusion limits up to 1050 GeV for the lightest top squark and up to 500 GeV for the lightest neutralino. For top squarks undergoing a cascade decay through charginos and sleptons, the mass limits reach up to 1300 GeV for top squarks and up to 800 GeV for the lightest neutralino. The results are also interpreted in a simplified model with a dark matter (DM) particle coupled to the top quark through a scalar or pseudoscalar mediator. For light DM, mediator masses up to 100 (50) GeV are excluded for scalar (pseudoscalar) mediators. The result for the scalar mediator achieves some of the most stringent limits to date in this model.

CD8(+) T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti-programmed cell death protein 1 or anti-cytotoxic T lymphocyte-associated protein 4 is currently unknown. We determined the HLA-I genotype of 1535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci ("A," "B," and "C") improved overall survival after ICB compared with patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed different elements that may impair CD8(+) T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.

Objective Mitochondria are multifunctional life-sustaining organelles that represent a potential intersection point between psychosocial experiences and biological stress responses. This article provides a systematic review of the effects of psychological stress on mitochondrial structure and function. Methods A systematic review of the literature investigating the effects of psychological stress on mitochondrial function was conducted. The review focused on experimentally controlled studies allowing us to draw causal inference about the effect of induced psychological stress on mitochondria. Results A total of 23 studies met the inclusion criteria. All studies involved male laboratory animals, and most demonstrated that acute and chronic stressors influenced specific facets of mitochondrial function, particularly within the brain. Nineteen studies showed significant adverse effects of psychological stress on mitochondria and four found increases in function or size after stress. In humans, only six observational studies were available, none with experimental designs, and most only measured biological markers that do not directly reflect mitochondrial function, such as mitochondrial DNA copy number. Conclusons Overall, evidence supports the notion that acute and chronic stressors influence various aspects of mitochondrial biology, and that chronic stress exposure can lead to molecular and functional recalibrations among mitochondria. Limitations of current animal and human studies are discussed. Maladaptive mitochondrial changes that characterize this subcellular state of stress are termed mitochondrial allostatic load. Prospective studies with sensitive measures of specific mitochondrial outcomes will be needed to establish the link between psychosocial stressors, emotional states, the resulting neuroendocrine and immune processes, and mitochondrial energetics relevant to mind-body research in humans.

Purpose: PD-1/PD-L1 pathway inhibition is effective against advanced renal cell carcinoma, although results are variable and may depend on host factors, including the tumor microenvironment. Vascular-targeted photodynamic (VTP) therapy with the photosensitizer WST11 induces a defined local immune response, and we sought to determine whether this could potentiate the local and systemic antitumor response to PD-1 pathway inhibition. Experimental Design: Using an orthotopic Renca murine model of renal cell carcinoma that develops lung metastases, we treated primary renal tumors with either VTP alone, PD-1/PD-L1 antagonistic antibodies alone, or a combination of VTP and antibodies and then examined treatment responses, including immune infiltration in primary and metastatic sites. Modulation of PD-L1 expression by VTP in human xenograft tumors was also assessed. Results: Treatment of renal tumors with VTP in combination with systemic PD-1/PD-L1 pathway inhibition, but neither treatment alone, resulted in regression of primary tumors, prevented growth of lung metastases, and prolonged survival in a preclinical mouse model. Analysis of tumor-infiltrating lymphocytes revealed that treatment effect was associated with increased CD8thorn: regulatory T cell (Treg) and CD4(+)FoxP3-: Treg ratios in primary renal tumors and increased T-cell infiltration in sites of lung metastasis. Furthermore, PD-L1 expression is induced following VTP treatment of human renal cell carcinoma xenografts. Conclusions: Our results demonstrate a role for local immune modulation with VTP in combination with PD-1/PD-L1 pathway inhibition for generation of potent local and systemic antitumor responses. This combined modality strategy may be an effective therapy in cancers resistant to PD-1/PD-L1 pathway inhibition alone. (C) 2017 AACR.

Although a hair bundle is normally deflected by mechanical stimuli, we found that irradiation of a hair cell from the bullfrog's sacculus with ultraviolet light causes rapid motion of the hair bundle toward its tall edge. This movement is associated with opening of mechanotransduction channels and disappears when tip links are disrupted. We localized the absorptive element responsible for the motion to the region directly below the hair bundle and measured an action spectrum similar to the absorption spectra of mitochondrial constituents. Temperature measurements revealed heating around the site of absorption; direct heating of the hair bundle confirmed that the response to light is mediated through heat. Although mechanical offsets of the hair bundle revealed that heat softens gating springs, it also acts directly to open transduction channels. This study identifies an unconventional method of hair-cell stimulation and clarifies the previously unexplained sensitivity of auditory organs to thermal stimulation.