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The second-order azimuthal anisotropy Fourier harmonics, nu(2), are obtained in p-Pb and PbPb collisions over a wide pseudorapidity (.) range based on correlations among six or more charged particles. The p-Pb data, corresponding to an integrated luminosity of 35 nb(-1), were collected during the 2013 LHC p-Pb run at a nucleon-nucleon center-of-mass energy of 5.02 TeV by the CMS experiment. A sample of semiperipheral PbPb collision data at root S-NN = 2.76 TeV, corresponding to an integrated luminosity of 2.5 mu b(-1) and covering a similar range of particle multiplicities as the p-Pb data, is also analyzed for comparison. The six-and eight-particle cumulant and the Lee-Yang zeros methods are used to extract the nu(2) coefficients, extending previous studies of two-and four-particle correlations. For both the p-Pb and PbPb systems, the nu(2) values obtained with correlations among more than four particles are consistent with previously published four-particle results. These data support the interpretation of a collective origin for the previously observed long-range (large..) correlations in both systems. The ratios of nu(2) values corresponding to correlations including different numbers of particles are compared to theoretical predictions that assume a hydrodynamic behavior of a p-Pb system dominated by fluctuations in the positions of participant nucleons. These results provide new insights into the multiparticle dynamics of collision systems with a very small overlapping region.

The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (LepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted LepR in T cells. In contrast with pleiotropic immune disorders reported in obese mice with leptin or LepR deficiency, we found that LepR deficiency in CD4(+) T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation toward a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the STAT3 and its downstream targets. This study establishes cell-intrinsic roles for LepR signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function.

Background: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained. Objective: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. Methods: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. Results: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R7OW and Q289* for the 3 patients with Candida albicans induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed Calbicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). Conclusion: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.

Why do some individuals succumb to stress and develop debilitating psychiatric disorders, whereas others adapt well in the face of adversity? There is a gap in understanding the neural bases of individual differences in the responses to environmental factors on brain development and functions. Here, using a novel approach for screening an inbred population of laboratory animals, we identified two subpopulations of mice: susceptible mice that show mood-related abnormalities compared with resilient mice, which cope better with stress. This approach combined with molecular and behavioral analyses, led us to recognize, in hippocampus, presynaptic mGlu2 receptors, which inhibit glutamate release, as a stress-sensitive marker of individual differences to stress-induced mood disorders. Indeed, genetic mGlu2 deletion in mice results in a more severe susceptibility to stress, mimicking the susceptible mouse sub-population. Furthermore, we describe an underlying mechanism by which glucocorticoids, acting via mineralocorticoid receptors (MRs), decrease resilience to stress via downregulation of mGlu2 receptors. We also provide a mechanistic link between MRs and an epigenetic control of the glutamatergic synapse that underlies susceptibility to stressful experiences. The approach and the epigenetic allostasis concept introduced here serve as a model for identifying individual differences based upon biomarkers and underlying mechanisms and also provide molecular features that may be useful in translation to human behavior and psychopathology.

Taylor's law (TL) states that the variance V of a nonnegative random variable is a power function of its mean M; i.e., V = aM(b). TL has been verified extensively in ecology, where it applies to population abundance, physics, and other natural sciences. Its ubiquitous empirical verification suggests a context-independent mechanism. Sample exponents b measured empirically via the scaling of sample mean and variance typically cluster around the value b=2. Some theoretical models of population growth, however, predict a broad range of values for the population exponent b pertaining to the mean and variance of population density, depending on details of the growth process. Is the widely reported sample exponent b similar or equal to 2 the result of ecological processes or could it be a statistical artifact? Here, we apply large deviations theory and finite-sample arguments to show exactly that in a broad class of growth models the sample exponent is b similar or equal to 2 regardless of the underlying population exponent. We derive a generalized TL in terms of sample and population exponents b(jk) for the scaling of the kth vs. the jth cumulants. The sample exponent b(jk) depends predictably on the number of samples and for finite samples we obtain b(jk) similar or equal to k/j asymptotically in time, a prediction that we verify in two empirical examples. Thus, the sample exponent b similar or equal to 2 may indeed be a statistical artifact and not dependent on population dynamics under conditions that we specify exactly. Given the broad class of models investigated, our results apply to many fields where TL is used although inadequately understood.

Pancreatic ductal adenocarcinomas (PDACs) are highly metastatic with poor prognosis, mainly due to delayed detection. We hypothesized that intercellular communication is critical for metastatic progression. Here, we show that PDAC-derived exosomes induce liver pre-metastatic niche formation in naive mice and consequently increase liver metastatic burden. Uptake of PDAC-derived exosomes by Kupffer cells caused transforming growth factor beta secretion and upregulation of fibronectin production by hepatic stellate cells. This fibrotic microenvironment enhanced recruitment of bone marrow-derived macrophages. We found that macrophage migration inhibitory factor (MIF) was highly expressed in PDAC-derived exosomes, and its blockade prevented liver pre-metastatic niche formation and metastasis. Compared with patients whose pancreatic tumours did not progress, MIF was markedly higher in exosomes from stage I PDAC patients who later developed liver metastasis. These findings suggest that exosomal MIF primes the liver for metastasis and may be a prognostic marker for the development of PDAC liver metastasis.

Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. In this study, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived Ags by these cells supported recall T cell responses in the fat and also generated Ag-bearing DCs for emigration into adjacent lymph nodes (LNs). Enhanced recruitment of DCs to inflammation-reactive LNs significantly relied on adipose tissue DCs to maintain sufficient numbers of Ag-bearing DCs as the LN expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for Ag transport into the adjacent LN.

The nuclear pore complex (NPC) arose in evolution as the cell's largest and most versatile transport channel. Current models for selective transport mediated by NPCs are focused on properties of intrinsically disordered regions of nucleoporins that bind transport factors. In contrast, structured regions are considered to provide static anchoring sites for the disordered regions without affecting transport factor binding. Here, we demonstrate allosteric coupling between a structured domain of a channel nucleoporin (Nup58) and its neighboring disordered domain in interaction with another channel nucleoporin (Nup54) and a transport factor (Kap beta 1). Analysis of multiple equilibria showed that multivalent interactions of Kapb1 with the disordered domains of Nup58 stabilize the neighboring structured domain associated with Nup54, shifting conformational equilibria from homo-oligomers to hetero-oligomers. Based on these and previous crystallographic results, a quantitative framework was established to describe constriction and dilation of the central channel as a function of transport factor occupancy.

Previous analysis of Drosophila circadian behavior under natural conditions has revealed a number of novel and unexpected features. Here we focus on the oscillations of per and tim mRNAs and their posttranscriptional regulation and observe significant differences in molecular cycling under laboratory and natural conditions. In particular, robust per mRNA cycling from fly heads is limited to the summers, whereas tim RNA cycling is observed throughout the year. When both transcripts do cycle, their phases are similar, except for the very warmest summer months. We also study the natural splicing profiles of per and tim transcripts and observe a clear relationship between temperature and splicing. In natural conditions, we confirm the relationship between accumulation of the per(spliced) variant, low temperature, and the onset of the evening component of locomotor activity, first described in laboratory conditions. Intriguingly, in the case of tim splicing, we detect the opposite relationship, with tim(spliced) expression increasing at higher temperatures. A first characterization of the 4 different TIM protein isoforms (resulting from the combination of the natural N-terminus length polymorphism and the C-terminus alternative splicing) using the 2-hybrid assay showed that the TIMunspliced isoforms have a stronger affinity for CRY, but not for PER, suggesting that the tim 3 splicing could have physiological significance, possibly in temperature entrainment and/or adaptation to seasonal environments.

The evolution of the field of neuroscience has been propelled by the advent of novel technological capabilities, and the pace at which these capabilities are being developed has accelerated dramatically in the past decade. Capitalizing on this momentum, the United States launched the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative to develop and apply new tools and technologies for revolutionizing our understanding of the brain. In this article, we review the scientific vision for this initiative set forth by the National Institutes of Health and discuss its implications for the future of neuroscience research. Particular emphasis is given to its potential impact on the mapping and study of neural circuits, and how this knowledge will transform our understanding of the complexity of the human brain and its diverse array of behaviours, perceptions, thoughts and emotions.