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WNIN (Wistar/NIN) is an inbred rat strain maintained at National Institute of Nutrition (NIN) for more than 90 years, and WNIN/Ob is an obese mutant originated from it. To determine their genetic relatedness with major rat strains in biomedical research, they were genotyped at various marker loci. The recently identified markers for albino and hooded mutations which clustered all the known albino rats into a single lineage also included WNIN and WNIN/Ob rats. Genotyping using microsatellite DNA markers and phylogenetic analysis with 49 different rat strains suggested that WNIN shares a common ancestor with many Wistar originated strains. Fst estimates and Fischer's exact test suggest that WNIN rats differed significantly from all other strains tested. WNIN/Ob though shows hyper-leptinemia, like Zucker fatty rat, did not share the Zucker fatty rat mutation. The above analyses suggest WNIN as a highly differentiated rat strain and WNIN/Ob a novel obese mutant evolved from it.

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.

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.

BackgroundCognitive decline and accompanying neurological changes associated with non-CNS cancer diagnosis and treatment have been increasingly identified in a subset of patients. Initially believed to be because of neurotoxic effects of chemotherapy exposure, observation of cognitive decline in patients not treated with chemotherapy, cancer-diagnosed individuals prior to treatment, and patients receiving alternative treatment modalities (surgery, endocrine therapy, and radiation) has led to the investigation of additional potential etiologies and moderating factors. Stressful experiences have long been posited as a contributor to these cognitive changes. Through reciprocal connectivity with peripheral systems, the brain maintains a dynamic circuitry to adapt to stress (allostasis). However, overuse of this system leads to dysregulation and contributes to pathophysiology (allostatic load). At this time, little research has been conducted to systematically examine the role of allostatic load in cancer-related cognitive dysfunction. Methods and ResultsHere, we integrate theories of stress biology, neuropsychology, and coping and propose a model through which individuals with a high level of allostatic load at diagnosis may be particularly vulnerable to the neurocognitive effects of cancer. ConclusionsOpportunities for future research to test and extend proposed mechanisms are discussed in addition to points of prevention and intervention based on individual variation in stress reactivity and coping skills. Copyright (c) 2014 John Wiley & Sons, Ltd.

The site on the HIV-1 gp120 glycoprotein that binds the CD4 receptor is recognized by broadly reactive antibodies, several of which neutralize over 90% of HIV-1 strains. To understand how antibodies achieve such neutralization, we isolated CD4-binding-site (CD4bs) antibodies and analyzed 16 co-crystal structures -8 determined here- of CD4bs antibodies from 14 donors. The 16 antibodies segregated by recognition mode and developmental ontogeny into two types: CDR H3-dominated and V-H-gene-restricted. Both could achieve greater than 80% neutralization breadth, and both could develop in the same donor. Although paratope chemistries differed, all 16 gp120-CD4bs antibody complexes showed geometric similarity, with antibody-neutralization breadth correlating with antibody-angle of approach relative to the most effective antibody of each type. The repertoire for effective recognition of the CD4 supersite thus comprises antibodies with distinct paratopes arrayed about two optimal geometric orientations, one achieved by CDR H3 ontogenies and the other achieved by V-H-gene-restricted ontogenies.

Objective To examine the relation between reaction time in adolescence and subsequent symptoms of anxiety and depression and investigate the mediating role of sociodemographic measures, health behaviors, and allostatic load. Methods Participants were 705 members of the West of Scotland Twenty-07 Study. Choice reaction time was measured at age 16. At age 36 years, anxiety and depression were assessed with the 12-item General Health Questionnaire (GHQ) and the Hospital Anxiety and Depression Scale (HADS), and measurements were made of blood pressure, pulse rate, waist-to-hip ratio, and total and high-density lipoprotein cholesterol, C-reactive protein, albumin, and glycosolated hemoglobin from which allostatic load was calculated. Results In unadjusted models, longer choice reaction time at age 16 years was positively associated with symptoms of anxiety and depression at age 36 years: for a standard deviation increment in choice reaction time, regression coefficients (95% confidence intervals) for logged GHQ score, and square-root-transformed HADS anxiety and depression scores were 0.048 (0.016-0.080), 0.064 (0.009-0.118), and 0.097 (0.032-0.163) respectively. Adjustment for sex, parental social class, GHQ score at age 16 years, health behaviors at age 36 years and allostatic load had little attenuating effect on the association between reaction time and GHQ score, but weakened those between reaction time and the HADS subscales. Part of the effect of reaction time on depression was mediated through allostatic load; this mediating role was of borderline significance after adjustment. Conclusions Adolescents with slower processing speed may be at increased risk for anxiety and depression. Cumulative allostatic load may partially mediate the relation between processing speed and depression.

Taylor's law (TL), a widely verified quantitative pattern in ecology and other sciences, describes the variance in a species' population density (or other nonnegative quantity) as a power-law function of the mean density (or other nonnegative quantity): Approximately, variance = a(mean)(b), a > 0. Multiple mechanisms have been proposed to explain and interpret TL. Here, we show analytically that observations randomly sampled in blocks from any skewed frequency distribution with four finite moments give rise to TL. We do not claim this is the only way TL arises. We give approximate formulae for the TL parameters and their uncertainty. In computer simulations and an empirical example using basal area densities of red oak trees from Black Rock Forest, our formulae agree with the estimates obtained by least-squares regression. Our results show that the correlated sampling variation of the mean and variance of skewed distributions is statistically sufficient to explain TL under random sampling, without the intervention of any biological or behavioral mechanisms. This finding connects TL with the underlying distribution of population density (or other nonnegative quantity) and provides a baseline against which more complex mechanisms of TL can be compared.

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.

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.

Unconventional T cells such as gamma delta T cells, natural killer T cells (NKT cells) and mucosal-associated invariant T cells (MAIT cells) are a major component of the immune system; however, the cytokine signaling pathways that control their development and function in humans are unknown. Primary immunodeficiencies caused by single gene mutations provide a unique opportunity to investigate the role of specific molecules in regulating human lymphocyte development and function. We found that individuals with loss-of-function mutations in STAT3 had reduced numbers of peripheral blood MAIT and NKT but not gamma delta T cells. Analysis of STAT3 mosaic individuals revealed that this effect was cell intrinsic. Surprisingly, the residual STAT3-deficient MAIT cells expressed normal levels of the transcription factor ROR gamma t. Despite this, they displayed a deficiency in secretion of IL-17A and IL-17F, but were able to secrete normal levels of cytokines such as IFN gamma and TNF The deficiency in MAIT and NKT cells in STAT3-deficient patients was mirrored by loss-of-function mutations in IL12RB1 and IL21R, respectively. Thus, these results reveal for the first time the essential role of STAT3 signaling downstream of IL-23R and IL-21R in controlling human MAIT and NKT cell numbers.