The rockefeller university

Inequalities for convex functions on the lattice of partitions of a set partially ordered by refinement lead to multivariate generalizations of inequalities of Cauchy and Rogers-Holder and to eigenvalue inequalities needed in the theory of population dynamics in Markovian environments: If A is an n x n nonnegative matrix, n > 1, D is an n x n diagonal matrix with positive diagonal elements, r(.) is the spectral radius of a square matrix, r(A) > 0, and x is an element of [1, infinity), then r(x-1)(A)r(D(x)A) >= r(x)(DA). When A is irreducible and A(T)A is irreducible and x > 1, then equality holds if and only if all elements of D are equal. Conversely, when x > 1 and r(x-1)(A) r(D(x)A) = r(x)(DA) if and only if all elements of D are equal, then A is irreducible and ATA is irreducible.

Previously, we identified miR-125b as a key regulator of the undifferentiated state of hair follicle stem cells. Here, we show that in both mice and humans, miR-125b is abundantly expressed, particularly at early stages of malignant progression to squamous cell carcinoma (SCC), the second most prevalent cancer worldwide. Moreover, when elevated in normal murine epidermis, miR-125b promotes tumor initiation and contributes to malignant progression. We further show that miR-125b can confer "oncomiR addiction'' in early stage malignant progenitors by delaying their differentiation and favoring an SCC cancer stem cell (CSC)-like transcriptional program. To understand how, we systematically identified and validated miR125b targets that are specifically associated with tumors that are dependent on miR-125b. Through molecular and genetic analysis of these targets, we uncovered new insights underlying miR-125b's oncogenic function. Specifically, we show that, on the one hand, mir-125b directly represses stress-responsive MAP kinase genes and associated signaling. On the other hand, it indirectly prolongs activated (phosphorylated) EGFR signaling by repressing Vps4b (vacuolar protein-sorting 4 homolog B), encoding a protein implicated in negatively regulating the endosomal sorting complexes that are necessary for the recycling of active EGFR. Together, these findings illuminate miR-125b as an important microRNA regulator that is shared between normal skin progenitors and their early malignant counterparts.

Objective: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. Methods: We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype. Results: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency <0.001) missense TLR3 alleles. Two alleles (M374T, D592N) heterozygous in 3 patients are not deleterious in vitro. The other 3 are deleterious via different mechanisms: G743D+R811I and L360P heterozygous in 2 patients are loss-of-function due to low levels of expression and lack of cleavage, respectively, and R867Q homozygous in 1 patient is hypomorphic. The 3 patients' fibroblasts display impaired TLR3 responses and enhanced herpes simplex virus 1 susceptibility. Overall, TLR3 deficiency is therefore found in 6 (5%) of the 120 patients studied. There is high allelic heterogeneity, with 3 forms of autosomal dominant partial defect by negative dominance or haploinsufficiency, and 2 forms of autosomal recessive defect with complete or partial deficiency. Finally, 4 (66%) of the 6 TLR3-deficient patients had at least 1 late relapse of HSE, whereas relapse occurred in only 12 (10%) of the total cohort of 120 patients. Conclusions: Childhood-onset HSE is due to TLR3 deficiency in a traceable fraction of patients, in particular the ones with HSE recurrence. Mutations in TLR3 and TLR3 pathway genes should be searched and experimentally studied in children with HSE, and patients with proven TLR3 deficiency should be followed carefully.

Emotional, behavioural, and health benefits of gentle stroking and vocalizations, otherwise known as gentling, have been documented for several species, but little is known about the effect of gentling on cats in stressful situations. In this study, 139 cats rated as anxious upon admission to an animal shelter were allocated to either a Gentled or Control group. Cats were gentled four times daily for 10 min over a period of 10 days, with the aid of a tool for cats that were too aggressive to handle. The cats' mood, or persistent emotional state, was rated daily for 10 d as Anxious, Frustrated or Content. Gentled cats were less likely to have negatively valenced moods (Anxious or Frustrated) than Control cats (Incidence Rate Ratio [IRR] = 0.61 CI 0.42-0.88, P = 0.007). Total secretory immunoglobulin A (S-IgA) was quantified from faeces by enzyme-linked immunosorbent assay. Gentled cats had increased S-IgA (6.9 +/- 0.7 log(e) mu g/g) compared to Control cats (5.9 +/- 0.5 log(e) mu g/g) (P < 0.0001). Within the Gentled group of cats, S-IgA values were higher for cats that responded positively to gentling (7.03 +/- 0.6, log(e) mu g/g), compared with those that responded negatively (6.14 +/- 0.8, log(e) mu g/g). Combined conjunctival and oropharyngeal swab specimens were tested by quantitative real-time polymerase chain reaction (rPCR) for feline herpesvirus type 1 (FHV-1), feline calicivirus (FCV), Mycoplasma fells, Chlamydophila fells, and Bordetella bronchiseptica. There was a significant increase in shedding over time in Control cats (23%, 35%, 52% on days 1, 4 and 10, respectively), but not in gentled cats (32%, 26%, 30% on days 1, 4 and 10, respectively) (P = 0.001). Onset of upper respiratory disease was determined by veterinary staff based on clinical signs, in particular ocular and/or nasal discharge. Control cats were 2.4 (CI: 1.35-4.15) times more likely to develop upper respiratory disease over time than gentled cats (P < 0.0001). It is concluded that gentling anxious cats in animal shelters can induce positive affect (contentment), increase production of S-IgA, and reduce the incidence of upper respiratory disease. (C) 2014 Elsevier B.V. All rights reserved.

Reproduction is an energy-expensive process that relies on indicators of energy availability to adjust its proper functioning. The adipokine leptin provides one such metabolic signal, with leptin receptorexpressing neurons at sites widespread within the CNS, including regions associated with the neuroendocrine reproductive axis. One substantial population lies within the hypothalamic ventral premammillary nucleus (PMv), a region itself linked to reproductive control, which may provide a strategic site for the integration of energy availability, sensory and gonadal cues. Here we review our current understanding of leptin and PMv regulation of reproduction, including emerging details about intracellular mechanisms of leptin action at this site. (C) 2014 Elsevier B.V. All rights reserved.

Bone marrow-derived inflammatory cells, including platelets, may contribute to the progression of pressure overload-induced left ventricular hypertrophy (LVH). However, the underlying mechanisms for this are still unclear. One potential mechanism is through release of granule cargo. Unc13-d(Jinx) (Jinx) mice, which lack Munc13-4, a limiting factor in vesicular priming and fusion, have granule secretion defects in a variety of hematopoietic cells, including platelets. In the current study, we investigated the role of granule secretion in the development of LVH and cardiac remodeling using chimeric mice specifically lacking Munc13-4 in marrow-derived cells. Pressure overload was elicited by transverse aortic constriction (TAC). Chimeric mice were created by bone marrow transplantation. Echocardiography, histology staining, immunohistochemistry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were used to study LVH progression and inflammatory responses. Wild-type (WT) mice that were transplanted with WT bone marrow (WT -> WT) and WT mice that received Jinx bone marrow (Jinx -> WT) developed LVH and a classic fetal reprogramming response early (7 days) after TAC. However, at late times (5 wk), mice lacking Munc13-4 in bone marrow-derived cells (Jinx -> WT) failed to sustain the cardiac hypertrophy observed in WT chimeric mice. No difference in cardiac fibrosis was observed at early or late time points. Reinjection of WT platelets or platelet releasate partially restored cardiac hypertrophy in Jinx chimeric mice. These results suggest that sustained LVH in the setting of pressure overload depends on one or more factors secreted from bone marrow-derived cells, possibly from platelets. Inhibiting granule cargo release may represent a novel target for preventing sustained LVH.

During gestation, development proceeds at a pace that is unmatched by any other stage of the life cycle. For these reasons the human fetus is particularly susceptible not only to organizing influences, but also to pathogenic disorganizing influences. Growing evidence suggests that exposure to prenatal adversity leads to neurological changes that underlie lifetime risks for mental illness. Beginning early in gestation, males and females show differential developmental trajectories and responses to stress. It is likely that sex-dependent organization of neural circuits during the fetal period influences differential vulnerability to mental health problems. We consider in this review evidence that sexually dimorphic responses to early life stress are linked to two developmental disorders: affective problems (greater female prevalence) and autism spectrum disorder (greater male prevalence). Recent prospective studies illustrating the neurodevelopmental consequences of fetal exposure to stress and stress hormones for males and females are considered here. Plausible biological mechanisms including the role of the sexually differentiated placenta are discussed. (C) 2014 Elsevier Ltd. All rights reserved.

Background: The relationship between the pathogenic amyloid beta-peptide species A beta 1-42 and tau pathology has been well studied and suggests that A beta 1-42 can accelerate tau pathology in vitro and in vivo. The manners if any in which A beta 1-40 interacts with tau remains poorly understood. In order to answer this question, we used cell-based system, transgenic fly and transgenic mice as models to study the interaction between A beta 1-42 and A beta 1-40. Results: In our established cellular model, live cell imaging (using confocal microscopy) combined with biochemical data showed that exposure to A beta 1-42 induced cleavage, phosphorylation and aggregation of wild-type//full length tau while exposure to A beta 1-40 didn't. Functional studies with A beta 1-40 were carried out in tau-GFP transgenic flies and showed that A beta 1-42, as previously reported, disrupted cytoskeletal structure while A beta 1-40 had no effect at same dose. To further explore how A beta 1-40 affects tau pathology in vivo, P301S mice (tau transgenic mice) were injected intracerebrally with either A beta 1-42 or A beta 1-40. We found that treatment with A beta 1-42 induced tau phosphorylation, cleavage and aggregation of tau in P301S mice. By contrast, A beta 1-40 injection didn't alter total tau, phospho-tau (recognized by PHF-1) or cleavage of tau, but interestingly, phosphorylation at Ser(262) was shown to be significantly decreased after direct inject of A beta 1-40 into the entorhinal cortex of P301S mice. Conclusions: These results demonstrate that A beta 1-40 plays different role in tau pathogenesis compared to A beta 1-42. A beta 1-40 may have a protective role in tau pathogenesis by reducing phosphorylation at Ser(262), which has been shown to be neurotoxic.

Cell-surface proteins are central for the interaction of cells with their surroundings and are also associated with numerous diseases. These molecules are exposed to mechanical forces, but the exact relation between force and the functions and pathologies associated with cell-surface proteins is unclear. An important cell-surface protein is CD4, the primary receptor of HIV-1. Here we show that mechanical force activates conformational and chemical changes on CD4 that may be important during viral attachment. We have used single-molecule force spectroscopy and analysis on HIV-1 infectivity to demonstrate that the mechanical extension of CD4 occurs in a time-dependent manner and correlates with HIV-1 infectivity. We show that Ibalizumab, a monoclonal antibody that blocks HIV-1, prevents the mechanical extension of CD4 domains 1 and 2. Furthermore, we demonstrate that thiol/disulfide exchange in CD4 requires force for exposure of cryptic disulfide bonds. This mechanical perspective provides unprecedented information that can change our understanding on how viruses interact with their hosts.

A description is provided of the software algorithms developed for the CMS tracker both for reconstructing charged-particle trajectories in proton-proton interactions and for using the resulting tracks to estimate the positions of the LHC luminous region and individual primary-interaction vertices. Despite the very hostile environment at the LHC, the performance obtained with these algorithms is found to be excellent. For t (t) over bar events under typical 2011 pileup conditions, the average track-reconstruction efficiency for promptly-produced charged particles with transverse momenta of p(T) > 0.9GeV is 94% for pseudorapidities of vertical bar eta vertical bar < 0.9 and 85% for 0.9 < vertical bar eta vertical bar < 2.5. The inefficiency is caused mainly by hadrons that undergo nuclear interactions in the tracker material. For isolated muons, the corresponding efficiencies are essentially 100%. For isolated muons of p(T) = 100GeV emitted at vertical bar eta vertical bar < 1.4, the resolutions are approximately 2.8% in p(T), and respectively, 10 m m and 30 mu m in the transverse and longitudinal impact parameters. The position resolution achieved for reconstructed primary vertices that correspond to interesting pp collisions is 10-12 mu m in each of the three spatial dimensions. The tracking and vertexing software is fast and flexible, and easily adaptable to other functions, such as fast tracking for the trigger, or dedicated tracking for electrons that takes into account bremsstrahlung.