The rockefeller university

Psoriasis vulgaris is a chronic inflammatory skin disease that results from the complex interplay between keratinocytes, dendritic cells, and T cells. Keratinocytes trigger innate and adaptive immune responses. Dermal myeloid dendritic cells regulate T cell activation and production of cytokines and chemokines that amplify inflammation. Most of the psoriatic T cells discretely produce interferon-gamma, interleukin (IL)-17, and IL-22. The initiation phase of psoriasis involves Toll-like receptors, antimicrobial peptide LL37, and plasmacytoid dendritic cells. Keratinocytes are the main cutaneous cell type expressing IL-17 receptors and hence the immune circuit is amplified by keratinocytes upregulating mRNAs for a range of inflammatory products.

It has been assumed in models of cochlear mechanics that the primary role of the cochlear active process is to counteract the damping of the basilar membrane, the vibration of which is much larger in a living animal than post mortem. Recent measurements of the relative motion between the reticular lamina and basilar membrane imply that this assumption is incorrect. We propose that damping is distributed throughout the cochlear partition rather than being concentrated in the basilar membrane. In the absence of significant damping, the cochlear partition possesses three modes of vibration, each associated with its own locus of Hopf bifurcations. Hair-cell activity can amplify any of these modes if the system's operating point lies near the corresponding bifurcation. The distribution of damping determines which mode of vibration predominates. For physiological levels of damping, only one mode produces a vibration pattern consistent with experimental measurements of relative motion and basilar-membrane motion.

Colorectal cancer primarily metastasizes to the liver and globally kills over 600,000 people annually. By functionally screening 661 microRNAs (miRNAs) in parallel during liver colonization, we have identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP-fueling metastatic survival. Combinatorial therapeutic viral delivery of miR-551a and miR-483-5p through single-dose adeno-associated viral (AAV) delivery significantly suppressed colon cancer metastasis, as did CKB inhibition with a small-molecule inhibitor. Importantly, human liver metastases express higher CKB and SLC6A8 levels and reduced miR-551a/miR-483 levels relative to primary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting.

Scbizosaccharomyees pombe is a good model to study cell-size control. These cells integrate size information into cell cycle controls at both the G1/S and G2/M transitions, although the primary control operates at the entry into mitosis. At G2/M there is both a size threshold, demonstrated by the fact that cells divide when they reach 14 mu m in length, and also correction around this threshold, evident from the narrow distribution of sizes within a population. This latter property is referred to as size homeostasis. It has been argued that a population of cells accumulating mass in a linear fashion will have size homeostasis in the absence of size control, if cycle time is controlled by a fixed timer. Because fission yeast cells do not grow in a simple linear fashion, they require a size-sensing mechanism. However, current models do not fully describe all aspects of this control, especially the coordination of cell size with ploidy.

Markov's inequality gives an upper bound on the probability that a nonnegative random variable takes large values. For example, if the random variable is the lifetime of a person or a machine, Markov's inequality says that the probability that an individual survives more than three times the average lifetime in the population of such individuals cannot exceed one-third. Here we give a simple, intuitive geometric interpretation and derivation of Markov's inequality. These results lead to inequalities sharper than Markov's when information about conditional expectations is available, as in reliability theory, demography, and actuarial mathematics. We use these results to sharpen Chebyshev's tail inequality also.

The human geneticist Archibald Garrod noted in 1931 that, "It is, of necessity, no easy matter to distinguish between immunity which is inborn and that which has been acquired'' (The Inborn Factors in Disease). In this issue of Cell, Brodin et al. show that the heritability of blood counts rapidly decreases with age for the lymphoid subsets responsible for adaptive immunity, unlike cells from other hematopoietic lineages.

Aims: Mineralo-organic nanoparticles (NPs) detected in biological fluids have been described as precursors of physiological and pathological calcifications in the body. Our main objective was to examine the early stages of mineral NP formation in body fluids. Materials & methods: A nanomaterial approach based on atomic force microscopy, dynamic light scattering, electron microscopy and spectroscopy was used. Results: The mineral particles, which contain the serum proteins albumin and fetuin-A, initially precipitate in the form of round amorphous NPs that gradually grow in size, aggregate and coalesce to form crystalline mineral films similar to the structures observed in calcified human arteries. Conclusion: Our study reveals the early stages of particle formation and provides a platform to analyze the role(s) of mineralo-organic NPs in human tissues.

A search is performed in proton-proton collisions at root s = 8 TeV for exotic particles decaying via WZ to fully leptonic final states with electrons, muons, and neutrinos. The data set corresponds to an integrated luminosity of 19.5 fb(-1). No significant excess is observed above the expected standard model background. Upper bounds at 95% confidence level are set on the production cross section of a W boson as predicted by an extended gauge model, and on the W'WZ coupling. The expected and observed mass limits for a W' boson, as predicted by this model, are 1.55 and 1.47 TeV, respectively. Stringent limits are also set in the context of low-scale technicolor models under a range of assumptions for the model parameters. (C) 2014 The Authors. Published by Elsevier B.V.

Background: Drug addiction is influenced by genetic factors. Aim: To determine if genetic variants in the serotonergic and adrenergic pathways are associated with heroin and/or cocaine addiction. Subjects & methods: The study examined 140 polymorphisms in 19 genes in 1855 subjects with predominantly European or African ancestries. Results: A total of 38 polymorphisms (13 genes) showed nominal associations, including novel associations in S100A10 (p11) and SLC18A2 (VMAT2). The association of HTR3B SNP rs11606194 with heroin addiction in the European ancestry subgroup remained significant after correction for multiple testing (p(corrected) = 0.04). Conclusion: The study strengthens our previous findings of association of polymorphisms in HTR3A, HTR3B and ADRA1A. The study suggests partial overlap in genetic susceptibility between populations of different ancestry and between heroin and cocaine addiction.

Mutations of spliceosome components are common in myeloid neoplasms. One of the affected genes, PRPF8, encodes the most evolutionarily conserved spliceosomal protein. We identified either recurrent somatic PRPF8 mutations or hemizygous deletions in 15/447 and 24/450 cases, respectively. Fifty percent of PRPF8 mutant and del(17p) cases were found in AML and conveyed poor prognosis. PRPF8 defects correlated with increased myeloblasts and ring sideroblasts in cases without SF3B1 mutations. Knockdown of PRPF8 in K562 and CD34+ primary bone marrow cells increased proliferative capacity. Whole-RNA deep sequencing of primary cells from patients with PRPF8 abnormalities demonstrated consistent missplicing defects. In yeast models, homologous mutations introduced into Prp8 abrogated a block experimentally produced in the second step of the RNA splicing process, suggesting that the mutants have defects in proof-reading functions. In sum, the exploration of clinical and functional consequences suggests that PRPF8 is a novel leukemogenic gene in myeloid neoplasms with a distinct phenotype likely manifested through aberrant splicing.