The rockefeller university

Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists.

We measure the forward-backward asymmetry of the production of top-quark and antiquark pairs in proton-antiproton collisions at center-of-mass energy root s = 1.96 TeV using the full data set collected by the Collider Detector at Fermilab (CDF) in Tevatron Run II corresponding to an integrated luminosity of 9.1 fb(-1). The asymmetry is characterized by the rapidity difference between top quarks and antiquarks (Delta y) and measured in the final state with two charged leptons (electrons and muons). The inclusive asymmetry, corrected to the entire phase space at parton level, is measured to be A(FB)(t (t) over bar) = 0.12 +/- 0.13, consistent with the expectations from the standard model (SM) and previous CDF results in the final state with a single charged lepton. The combination of the CDF measurements of the inclusive A(FB)(t (t) over bar) in both final states yields A(FB)(t (t) over bar) 0.160 +/- 0.045, which is consistent with the SM predictions. We also measure the differential asymmetry as a function of Delta y. A linear fit to A(FB)(t (t) over bar) (vertical bar Delta y vertical bar),assuming zero asymmetry at Delta y = 0, yields a slope of alpha = 0.14 +/- 0.15, consistent with the SM prediction and the previous CDF determination in the final state with a single charged lepton. The combined slope of A(FB)(t (t) over bar) (vertical bar Delta y vertical bar) the two final states is alpha = 0.227 +/- 0.057, which is 2.0 sigma larger than the SM prediction.

Background: Tofacitinib is a Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis. We report efficacy of tofacitinib in patient subgroups based on pooled data from two Phase 3 trials (NCT01276639, NCT01309737). Objectives: To assess consistency of treatment effects of tofacitinib versus placebo in subgroups defined by baseline characteristics, and to ascertain whether baseline characteristics are of value in optimizing tofacitinib use. Methods: Pooled data from the two trials were used to evaluate >= 75% reduction in PASI from baseline (PASI75 response) in subgroups defined by age, age at psoriasis onset, gender, race, geographical region, weight, body mass index, diabetes, metabolic syndrome, tobacco/alcohol use, psoriatic arthritis, disease activity, and prior therapy. Results: Week 16 PASI75 response rates (N=1843) were 43%, 59% and 9% with tofacitinib 5 and 10mg twice daily (BID) and placebo, respectively (each P<0.0001 versus placebo). Tofacitinib 5 and 10mg BID were effective regardless of baseline characteristics. Across subgroups, tofacitinib generally produced greater response rates with the 10 versus 5mg BID dosage. Lower absolute response rates were seen in heavier patients and patients with prior biologic experience. Conclusions: Both tofacitinib dosages demonstrated consistent efficacy versus placebo across subgroups. Lower response rates were seen in heavier patients and those with prior biologic experience. Tofacitinib 10mg BID resulted in a substantial proportion of responders regardless of baseline characteristics.

AimClarifying whether multiple introductions of a species remain relatively isolated or merge and interbreed is essential for understanding the dynamics of invasion processes. Multiple introductions from different sources can result in a mixture of genetically distinct populations, increasing the total genetic diversity. This mixing can resolve the genetic paradox', whereby in spite of the relatively small numbers of introduced individuals, the augmented diversity due to this mixing increases adaptability and the ability of the species to spread in new environments. Here, we aim to assess whether the expansion of a successful invader, the Eastern grey squirrel, was partly driven by the merger of multiple introductions and the effects of such a merger on diversity. LocationUK, Ireland. MethodsWe analysed the genetic variation at 12 microsatellite loci of 381 individuals sampled from one historical and 14 modern populations of grey squirrels. ResultsOur data revealed that current UK population structure resembles a mosaic, with minimal interpopulation mixing and each element reflecting the genetic make-up of historic introductions. The genetic diversity of each examined population was lower than a US population or a historical UK population. Numbers of releases in a county did not correlate with county-level genetic diversity. Inbreeding coefficients remain high, and effective population sizes remain small. Main conclusionsOur results support the conclusion that rapid and large-scale expansion in this species in the UK was not driven by a genetic mixing of multiple introduced populations with a single expansion front, but was promoted by repeated translocations of small propagules. Our results have implications for the management of grey squirrels and other invasive species and also demonstrate how invaders can overcome the genetic paradox, if spread is facilitated by human-mediated dispersal.

Human male germ cell tumors (GCTs) are derived from primordial germ cells (PGCs). The master pluripotency regulator and neuroectodermal lineage effector transcription factor SOX2 is repressed in PGCs and the seminoma (SEM) subset of GCTs. The mechanism of SOX2 repression and its significance to GC and GCT development currently are not understood. Here, we show that SOX2 repression in SEM-derived TCam-2 cells is mediated by the Polycomb repressive complex (PcG) and the repressive H3K27me3 chromatin mark that are enriched at its promoter. Furthermore, SOX2 repression in TCam-2 cells can be abrogated by recruitment of the constitutively expressed H3K27 demethylase UTX to the SOX2 promoter through retinoid signaling, leading to expression of neuronal and other lineage genes. SOX17 has been shown to initiate human PGC specification, with its target PRDM1 suppressing mesendodermal genes. Our results are consistent with a role for SOX2 repression in normal germline development by suppressing neuroectodermal genes.

Actin, spectrin, and associated molecules form a periodic, submembrane cytoskeleton in the axons of neurons. For a better understanding of this membrane-associated periodic skeleton (MPS), it is important to address how prevalent this structure is in different neuronal types, different subcellular compartments, and across different animal species. Here, we investigated the organization of spectrin in a variety of neuronal-and glial-cell types. We observed the presence of MPS in all of the tested neuronal types cultured from mouse central and peripheral nervous systems, including excitatory and inhibitory neurons from several brain regions, as well as sensory and motor neurons. Quantitative analyses show that MPS is preferentially formed in axons in all neuronal types tested here: Spectrin shows a long-range, periodic distribution throughout all axons but appears periodic only in a small fraction of dendrites, typically in the form of isolated patches in subregions of these dendrites. As in dendrites, we also observed patches of periodic spectrin structures in a small fraction of glial-cell processes in four types of glial cells cultured from rodent tissues. Interestingly, despite its strong presence in the axonal shaft, MPS is disrupted in most presynaptic boutons but is present in an appreciable fraction of dendritic spine necks, including some projecting from dendrites where such a periodic structure is not observed in the shaft. Finally, we found that spectrin is capable of adopting a similar periodic organization in neurons of a variety of animal species, including Caenorhabditis elegans, Drosophila, Gallus gallus, Mus musculus, and Homo sapiens.

More than half of the >5000 approved mineral species are known from five or fewer localities and thus are rare. Mineralogical rarity arises from different circumstances, but all rare mineral species conform to one or more of four criteria: (1) P-T-Xrange: minerals that form only under highly restricted conditions in pressure-temperature-composition space; (2) Planetary constraints: minerals that incorporate essential elements that are rare or that form at extreme conditions that seldom occur in Earth's near-surface environment; (3) Ephemeral phases: minerals that rapidly break down under ambient conditions; and (4) Collection biases: phases that are difficult to recognize because they lack crystal faces or are microscopic, or minerals that arise in lithological contexts that are difficult to access. Minerals that conform to criterion 1, 2, or 3 are inherently rare, whereas those matching criterion 4 may be much more common than represented by reported occurrences. Rare minerals, though playing minimal roles in Earth's bulk properties and dynamics, are nevertheless of significance for varied reasons. Uncommon minerals are key to understanding the diversity and disparity of Earth's mineralogical environments, for example in the prediction of as yet undescribed minerals. Novel minerals often point to extreme compositional regimes that can arise in Earth's shallow crust and they are thus critical to understanding Earth as a complex evolving system. Many rare minerals have unique crystal structures or reveal the crystal chemical plasticity of well-known structures, as dramatically illustrated by the minerals of boron. Uncommon minerals may have played essential roles in life's origins; conversely, many rare minerals arise only as a consequence, whether direct or indirect, of biological processes. The distribution of rare minerals may thus be a robust biosignature, while these phases individually and collectively exemplify the co-evolution of the geosphere and biosphere. Finally, mineralogical rarities, as with novelty in other natural domains, are inherently fascinating.

Background: A high dietary calcium intake with adequate vitamin D status has been linked to lower colorectal cancer risk, but the mechanisms of these effects are poorly understood. Objective: The objective of this study was to elucidate the effects of a Western-style diet (WD) and supplemental calcium and/or 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] on the colorectal mucosa. Design: We conducted 2 crossover trials to define molecular pathways in the human colorectum altered by 1) a 4-wk WD supplemented with and without 2 g calcium carbonate/d and 2) a 4-wk WD supplemented with 1,25(OH)(2)D-3 (0.5 mu g/d) with or without 2 g calcium carbonate/d. The primary study endpoint was genome-wide gene expression in biopsy specimens of the rectosigmoid colonic mucosa. Serum and urinary calcium concentrations were also measured. Results: Changes in urinary calcium accurately reflected calcium consumption. The WD induced modest upregulation of genes involved in inflammatory pathways, including interferon signaling, and calcium supplementation reversed these toward baseline. In contrast, supplementation of the WD with 1,25(OH)(2)D-3 induced striking upregulation of genes involved in inflammation, immune response, extracellular matrix, and cell adhesion. Calcium supplementation largely abrogated these changes. Conclusions: Supplementing 1,25(OH)(2)D-3 to a WD markedly up regulated genes in immune response and inflammation pathways, which were largely reversed by calcium supplementation. This study provides clinical trial evidence of global gene expression changes occurring in the human colorectum in response to calcium and 1,25(OH)(2)D-3 intervention. One action of 1,25(OH)(2)D-3 is to upregulate adaptive immunity. Calcium appears to modulate this effect, pointing to its biological interaction in the mucosa.

Gestational ex posure to a fat-rich diet, while elevating maternal circulating fatty acids, increases in the offspring's hypothalamus and amygdala the proliferation and density of neurons that express neuropeptides known to stimulate consummatory behavior. To understand the relationship between these phenomena, this study examined in the brain of postnatal offspring (day 15) the effect of prenatal fat exposure on the transcription factor, peroxisome proliferator-activated receptor (PPAR) beta/delta, which is sensitive to fatty acids, and the relationship of PPAR beta/delta to the orexigenic neuropeptides, orexin, melanin-concentrating hormone, and enkephalin. Prenatal exposure to a fat-rich diet compared to low-fat chow increased the density of cells immunoreactive for PPAR beta/delta in the hypothalamic paraventricular nucleus (PVN), perifornical lateral hypothalamus (PFLH), and central nucleus of the amygdala (CeA), but not the hypothalamic arcuate nucleus or basolateral amygdaloid nucleus. It also increased co-labeling of PPAR beta/delta with the cell proliferation marker, BrdU, or neuronal marker, NeuN, and the triple labeling of PPAR beta/delta with BrdU plus NeuN, indicating an increase in proliferation and density of new PPAR beta/delta neurons. Prenatal fat exposure stimulated the double-labeling of PPAR beta/delta with orexin or melanin-concentrating hormone in the PFLH and enkephalin in the PVN and CeA and also triple-labeling of PPAR beta/delta with BrdU and these neuropeptides, indicating that dietary fat increases the genesis of PPAR beta/delta neurons that produce these peptides. These findings demonstrate a close anatomical relationship between PPAR beta/delta and the increased proliferation and density of peptide-expressing neurons in the hypothalamus and amygdala of fat-exposed offspring. (C) 2016 Elsevier Inc. All rights reserved.

Alzheimer's disease (AD) is often characterized by vascular pathology, a procoagulant state, and chronic inflammation. The mechanisms behind these abnormalities in AD are not clear. Here, we review evidence for the role of the AD-associated peptide A beta in promoting inflammation and thrombosis in AD via its interaction with the circulating proteins factor XII and fibrinogen. (C) 2016 Elsevier Ltd. All rights reserved.