The rockefeller university

Proteins that associate with microtubules (MTs) are crucial to generate MT arrays and establish different cellular architectures. One example is PRC1 (protein regulator of cytokinesis 1), which cross-links antiparallel MTs and is essential for the completion of mitosis and cytokinesis. Here we describe a 4-angstrom-resolution cryo-EM structure of monomeric PRC1 bound to MTs. Residues in the spectrin domain of PRC1 contacting the MT are highly conserved and interact with the same pocket recognized by kinesin. We additionally found that PRC1 promotes MT assembly even in the presence of the MT stabilizer taxol. Interestingly, the angle of the spectrin domain on the MT surface corresponds to the previously observed cross-bridge angle between MTs cross-linked by full-length, dimeric PRC1. This finding, together with molecular dynamic simulations describing the intrinsic flexibility of PRC1, suggests that the MT-spectrin domain interface determines the geometry of the MT arrays cross-linked by PRC1.

The exclusive deep inelastic electroproduction of psi(2S) and J/psi (1S) at an ep centre-of-mass energy of 317 GeV has been studied with the ZEUS detector at HERA in the kinematic range 2 < Q(2) < 80 GeV2, 30 < W < 210 GeV and vertical bar t vertical bar < 1 GeV2, where Q(2) is the photon virtuality, W is the photon-proton centre-of-mass energy and t is the squared four-momentum transfer at the proton vertex. The data for 2 < Q(2) < 5 GeV2 were taken in the HERA I running period and correspond to an integrated luminosity of 114 pb(-1). The data for 5 < Q(2) < 80 GeV2 are from both HERA I and HERA II periods and correspond to an integrated luminosity of 468 pb(-1). The decay modes analysed were mu(+)mu(-) and J/psi(1S)pi(+)pi(-) for the psi(2S) and mu(+)mu(-) for the J/psi(1S). The cross-section ratio sigma(psi(2S))/sigma(J/psi(1S)) has been measured as a function of Q(2), W and t. The results are compared to predictions of QCD-inspired models of exclusive vector-meson production. (C) 2016 The Author(s). Published by Elsevier B.V.

Over the past 20 years, breakthrough discoveries of chromatin-modifying enzymes and associated mechanisms that alter chromatin in response to physiological or pathological signals have transformed our knowledge of epigenetics from a collection of curious biological phenomena to a functionally dissected research field. Here, we provide a personal perspective on the development of epigenetics, from its historical origins to what we define as 'the modern era of epigenetic research'. We primarily highlight key molecular mechanisms of and conceptual advances in epigenetic control that have changed our understanding of normal and perturbed development.

Background: Understanding the relationship between a stimulus and how it is perceived reveals fundamental principles about the mechanisms of sensory perception. While this stimulus-percept problem is mostly understood for color vision and tone perception, it is not currently possible to predict how a given molecule smells. While there has been some progress in predicting the pleasantness and intensity of an odorant, perceptual data for a larger number of diverse molecules are needed to improve current predictions. Towards this goal, we tested the olfactory perception of 480 structurally and perceptually diverse molecules at two concentrations using a panel of 55 healthy human subjects. Results: For each stimulus, we collected data on perceived intensity, pleasantness, and familiarity. In addition, subjects were asked to apply 20 semantic odor quality descriptors to these stimuli, and were offered the option to describe the smell in their own words. Using this dataset, we replicated several previous correlations between molecular features of the stimulus and olfactory perception. The number of sulfur atoms in a molecule was correlated with the odor quality descriptors "garlic," "fish," and "decayed," and large and structurally complex molecules were perceived to be more pleasant. We discovered a number of correlations in intensity perception between molecules. We show that familiarity had a strong effect on the ability of subjects to describe a smell. Many subjects used commercial products to describe familiar odorants, highlighting the role of prior experience in verbal reports of olfactory perception. Nonspecific descriptors like "chemical" were applied frequently to unfamiliar odorants, and unfamiliar odorants were generally rated as neither pleasant nor unpleasant. Conclusions: We present a very large psychophysical dataset and use this to correlate molecular features of a stimulus to olfactory percept. Our work reveals robust correlations between molecular features and perceptual qualities, and highlights the dominant role of familiarity and experience in assigning verbal descriptors to odorants.

BackgroundChronic hand and foot eczema (CHFE), a prevalent debilitating disorder affecting approximately 15% of the population, presents a socioeconomic and psychosocial burden for patients and often follows a chronic course, refractory to conventional therapies. Thus, a large need exists for more effective therapeutics; the excimer laser (308 nm) is effective for some inflammatory skin diseases, but its efficacy has not been evaluated for CHFE. MethodsThe study is a retrospective chart review conducted on 30 patients with recalcitrant CHFE (19 with hand involvement, four with foot involvement, and seven with both) treated twice weekly with excimer laser (308 nm) single wavelength ultraviolet (UV)B radiation between January 2013 and December 2014. ResultsImprovements in clinical scores included a 69% reduction in average physician's global assessment (PGA) scores (from 2.77 at baseline to 0.87 after treatment, P < 0.0001) with a parallel reduction in average modified total lesion/symptom scores of 70% (from 10.2 to 3.1, P < 0.0001). Only mild sunburn-like reactions were observed. ConclusionThis report evaluates excimer laser for patients with refractory CHFE and shows excellent and sustained efficacy for this treatment. Compared to other UV therapies, excimer laser offers lower cumulative doses of UV radiation by targeting specific areas. This effective treatment should be considered alone or in combination with other established or newer therapies.

Background The interleukin-17 cytokine family plays a central role in psoriasis pathogenesis. Objectives To evaluate the efficacy and safety of brodalumab, a human anti-interleukin-17 receptor antibody, in treating patients with moderate-to-severe plaque psoriasis. Methods In this phase III, double-blind, placebo-controlled study (NCT01708590; AMAGINE-1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210 mg) or placebo every 2 weeks (Q2W), with an additional dose at week 1, for a 12-week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA >= 3 were re-treated with the induction dose. After >= 12 weeks of retreatment, patients with sPGA 2 for >= 4 weeks or sPGA >= 3 were rescued with brodalumab 210 mg Q2W. At week 12, patients randomized to brodalumab with sPGA >= 2 or placebo received brodalumab 210 mg Q2W. Coprimary end points were the percentage of patients with >= 75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12. Results There were 661 patients randomized: 220 placebo, 219 brodalumab 140 mg and 222 brodalumab 210 mg. At week 12, 60% (140 mg) and 83% (210 mg) vs. 3% (placebo) achieved PASI 75, and 54% (140 mg) and 76% (210 mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable. Conclusions Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate-to-severe plaque psoriasis.

The discovery of steroid hormone receptors in brain regions that mediate virtually every aspect of brain function has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as determining the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neurogenesis leading to neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. The two Brain Research papers noted in this review played an important role in triggering these advances. This article is part of a Special Issue entitled SI:50th Anniversary Issue. (C) 2016 Published by Elsevier B.V.

Giant cell tumor of bone (GCTB) is a locally aggressive primary bone tumor. Its malignant counterpart is quite rare. Rarely, a conventional GCTB shows marked nuclear atypia, referred to as symplastic/pseudoanaplastic change, which can mimic sarcomatous transformation. Recently, somatic driver mutations of histone H3.3 exclusively in H3F3A have been described in GCTB. We report a series of 9 cases of GCTB with symplastic/pseudoanaplastic change, along with analysis of H3F3A variants. Nine cases of GCTB with symplastic change were identified. Clinico-radiological features, morphological features, and immunohistochemical stain for Ki-67 stain were reviewed. H3F3A variants were also analyzed using Sanger sequencing. Histologically, conventional giant cell tumor areas with scattered foci of markedly atypical cells were seen in all of the cases and all showed rare if any Ki-67 labeling. One patient had received denosumab treatment and another radiation therapy. Radiological features were characteristic of conventional GCTB. Mutation in H3F3A (p.Gly34Trp [G34W]) was found in 6 of the 7 cases. Clinical follow-up ranged from 6 to 208 months. Local recurrences were seen in 4 cases (44 %). GCTB with symplastic/pseudoanaplastic change is an uncommon variant of conventional GCTB, which can mimic primary sarcoma or sarcomatous transformation. These tumors possess the same missense mutation in histone H3.3 as conventional GCTB.

Chordoma is a rare primary bone neoplasm that is resistant to standard chemotherapies. Despite aggressive surgical management, local recurrence and metastasis is not uncommon. To identify the specific genetic aberrations that play key roles in chordoma pathogenesis, we utilized a genome-wide high-resolution SNP-array and next generation sequencing (NGS)-based molecular profiling platform to study 24 patient samples with typical histopathologic features of chordoma. Matching normal tissues were available for 16 samples. SNP-array analysis revealed nonrandom copy number losses across the genome, frequently involving 3, 9p, 1p, 14, 10, and 13. In contrast, copy number gain is uncommon in chordomas. Two minimum deleted regions were observed on 3p within a similar to 8 Mb segment at 3p21.1-p21.31, which overlaps SETD2, BAP1 and PBRM1. The minimum deleted region on 9p was mapped to CDKN2A locus at 9p21.3, and homozygous deletion of CDKN2A was detected in 5/22 chordomas (similar to 23%). NGS-based molecular profiling demonstrated an extremely low level of mutation rate in chordomas, with an average of 0.5 mutations per sample for the 16 cases with matched normal. When the mutated genes were grouped based on molecular functions, many of the mutation events (similar to 40%) were found in chromatin regulatory genes. The combined copy number and mutation profiling revealed that SETD2 is the single gene affected most frequently in chordomas, either by deletion or by mutations. Our study demonstrated that chordoma belongs to the C-class (copy number changes) tumors whose oncogenic signature is non-random multiple copy number losses across the genome and genomic aberrations frequently alter chromatin regulatory genes. (C) 2016 Wiley Periodicals, Inc.