Screening of DUB activity and specificity by MALDI-TOF mass spectrometry

Deubiquitylases (DUBs) are key regulators of the ubiquitin system which cleave ubiquitin moieties from proteins and polyubiquitin chains. Several DUBs have been implicated in various diseases and are attractive drug targets. We have developed a sensitive and fast assay to quantify in vitro DUB enzyme activity using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Unlike other current assays, this method uses unmodified substrates, such as diubiquitin topoisomers. By analyzing 42 human DUBs against all diubiquitin topoisomers we provide an extensive characterization of DUB activity and specificity. Our results confirm the high specificity of many members of the OTU and JAMM DUB families and highlight that all USPs tested display low linkage selectivity. We also demonstrate that this assay can be deployed to assess the potency and specificity of DUB inhibitors by profiling 11 compounds against a panel of 32 DUBs

Precision Measurement of the First Ionization Potential of Nobelium

One of the most important atomic properties governing an element’s chemical behavior is the energy required to remove its least-bound electron, referred to as the first ionization potential. For the heaviest elements, this fundamental quantity is strongly influenced by relativistic effects which lead to unique chemical properties. Laser spectroscopy on an atom-at-a-time scale was developed and applied to probe the optical spectrum of neutral nobelium near the ionization threshold. The first ionization potential of nobelium is determined here with a very high precision from the convergence of measured Rydberg series to be 6.626   21 ± 0.000   05     eV . This work provides a stringent benchmark for state-of-the-art many-body atomic modeling that considers relativistic and quantum electrodynamic effects and paves the way for high-precision measurements of atomic properties of elements only available from heavy-ion accelerator facilities

Gene Ontology: Pitfalls, Biases, and Remedies.

The Gene Ontology (GO) is a formidable resource, but there are several considerations about it that are essential to understand the data and interpret it correctly. The GO is sufficiently simple that it can be used without deep understanding of its structure or how it is developed, which is both a strength and a weakness. In this chapter, we discuss some common misinterpretations of the ontology and the annotations. A better understanding of the pitfalls and the biases in the GO should help users make the most of this very rich resource. We also review some of the misconceptions and misleading assumptions commonly made about GO, including the effect of data incompleteness, the importance of annotation qualifiers, and the transitivity or lack thereof associated with different ontology relations. We also discuss several biases that can confound aggregate analyses such as gene enrichment analyses. For each of these pitfalls and biases, we suggest remedies and best practices

Longitudinal study of adolescent tobacco use and tobacco control policies in India

Abstract Background This project will use a multilevel longitudinal cohort study design to assess whether changes in Community Tobacco Environmental (CTE) factors, measured as community compliance with tobacco control policies and community density of tobacco vendors and tobacco advertisements, are associated with adolescent tobacco use in urban India. India’s tobacco control policies regulate secondhand smoke exposure, access to tobacco products and exposure to tobacco marketing. Research data about the association between community level compliance with tobacco control policies and youth tobacco use are largely unavailable, and are needed to inform policy enforcement, implementation and development. Methods The geographic scope will include Mumbai and Kolkata, India. The study protocol calls for an annual comprehensive longitudinal population-based tobacco use risk and protective factors survey in a cohort of 1820 adolescents ages 12–14 years (and their parent) from baseline (Wave 1) to 36-month follow-up (Wave 4). Geographic Information Systems data collection will be used to map tobacco vendors, tobacco advertisements, availability of e-cigarettes, COTPA defined public places, and compliance with tobacco sale, point-of-sale and smoke-free laws. Finally, we will estimate the longitudinal associations between CTE factors and adolescent tobacco use, and assess whether the associations are moderated by family level factors, and mediated by individual level factors. Discussion India experiences a high burden of disease and mortality from tobacco use. To address this burden, significant long-term prevention and control activities need to include the joint impact of policy, community and family factors on adolescent tobacco use onset. The findings from this study can be used to guide the development and implementation of future tobacco control policy designed to minimize adolescent tobacco use.https://deepblue.lib.umich.edu/bitstream/2027.42/144539/1/12889_2018_Article_5727.pd

Socio-Economic Inequalities in the Use of Postnatal Care in India

OBJECTIVES: First, our objective was to estimate socio-economic inequalities in the use of postnatal care (PNC) compared with those in the use of care at birth and antenatal care. Second, we wanted to compare inequalities in the use of PNC between facility births and home births and to determine inequalities in the use of PNC among mothers with high-risk births. METHODS AND FINDINGS: Rich-poor ratios and concentration indices for maternity care were estimated using the third round of the District Level Household Survey conducted in India in 2007-08. Binary logistic regression models were used to examine the socio-economic inequalities associated with use of PNC after adjusting for relevant socio-economic and demographic characteristics. PNC for both mothers and newborns was substantially lower than the care received during pregnancy and child birth. Only 44% of mothers in India at the time of survey received any care within 48 hours after birth. Likewise, only 45% of newborns received check-up within 24 hours of birth. Mothers who had home births were significantly less likely to have received PNC than those who had facility births, with significant differences across the socio-economic strata. Moreover, the rich-poor gap in PNC use was significantly wider for mothers with birth complications. CONCLUSIONS: PNC use has been unacceptably low in India given the risks of mortality for mothers and babies shortly after birth. However, there is evidence to suggest that effective use of pregnancy and childbirth care in health facilities led to better PNC. There are also significant socio-economic inequalities in access to PNC even for those accessing facility-based care. The coverage of essential PNC is inadequate, especially for mothers from economically disadvantaged households. The findings suggest the need for strengthening PNC services to keep pace with advances in coverage for care at birth and prenatal services in India through targeted policy interventions

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

H4 Histamine Receptors Mediate Cell Cycle Arrest in Growth Factor-Induced Murine and Human Hematopoietic Progenitor Cells

The most recently characterized H4 histamine receptor (H4R) is expressed preferentially in the bone marrow, raising the question of its role during hematopoiesis. Here we show that both murine and human progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid colony formation. H4R activation prevents the induction of cell cycle genes through a cAMP/PKA-dependent pathway that is not associated with apoptosis. It is mediated specifically through H4R signaling since gene silencing or treatment with selective antagonists restores normal cell cycle progression. The arrest of growth factor-induced G1/S transition protects murine and human progenitor cells from the toxicity of the cell cycle-dependent anticancer drug Ara-C in vitro and reduces aplasia in a murine model of chemotherapy. This first evidence for functional H4R expression in hematopoietic progenitors opens new therapeutic perspectives for alleviating hematotoxic side effects of antineoplastic drugs