Activation of pruritogenic TGR5, MRGPRA3, and MRGPRC11 on colon-innervating afferents induces visceral hypersensitivity

Itch induces scratching that removes irritants from the skin, whereas pain initiates withdrawal or avoidance of tissue damage. While pain arises from both the skin and viscera, we investigated whether pruritogenic irritant mechanisms also function within visceral pathways. We show that subsets of colon-innervating sensory neurons in mice express, either individually or in combination, the pruritogenic receptors Tgr5 and the Mas-gene-related GPCRs Mrgpra3 and Mrgprc11. Agonists of these receptors activated subsets of colonic sensory neurons and evoked colonic afferent mechanical hypersensitivity via a TRPA1-dependent mechanism. In vivo intracolonic administration of individual TGR5, MRGPRA3, or MRGPRC11 agonists induced pronounced visceral hypersensitivity to colorectal distension. Coadministration of these agonists as an "itch cocktail" augmented hypersensitivity to colorectal distension and changed mouse behavior. These irritant mechanisms were maintained and enhanced in a model of chronic visceral hypersensitivity relevant to irritable bowel syndrome. Neurons from human dorsal root ganglia also expressed TGR5, as well as the human ortholog MRGPRX1, and showed increased responsiveness to pruritogenic agonists in pathological states. These data support the existence of an irritant-sensing system in the colon that is a visceral representation of the itch pathways found in skin, thereby contributing to sensory disturbances accompanying common intestinal disorders. - 2019 American Society for Clinical Investigation. All rights reserved.Work was supported by a National Health and Medical Research Council of Australia (NHMRC) Project Grant (1083480 to SMB and DPP), an NHMRC R.D. Wright Biomedical Research Fellow (APP1126378 to SMB), and an Australian Research Council (ARC) Discovery Early Career Research Award (DE130100223 to AMH). NWB was supported by grants from the NIH (NS102722; DE026806; DK118971) and the US Department of Defence (W81XWH1810431).Scopu

Processed pseudogenes acquired somatically during cancer development.

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context

Reduction of cardiovascular risk in patients with metabolic syndrome in a community health center after a pharmaceutical care program of pharmacotherapy follow-up

The objective of this study was to determine the impact of a pharmaceutical care (PC) program in a sample of public outpatients with metabolic syndrome (MS) who were being treated in Brazil's health system; the patients were randomized into PC or standard care. The pharmacotherapy follow-up (PF) was performed in a total of 120 patients with type 2 diabetes for 6 months. Adherence to treatment (measured with the Morisky test), negative outcomes associated with medication (NOM) and anthropometric and biochemical parameters were measured before and after PF. The Framingham scoring method was used to estimate changes in 10-year coronary heart disease risk scores in all patients. Ninety-six of 120 patients had characteristics of MS and were randomized into two groups (G): the control group (CG: 36) and the intervention group (IG: 38). Among the MS patients, 100% were taking a glucose-lowering drug; many were also taking anti-hypertensive drugs (CG: 72%; IG: 73%), and some patients were also taking hypolipemic drugs (CG: 12.0%; IG: 14.7%). Only 20.7% of the IG patients were considered adherent to their prescribed drugs. In the CG, an increase of coronary heart disease (CHD) risk (22±2 to 26±3; pO objetivo deste estudo foi o de determinar o impacto de um Programa de atenção Farmacêutica (AF) em uma amostra de pacientes ambulatoriais de Sistema Público de Saúde do Brasil portadores de Síndrome Metabólica, randomizados em AF ou atenção à saúde usual. Realizou-se o seguimento farmacoterapêutico com 120 pacientes com diabetes tipo 2 durante seis meses. Avaliou-se o nível de aderência ao tratamento (teste Morisky), resultados clínicos negativos associados a medicamentos (RNM), parâmetros bioquímicos e antropométricos, antes e após o seguimento. O método de Framingham foi usado para calcular as variações no risco de doenças coronarianas em 10 anos em todos os pacientes. Dos 120 pacientes, 96 tiveram características de SM e foram então randomizados em dois grupos (G): Controle (GC: 36) e Intervenção (GI: 38). Entre os pacientes com SM, 100% faziam uso de medicamentos para diminuir a glicose, anti-hipertensivos (GC: 72%; GI: 73%) e hipoglicemiantes (GC: 12.0%; GI: 14.7%). Apenas 20,7% do GI foram considerados aderentes aos fármacos prescritos. No GC foi observado aumento do risco de Doença Arterial Coronariana (DAC) (22±2 para 26±3; p<0,05), enquanto no GI foi observado redução (22±2 para 14±2%; p<0,01). O Programa de AF para pacientes com SM monitorados na atenção primária do Sistema de Saúde Pública brasileiro melhora o funcionamento do serviço resultando na melhoria clínica dos pacientes com redução do risco de doença cardiovascular em um período de dez anos

Scholarly publishing depends on peer reviewers

The peer-review crisis is posing a risk to the scholarly peer-reviewed journal system. Journals have to ask many potential peer reviewers to obtain a minimum acceptable number of peers accepting reviewing a manuscript. Several solutions have been suggested to overcome this shortage. From reimbursing for the job, to eliminating pre-publication reviews, one cannot predict which is more dangerous for the future of scholarly publishing. And, why not acknowledging their contribution to the final version of the article published? PubMed created two categories of contributors: authors [AU] and collaborators [IR]. Why not a third category for the peer-reviewer?Scopu

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

Search for heavy resonances decaying into a Z or W boson and a Higgs boson in final states with leptons and b-jets in 139 fb−1 of pp collisions at s√ = 13 TeV with the ATLAS detector

This article presents a search for new resonances decaying into a Z or W boson and a 125 GeV Higgs boson h, and it targets the νν¯¯¯bb¯¯, ℓ+ℓ−bb¯¯, or ℓ±νbb¯¯ final states, where ℓ = e or μ, in proton-proton collisions at s√ = 13 TeV. The data used correspond to a total integrated luminosity of 139 fb−1 collected by the ATLAS detector during Run 2 of the LHC at CERN. The search is conducted by examining the reconstructed invariant or transverse mass distributions of Zh or Wh candidates for evidence of a localised excess in the mass range from 220 GeV to 5 TeV. No significant excess is observed and 95% confidence-level upper limits between 1.3 pb and 0.3 fb are placed on the production cross section times branching fraction of neutral and charged spin-1 resonances and CP-odd scalar bosons. These limits are converted into constraints on the parameter space of the Heavy Vector Triplet model and the two-Higgs-doublet model

The ATLAS trigger system for LHC Run 3 and trigger performance in 2022

The ATLAS trigger system is a crucial component of the ATLAS experiment at the LHC. It is responsible for selecting events in line with the ATLAS physics programme. This paper presents an overview of the changes to the trigger and data acquisition system during the second long shutdown of the LHC, and shows the performance of the trigger system and its components in the proton-proton collisions during the 2022 commissioning period as well as its expected performance in proton-proton and heavy-ion collisions for the remainder of the third LHC data-taking period (2022–2025)

Observation of quantum entanglement with top quarks at the ATLAS detector

Entanglement is a key feature of quantum mechanics with applications in fields such as metrology, cryptography, quantum information and quantum computation. It has been observed in a wide variety of systems and length scales, ranging from the microscopic to the macroscopic. However, entanglement remains largely unexplored at the highest accessible energy scales. Here we report the highest-energy observation of entanglement, in top–antitop quark events produced at the Large Hadron Collider, using a proton–proton collision dataset with a centre-of-mass energy of √s = 13 TeV and an integrated luminosity of 140 inverse femtobarns (fb)−1 recorded with the ATLAS experiment. Spin entanglement is detected from the measurement of a single observable D, inferred from the angle between the charged leptons in their parent top- and antitop-quark rest frames. The observable is measured in a narrow interval around the top–antitop quark production threshold, at which the entanglement detection is expected to be significant. It is reported in a fiducial phase space defined with stable particles to minimize the uncertainties that stem from the limitations of the Monte Carlo event generators and the parton shower model in modelling top-quark pair production. The entanglement marker is measured to be D = −0.537 ± 0.002 (stat.) ± 0.019 (syst.) for 340 GeV < mtt < 380 GeV. The observed result is more than five standard deviations from a scenario without entanglement and hence constitutes the first observation of entanglement in a pair of quarks and the highest-energy observation of entanglement so far