Role of sphingosine 1-phosphate signalling axis in muscle atrophy induced by tnfα in c2c12 myotubes

Skeletal muscle atrophy is characterized by a decrease in muscle mass causing reduced agility, increased fatigability and higher risk of bone fractures. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), are strong inducers of skeletal muscle atrophy. The bioactive sphingolipid sphingosine 1-phoshate (S1P) plays an important role in skeletal muscle biology. S1P, generated by the phosphorylation of sphingosine catalyzed by sphingosine kinase (SK1/2), exerts most of its actions through its specific receptors, S1P1–5. Here, we provide experimental evidence that TNFα induces atrophy and autophagy in skeletal muscle C2C12 myotubes, modulating the expression of specific markers and both active and passive membrane electrophysiological properties. NMR-metabolomics provided a clear picture of the deep remodelling of skeletal muscle fibre metabolism induced by TNFα challenge. The cytokine is responsible for the modulation of S1P signalling axis, upregulating mRNA levels of S1P2 and S1P3 and downregulating those of SK2. TNFα increases the phosphorylated form of SK1, readout of its activation. Interestingly, pharmacological inhibition of SK1 and specific antagonism of S1P3 prevented the increase in autophagy markers and the changes in the electrophysiological properties of C2C12 myotubes without affecting metabolic remodelling induced by the cytokine, highlighting the involvement of S1P signalling axis on TNFα-induced atrophy in skeletal muscle

Re-Evaluation of the Role of Antifibrinolytic Therapy with Lysine Analogs in Liver Transplantation in The Post-Aprotinin Era

Purpose of review: Hemorrhage, blood and blood product transfusions and the need for surgical re-exploration for bleeding can have a detrimental effect on patient outcome during liver surgery. Following the suspension of aprotinin from the market only the antifibrinolyticstranexamic acid (TA) and epsilon-aminocaproic acid (EACA) are left as pharmacological options to reduce hemostatic activation and associated bleeding complications. Considering the apparent usefulnes of aprotinin in liver surgery and transplantation, its loss has left a void within the armamentarium of drugs available to reduce blood loss. The need for large independent safety studies has become evident. The current review focuses on the drugs that are available, the safety and efficacydata that supports their use and the indications warranting further trailsRecent findings Both TA and EACA are effective in reducing blood loss and transfusion requirements in liver surgery. Analysis of data is complicated as the dosing regimens, especially for tranexamic acid, varies enormously and the agents are highly overdosed in most relevant trials. New data indicates that in a dose-dependent fashion, TA is associated with an increase in adverse events with transient renal failure highlighted as a particular problem. It appears that all the anti-fibrinolyticshave side effects that may impact on morbidity and mortality and it may be that aprotinin is no worse. The use of these agents needs to be balanced against benefitespecially in the management of high risk cases

(−)-Kolavenic acid

In the two, almost identical, mol­ecules in the asymmetric unit of the title compound [systematic name: (E)-3-methyl-5-(1,2,4a,5-tetra­methyl-1,2,3,4,4a,7,8,8a-octa­hydro­naphthalen-1-yl)pent-2-enoic acid], C20H32O2, the rings are trans fused. The cyclo­hexane ring has a chair conformation and the cyclo­hexene ring a distorted half-boat conformation. The two independent mol­ecules are connected into a dimer via O—H⋯O hydrogen bonds. The dimers are associated into supra­molecular chains along c via C—H⋯O contacts

Modelling the overdiagnosis of breast cancer due to mammography screening in women aged 40 to 49 in the United Kingdom

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited

TOWARDS ACCURATE INSTANCE SEGMENTATION IN LARGE-SCALE LIDAR POINT CLOUDS

Panoptic segmentation is the combination of semantic and instance segmentation: assign the points in a 3D point cloud to semantic categories and partition them into distinct object instances. It has many obvious applications for outdoor scene understanding, from city mapping to forest management. Existing methods struggle to segment nearby instances of the same semantic category, like adjacent pieces of street furniture or neighbouring trees, which limits their usability for inventory- or management-type applications that rely on object instances. This study explores the steps of the panoptic segmentation pipeline concerned with clustering points into object instances, with the goal to alleviate that bottleneck. We find that a carefully designed clustering strategy, which leverages multiple types of learned point embeddings, significantly improves instance segmentation. Experiments on the NPM3D urban mobile mapping dataset and the FOR-instance forest dataset demonstrate the effectiveness and versatility of the proposed strategy

Mastectomy rates are decreasing in the era of service screening: a population-based study in Italy (1997-2001)

We enrolled all 2162 in situ and 21 148 invasive cases of breast cancer in 17 areas of Italy, diagnosed in 1997-2001. Rates of early cancer increased by 13.7% in the screening age group (50-69 years), and breast conserving surgery by 24.6%. Advanced cancer rates decreased by 19.4%, and mastectomy rates by 24.2%. Service screening did not increase mastectomy rates in the study population

Case Report: Whole Exome Sequencing Revealed Disease-Causing Variants in Two Genes in a Patient With Autism Spectrum Disorder, Intellectual Disability, Hyperactivity, Sleep and Gastrointestinal Disturbances

Autism Spectrum Disorder (ASD) refers to a broad range of conditions characterized by difficulties in communication, social interaction and behavior, and may be accompanied by other medical or psychiatric conditions. Patients with ASD and comorbidities are often difficult to diagnose because of the tendency to consider the multiple symptoms as the presentation of a complicated syndromic form. This view influences variant filtering which might ignore causative variants for specific clinical features shown by the patient. Here we report on a male child diagnosed with ASD, showing cognitive and motor impairments, stereotypies, hyperactivity, sleep, and gastrointestinal disturbances. The analysis of whole exome sequencing (WES) data with bioinformatic tools for oligogenic diseases helped us to identify two major previously unreported pathogenetic variants: a maternally inherited missense variant (p.R4122H) in HUWE1, an ubiquitin protein ligase associated to X-linked intellectual disability and ASD; and a de novo stop variant (p.Q259X) in TPH2, encoding the tryptophan hydroxylase 2 enzyme involved in serotonin synthesis and associated with susceptibility to attention deficit-hyperactivity disorder (ADHD). TPH2, expressed in central and peripheral nervous tissues, modulates various physiological functions, including gut motility and sleep. To the best of our knowledge, this is the first case presenting with ASD, cognitive impairment, sleep, and gastrointestinal disturbances linked to both HUWE1 and TPH2 genes. Our findings could contribute to the existing knowledge on clinical and genetic diagnosis of patients with ASD presentation with comorbidities

Mastectomy rates are decreasing in the era of service screening: a population-based study in Italy (1997–2001)

We enrolled all 2162 in situ and 21 148 invasive cases of breast cancer in 17 areas of Italy, diagnosed in 1997–2001. Rates of early cancer increased by 13.7% in the screening age group (50–69 years), and breast conserving surgery by 24.6%. Advanced cancer rates decreased by 19.4%, and mastectomy rates by 24.2%. Service screening did not increase mastectomy rates in the study population