Membranes by the Numbers

Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters.Comment: 27 pages, 12 figure

Mucosal Healing in Ulcerative Colitis: A Comprehensive Review

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by periods of remission and periods of relapse. Patients often present with symptoms such as rectal bleeding, diarrhea and weight loss, and may require hospitalization and even colectomy. Long-term complications of UC include decreased quality of life and productivity and an increased risk of colorectal cancer. Mucosal healing (MH) has gained progressive importance in the management of UC patients. In this article, we review the endoscopic findings that define both mucosal injury and MH, and the strengths and limitations of the scoring systems currently available in clinical practice. The basic mechanisms behind colonic injury and MH are covered, highlighting the pathways through which different drugs exert their effect towards reducing inflammation and promoting epithelial repair. A comprehensive review of the evidence for approved drugs for UC to achieve and maintain MH is provided, including a section on the pharmacokinetics of anti-tumor necrosis factor (TNF)-alpha drugs. Currently approved drugs with proven efficacy in achieving MH in UC include salicylates, corticosteroids (induction only), calcineurin inhibitors (induction only), thiopurines, vedolizumab and anti-TNF alpha drugs (infliximab, adalimumab, and golimumab). MH is of crucial relevance in the outcomes of UC, resulting in lower incidences of clinical relapse, the need for hospitalization and surgery, as well as reduced rates of dysplasia and colorectal cancer. Finally, we present recent evidence towards the need for a more strict definition of complete MH as the preferred endpoint for UC patients, using a combination of both endoscopic and histological findings.info:eu-repo/semantics/publishedVersio

Two-particle BoseEinstein correlations in pp collisions at √s = 0.9 and 7 TeV measured with the ATLAS detector

The paper presents studies of Bose–Einstein Correlations (BEC) for pairs of like-sign charged particles measured in the kinematic range pT > 100 MeV and |η| <2.5 in proton–proton collisions at centre-of-mass energies of 0.9 and 7 TeV with the ATLAS detector at the CERN Large Hadron Collider. The integrated luminosities are approximately 7 μb−1, 190 μb−1 and 12.4 nb-1 for 0.9 TeV,7 TeV minimum-bias and 7 TeV high-multiplicity data samples, respectively. The multiplicity dependence of the BEC parameters characterizing the correlation strength and the correlation source size are investigated for charged-particle multiplicities of up to 240. A saturation effect in the multiplicity dependence of the correlation source size parameter is observed using the high-multiplicity 7 TeV data sample. The dependence of the BEC parameters on the average transverse momentum of the particle pair is also investigated

Modulation of cell death and inflammation in Influenza A Virus infection through PB1-F2-specific targeting of host proteins

Influenza A virus (IAV) is a major etiologic agent of acute respiratory infections in humans. Annually, IAV infections lead to 3-5 millions of severe cases and up to 650.000 deaths. Severe IAV pathology is accompanied by excessive inflammatory host responses. Proinflammatory cytokines in IAV infected hosts are predominantly produced by monocytic cells. PB1-F2 is a 90 amino acid IAV accessory protein, modulating inflammatory host responses and cell death. The molecular mechanism underlying these processes was unknown. We identified three novel host protein interactors of viral PB1-F2: AIF, DNAJA3 and NLRP3. We show that AIF and DNAJA3 are involved in cell death modulation and viral replication, albeit in a PB1-F2 independent fashion. In contrast, interaction of PB1-F2 with NLRP3 leads to diminished inflammasome activation. Our data suggests that PB1-F2 binding arrests NLRP3 in its closed conformation, preventing the binding of the licensing kinase Nek7 and ultimately activation and oligomerization of NLRP3

Respiratory tissue-associated commensal bacteria offer therapeutic potential against pneumococcal colonization.

Under eubiotic conditions commensal microbes are known to provide a competitive barrier against invading bacterial pathogens in the intestinal tract, on the skin or on the vaginal mucosa. Here, we evaluate the role of lung microbiota in Pneumococcus colonization of the lungs. In eubiosis, the lungs of mice were dominantly colonized by Lactobacillus murinus. Differential analysis of 16S rRNA gene sequencing or L. murinus-specific qPCR of DNA from total organ homogenates vs.broncho alveolar lavages implicated tight association of these bacteria with the host tissue. Pure L. murinus conditioned culture medium inhibited growth and reduced the extension of pneumococcal chains. Growth inhibition in vitro was likely dependent on L. murinus-produced lactic acid, since pH neutralization of the conditioned medium aborted the antibacterial effect. Finally, we demonstrate that L. murinus provides a barrier against pneumococcal colonization in a respiratory dysbiosis model after an influenza A virus infection, when added therapeutically

AIMS65 score: a new prognostic tool to predict mortality in variceal bleeding

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ORBIT score: an useful predictor of small bowel rebleeding in patients under chronic anticoagulation

Background and study aims: Available scoring systems to assess the risk for major bleeding in patients on chronic anticoagulation seem inadequate in predicting higher diagnostic yields of small bowel capsule endoscopy (SBCE) or higher rebleeding rates in patients with suspected small bowel bleeding. The aim of this study was to evaluate the ability of the new ORBIT score in predicting positive findings of SBCE or higher rebleeding rates in chronically anticoagulated patients with suspected small bowel bleeding.Patients and methods: Retrospective analysis of 570 patients who consecutively underwent SBCE for the study of suspected small bowel bleeding. For each of the 67 patients who were on chronic anticoagulation, ORBIT score (Older age, Reduced hemoglobin/hematocrit, Bleeding history, Insufficient kidney function and Treatment with antiplatelets) was calculated. Patients were classified as high-risk (ORBIT score4) or low/intermediate-risk (ORBIT score<4). Data on SBCE findings, diagnostic yield and rebleeding were compared between groups.Results: When ORBIT score was calculated, 41 and 26 patients were classified as low/intermediate-risk and high-risk, respectively. When low/intermediate-risk and high-risk groups were compared, no differences were found in the diagnostic yield of SBCE (39.0% vs. 23.1%; p=.176). However, in high-risk patients, rebleeding was significantly more common than in low/intermediate-risk patients (80.0% vs. 36.6%; p=.003).Conclusions: In patients presenting with suspected small bowel bleeding and on chronic anticoagulation, the new ORBIT score seems promising in identifying those with a higher risk of rebleeding, in whom a closer follow-up and a more aggressive diagnostic and therapeutic strategy is advisable

"Suspected Blood Indicator" na enteroscopia por cápsula: uma ferramenta útil no diagnóstico de hemorragia gastrointestinal

Small bowel bleeding is a leading indication for small bowel capsule endoscopy. The Suspected Blood Indicator (SBI) is a software feature directed to automatically detect bleeding lesions during small bowel capsule endoscopy. Objective – We aimed to assess SBI diagnostic accuracy for small bowel haemorrhage or potentially bleeding lesions during small bowel capsule endoscopy for small bowel bleeding. Methods – Single-centre retrospective study including 281 consecutive small bowel capsule endoscopy performed for small bowel bleeding during 6 years. The investigators marked lesions with high bleeding potential (P2), such as angioectasias, ulcers and tumours, as well as active bleeding during regular small bowel capsule endoscopy viewing with PillCam SB2®. All small bowel capsule endoscopy were independently reviewed by another central reader using SBI. Results – Among the 281 patients, 29 (10.3%) presented with active haemorrhage while 81 (28.9%) presented with a P2 lesion. The most frequently observed P2 lesions were angioectasias (52), ulcers (15), polyps (7) and ulcerated neoplasias (7). SBI showed a 96.6% (28/29) sensitivity for active small bowel bleeding, with a 97.7% negative predictive value. Regarding P2 lesions, the SBI displayed an overall sensitivity of 39.5%, being highest for ulcerated neoplasias (100%), but significantly lower for angioectasias (38.5%) or ulcers (20.0%). Conclusion – Although SBI sensitivity for the automatic detection of potentially bleeding lesions was low, it effectively detected active small bowel bleeding with very high sensitivity and negative predictive value.(undefined)info:eu-repo/semantics/publishedVersio

Influenza A viruses limit NLRP3-NEK7-complex formation and pyroptosis in human macrophages

Pyroptosis is a fulminant form of macrophage cell death, contributing to release of pro-inflammatory cytokines. In humans, it depends on caspase 1/4-activation of gasdermin D and is characterized by the release of cytoplasmic content. Pathogens apply strategies to avoid or antagonize this host response. We demonstrate here that a small accessory protein (PB1-F2) of contemporary H5N1 and H3N2 influenza A viruses (IAV) curtails fulminant cell death of infected human macrophages. Infection of macrophages with a PB1-F2-deficient mutant of a contemporary IAV resulted in higher levels of caspase-1 activation, cleavage of gasdermin D, and release of LDH and IL-1β. Mechanistically, PB1-F2 limits transition of NLRP3 from its auto-repressed and closed confirmation into its active state. Consequently, interaction of a recently identified licensing kinase NEK7 with NLRP3 is diminished, which is required to initiate inflammasome assembly