Interpreting Potts and Transformer Protein Models Through the Lens of Simplified Attention

The established approach to unsupervised protein contact prediction estimates coevolving positions using undirected graphical models. This approach trains a Potts model on a Multiple Sequence Alignment. Increasingly large Transformers are being pretrained on unlabeled, unaligned protein sequence databases and showing competitive performance on protein contact prediction. We argue that attention is a principled model of protein interactions, grounded in real properties of protein family data. We introduce an energy-based attention layer, factored attention, which, in a certain limit, recovers a Potts model, and use it to contrast Potts and Transformers. We show that the Transformer leverages hierarchical signal in protein family databases not captured by single-layer models. This raises the exciting possibility for the development of powerful structured models of protein family databases

Paneth cell dysfunction in radiation injury and radio-mitigation by human α-defensin 5

IntroductionThe mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5).MethodsAdult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels.ResultsIonizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation.ConclusionThese data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk

RR Interval-based atrial fibrillation detection using traditional and ensemble machine learning algorithms

Atrial fibrillation (AF) is a life threatening disease and can cause stroke, heart failure, and sometimes death. To reduce the rate of mortality and morbidity due to increased prevalence of AF, early detection of the same becomes a prior concern. Traditional machine learning (TML) algorithms and ensemble machine learning (EML) algorithms are proposed to detect AF in this article. The performances of both these methods are compared in this study. Methodology involves computation of RR interval features extracted from electrocardiogram and its classification into: normal, AF, and other rhythms. TML techniques such as Classification and Regression Tree, K Nearest Neighbor, C4.5, Iterative Dichotomiser 3, Support Vector Machine and EML classifier such as Random Forest (RF), and Rotation Forest are used for classification. The proposed method is evaluated using PhysioNet challenge 2017. During the tenfold cross validation, it is observed that RF classifier provided good classification accuracy of 99.10% with area under the curve of 0.998. Apart from contributing a new methodology, the proposed study also experimentally proves higher performance with ensemble learning method, RF. The methodology has many applications in health care management systems including defibrillators, cardiac pacemakers, etc

Comparison of performance of solar photovoltaics on dual axis tracker with fixed axis at 13 degrees N latitude

Tracking systems, that continually orient photovoltaic (PV) panels towards the Sun, are expected to increase the power output from the PV panels. Tremendous amount of research is being done and funds are being spent in order to increase the efficiency of PV cells to generate more power. We report the performance of two almost identical PV systems; one at a fixed latitude tilt and the other on a two-axis tracker. We observed that the fixed axis PV panels generated 336.3 kWh, and the dual-axis Sun-tracked PV panels generated 407.2 kWh during August 2012 March 2013. The tracked panels generated 21.2% more electricity than the optimum tilt angle fixed-axis panels. The cost payback calculations indicate that the additional cost of the tracker can be recovered in 450 days

Deformation processing of an aluminum alloy containing particles: studies on AI-5 pct Si alloy 4043

Al-5 wt pct Si alloy is processed by upset forging in the temperature range 300 K to 800 K and in the strain rate range 0.02 to 200 s−1. The hardness and tensile properties of the product have been studied. A "safe" window in the strain rate-temperature field has been identified for processing of this alloy to obtain maximum tensile ductility in the product. For the above strain rate range, the temperature range of processing is 550 K to 700 K for obtaining high ductility in the product. On the basis of microstructure and the ductility of the product, the temperature-strain rate regimes of damage due to cavity formation at particles and wedge cracking have been isolated for this alloy. The tensile fracture features recorded on the product specimens are in conformity with the above damage mechanisms. A high temperature treatment above ≈600 K followed by fairly fast cooling gives solid solution strengthening in the alloy at room temperature