LoopIng: A template-based tool for predicting the structure of protein loops

MOTIVATION: Predicting the structure of protein loops is very challenging, mainly because they are not necessarily subject to strong evolutionary pressure. This implies that, unlike the rest of the protein, standard homology modeling techniques are not very effective in modeling their structure. However, loops are often involved in protein function, hence inferring their structure is important for predicting protein structure as well as function. RESULTS: We describe a method, LoopIng, based on the Random Forest automated learning technique, which, given a target loop, selects a structural template for it from a database of loop candidates. Compared to the most recently available methods, LoopIng is able to achieve similar accuracy for short loops (4-10 residues) and significant enhancements for long loops (11-20 residues). The quality of the predictions is robust to errors that unavoidably affect the stem regions when these are modeled. The method returns a confidence score for the predicted template loops and has the advantage of being very fast (on average: 1 min/loop)

On the mechanics of “false vaults”: new analytical and computational approaches

The aim of this paper is to present new analytical and computational approaches for assessing the structural safety of “false vaults” structures like Trulli, and more generally for corbelled structures. In particular, the proposed procedure is capable of taking into account the three-dimensional behavior of such complex masonry structures

PIGSPro: prediction of immunoGlobulin structures v2

PIGSpro is a significant upgrade of the popular PIGS server for the prediction of the structure of immunoglobulins. The software has been completely rewritten in python following a similar pipeline as in the original method, but including, at various steps, relevant modifications found to improve its prediction accuracy, as demonstrated here. The steps of the pipeline include the selection of the appropriate framework for predicting the conserved regions of the molecule by homology; the target template alignment for this portion of the molecule; the selection of the main chain conformation of the hypervariable loops according to the canonical structure model, the prediction of the third loop of the heavy chain (H3) for which complete canonical structures are not available and the packing of the light and heavy chain if derived from different templates. Each of these steps has been improved including updated methods developed along the years. Last but not least, the user interface has been completely redesigned and an automatic monthly update of the underlying database has been implemented. The method is available as a web server at http://biocomputing.it/pigspro

Clostridium difficile outbreak: epidemiological surveillance, infection prevention and control

INTRODUCTION: Clostridium difficile infection (CDI) is currently considered the most common cause of health care-associated infections. The aim is to describe the trend of CDI in an Italian hospital and to assess the efficacy of the measures adopted to manage the burden. METHODS: we looked at CDI from 2016 to 2018. The incidence rate of CDIs was calculated as the number of new infected persons per month by the overall length of stay (incidence per 10,000 patient-days). Changes in the CDI rate during the period considered were analysed using a joinpoint regression model. RESULTS: thanks to the monitoring activity it was possible to adopt a new protocol, in order to manage CDI: the CDI episodes decreased from 85 in 2017 to 31 in 2018 (63% decrease). The joinpoint regression model was a useful tool to identify an important decrement during 2017, statistically significant (slope=-15.84; p= 0.012). CONCLUSIONS: reports based on routine laboratory data can accurately measure population burden of CDI with limited surveillance resources. This acitivity can help target prevention programs and evaluate their effect

Control of the adaptive response of the heart to stress via the Notch1 receptor pathway

In the damaged heart, cardiac adaptation relies primarily on cardiomyocyte hypertrophy. The recent discovery of cardiac stem cells in the postnatal heart, however, suggests that these cells could participate in the response to stress via their capacity to regenerate cardiac tissues. Using models of cardiac hypertrophy and failure, we demonstrate that components of the Notch pathway are up-regulated in the hypertrophic heart. The Notch pathway is an evolutionarily conserved cell-to-cell communication system, which is crucial in many developmental processes. Notch also plays key roles in the regenerative capacity of self-renewing organs. In the heart, Notch1 signaling takes place in cardiomyocytes and in mesenchymal cardiac precursors and is activated secondary to stimulated Jagged1 expression on the surface of cardiomyocytes. Using mice lacking Notch1 expression specifically in the heart, we show that the Notch1 pathway controls pathophysiological cardiac remodeling. In the absence of Notch1, cardiac hypertrophy is exacerbated, fibrosis develops, function is altered, and the mortality rate increases. Therefore, in cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response, and may thereby contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and may facilitate the expansion of a transient amplifying cell compartment

Hepatitis B: The view from West Africa

The Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study began in 2011 in The Gambia, Sénégal and Nigeria. The study aims to reduce the risk of hepatocellular carcinoma (HCC) in West Africa through the suppression of the Hepatitis B virus (HBV). The biological samples collected allow for the detection of novel liver cancer biomarkers in the hope of improving the diagnostic ability of early disease states. The PROLIFICA platform hopes to improve cancer diagnostics whilst simultaneously providing the training, skills and infrastructure necessary to develop the quality of liver cancer care in West Africa

The Notch pathway controls fibrotic and regenerative repair in the adult heart

Aims In the adult heart, Notch signalling regulates the response to injury. Notch inhibition leads to increased cardiomyocyte apoptosis, and exacerbates the development of cardiac hypertrophy and fibrosis. The role of Notch in the mesenchymal stromal cell fraction, which contains cardiac fibroblasts and cardiac precursor cells, is, however, largely unknown. In the present study, we evaluate, therefore, whether forced activation of the Notch pathway in mesenchymal stromal cells regulates pathological cardiac remodelling. Methods and results We generated transgenic mice overexpressing the Notch ligand Jagged1 on the surface of cardiomyocytes to activate Notch signalling in adjacent myocyte and non-myocyte cells. In neonatal transgenic mice, activated Notch sustained cardiac precursor and myocyte proliferation after birth, and led to increased numbers of cardiac myocytes in adult mice. In the adult heart under pressure overload, Notch inhibited the development of cardiomyocyte hypertrophy and transforming growth factor-β/connective tissue growth factor-mediated cardiac fibrosis. Most importantly, Notch activation in the stressed adult heart reduced the proliferation of myofibroblasts and stimulated the expansion of stem cell antigen-1-positive cells, and in particular of Nkx2.5-positive cardiac precursor cells. Conclusions We conclude that Notch is pivotal in the healing process of the injured heart. Specifically, Notch regulates key cellular mechanisms in the mesenchymal stromal cell population, and thereby controls the balance between fibrotic and regenerative repair in the adult heart. Altogether, these findings indicate that Notch represents a unique therapeutic target for inducing regeneration in the adult heart via mobilization of cardiac precursor cell

Overexpression of a mutant form of TGFBI/BIGH3 induces retinal degeneration in transgenic mice

PURPOSE: Despite ubiquitous expression of the keratoepithelin (KE) protein encoded by the transforming growth factor beta induced/beta induced gene human clone 3 (TGFBI/BIGH3) gene, corneal dystrophies are restricted to the cornea, and no other tissues are affected. We investigated the role of TGFBI/BIGH3 in Groenouw corneal dystrophies by generating transgenic mice overexpressing TGFBI/BIGH3 containing the R555W mutation. METHODS: Transgenic animals expressing the Groenouw mutation of human TGFBI/BIGH3 were generated using lentiviral vectors. The line expressed TGFBI/BIGH3 containing the R555W mutation under the control of the phosphoglycerate kinase (PGK) promoter. Expression of the transgene was monitored by Southern and western blotting and by RT-PCR. Electroretinogram analysis was performed and four mice were subjected to complete necroscopy. RESULTS: Transgene expression was observed in different organs although without specific expression in the cornea. The overall morphology of the transgenic animals was not severely affected by KE overexpression. However, we observed an age-dependent retinal degeneration both functionally and histologically. Female-specific follicular hyperplasia in the spleen and increased levels of lipofuscin in the adrenal gland were also seen in transgenic animals. CONCLUSIONS: Cellular degeneration in the retina of transgenic animals suggest that perturbation of the transforming growth factor beta (TGFbeta) family regulation may affect photoreceptor survival and may induce possible accelerated aging in several tissues. No corneal phenotype could be observed, probably due to the lack of transgene expression in this tissue

Sentinel Lymph Node Analysis in Colorectal Cancer Patients Using One-Step Nucleic Acid Amplification in Combination With Fluorescence and Indocyanine Green

Purpose: Analysis of the sentinel lymph node (SLN) in colorectal cancer (CRC) patients was proposed for more accurate staging and tailored lymphadenectomy. The aim of this study was to assess the ability to predict lymph node (LN) involvement through analysis of the SLN with a one-step nucleic acid (OSNA) technique in combination with peritumoral injection of indocyanine green (ICG) and near-infrared (NIR) lymphangiography in CRC patients. Methods: A total of 34 patients were enrolled. Overall, 51 LNs were analyzed with OSNA. LNs of 17 patients (50%) were examined simultaneously with hematoxylin and eosin (H&E) and OSNA. Results: SLN analysis of 17 patients examined with H&E and OSNA revealed that OSNA had a higher sensitivity (1 vs. 0.55), higher negative predictive value (1 vs. 0.66) and higher accuracy (100% vs. 76.4%) in predicting LN involvement. Overall, OSNA showed a sensitivity of 0.69, specificity of 1, accuracy of 88.2%, and stage migration of 8.8%. Compared to those who were OSNA (−), OSNA (+) patients had a greater number of LN metastases (4.8 vs. 0.16, P = 0.04), higher G3 rate (44.4% vs. 4%, P = 0.01), more advanced stage of disease (stage III: 77.8% vs. 16%; P = 0.00) and were more rapidly subjected to adjuvant chemotherapy (39.1 days vs. 50.2 days, P = 0.01). Conclusion: SLN analysis with OSNA in combination with ICG-NIR lymphangiography is feasible and can detect LN involvement in CRC patients. Furthermore, it allows for more accurate staging reducing the delay between surgery and adjuvant chemotherap