The structural effects of mutations can aid in differential phenotype prediction of beta-myosin heavy chain (Myosin-7) missense variants

MOTIVATION: High-throughput sequencing platforms are increasingly used to screen patients with genetic disease for pathogenic mutations, but prediction of the effects of mutations remains challenging. Previously we developed SAAPdap (Single Amino Acid Polymorphism Data Analysis Pipeline) and SAAPpred (Single Amino Acid Polymorphism Predictor) that use a combination of rule-based structural measures to predict whether a missense genetic variant is pathogenic. Here we investigate whether the same methodology can be used to develop a differential phenotype predictor, which, once a mutation has been predicted as pathogenic, is able to distinguish between phenotypes-in this case the two major clinical phenotypes (hypertrophic cardiomyopathy, HCM, and dilated cardiomyopathy, DCM) associated with mutations in the beta-myosin heavy chain (MYH7) gene product (Myosin-7). RESULTS: A random forest predictor trained on rule-based structural analyses together with structural clustering data gave a Matthews' correlation coefficient (MCC) of 0.53 (accuracy, 75%). A post hoc removal of machine learning models that performed particularly badly, increased the performance (MCC = 0.61, Acc = 79%). This proof of concept suggests that methods used for pathogenicity prediction can be extended for use in differential phenotype prediction

Non-AIDS-related comorbidities in people living with HIV-1 aged 50 years and older: The AGING POSITIVE study.

OBJECTIVE: To characterize the profile of non-AIDS-related comorbidities (NARC) in the older HIV-1-infected population and to explore the factors associated with multiple NARC. METHODS: This was a multicentre, cross-sectional study including HIV-1-infected patients aged ≥50 years, who were virologically suppressed and had been on a stable antiretroviral therapy (ART) regimen for at least 6 months. A multiple regression model explored the association between demographic and clinical variables and the number of NARC. RESULTS: Overall, 401 patients were enrolled. The mean age of the patients was 59.3 years and 72.6% were male. The mean duration of HIV-1 infection was 12.0 years and the median exposure to ART was 10.0 years. The mean number of NARC was 2.1, and 34.7% of patients had three or more NARC. Hypercholesterolemia was the most frequent NARC (60.8%), followed by arterial hypertension (39.7%) and chronic depression/anxiety (23.9%). Arterial hypertension and diabetes mellitus were the most frequently treated NARC (95.6% and 92.6% of cases, respectively). The linear regression analysis showed a positive relationship between age and NARC (B=0.032, 95% confidence interval 0.015-0.049; p=0.0003) and between the duration of HIV-1 infection and NARC (B=0.039, 95% confidence interval 0.017-0.059; p=0.0005). CONCLUSIONS: A high prevalence of NARC was found, the most common being metabolic, cardiovascular, and psychological conditions. NARC rates were similar to those reported for the general population, suggesting a larger societal problem beyond HIV infection. A multidisciplinary approach is essential to reduce the burden of complex multi-morbid conditions in the HIV-1-infected population.info:eu-repo/semantics/publishedVersio

Influence of P53 on the radiotherapy response of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and it has a poor prognosis and few therapeutic options. Radiotherapy is one of the most effective forms of cancer treatment, and P53 protein is one of the key molecules determining how a cell responds to radiotherapy. The aim of this study was to determine the therapeutic efficacy of iodine-131 in three human HCC cell lines

Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile

<p>Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.</p> <p>Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).</p> <p>Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.</p> <p>Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.</p&gt

Exclusive neuronal expression of SUCLA2 in the human brain

SUCLA2 encodes the ATP-forming subunit (A-SUCL-) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here we show that immunoreactivity of A-SUCL- in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL- immunoreactivity co-localized >99% with that of the d subunit of the mitochondrial F0-F1 ATP synthase. Specificity of the anti-A-SUCL- antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL- immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming subunit (G-SUCL-) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL- immunoreactivity that was however, not upregulated in samples obtained from diabetic versus non-diabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex

Imaging Electronic Correlations in Twisted Bilayer Graphene near the Magic Angle

Twisted bilayer graphene with a twist angle of around 1.1{\deg} features a pair of isolated flat electronic bands and forms a strongly correlated electronic platform. Here, we use scanning tunneling microscopy to probe local properties of highly tunable twisted bilayer graphene devices and show that the flat bands strongly deform when aligned with the Fermi level. At half filling of the bands, we observe the development of gaps originating from correlated insulating states. Near charge neutrality, we find a previously unidentified correlated regime featuring a substantially enhanced flat band splitting that we describe within a microscopic model predicting a strong tendency towards nematic ordering. Our results provide insights into symmetry breaking correlation effects and highlight the importance of electronic interactions for all filling factors in twisted bilayer graphene.Comment: Main text 9 pages, 4 figures; Supplementary Information 25 page

Projected WIMP sensitivity of the LUX-ZEPLIN dark matter experiment

LUX-ZEPLIN (LZ) is a next-generation dark matter direct detection experiment that will operate 4850 feet underground at the Sanford Underground Research Facility (SURF) in Lead, South Dakota, USA. Using a two-phase xenon detector with an active mass of 7 tonnes, LZ will search primarily for low-energy interactions with weakly interacting massive particles (WIMPs), which are hypothesized to make up the dark matter in our galactic halo. In this paper, the projected WIMP sensitivity of LZ is presented based on the latest background estimates and simulations of the detector. For a 1000 live day run using a 5.6-tonne fiducial mass, LZ is projected to exclude at 90% confidence level spin-independent WIMP-nucleon cross sections above 1.4×10-48 cm2 for a 40 GeV/c2 mass WIMP. Additionally, a 5σ discovery potential is projected, reaching cross sections below the exclusion limits of recent experiments. For spin-dependent WIMP-neutron(-proton) scattering, a sensitivity of 2.3×10-43 cm2 (7.1×10-42 cm2) for a 40 GeV/c2 mass WIMP is expected. With underground installation well underway, LZ is on track for commissioning at SURF in 2020

Weight following birth and childhood dietary intake: A prospective cohort study

Objectives: Unhealthy childhood dietary habits track through life and are independent and modifiable risk factors for disease. Therefore, it is essential to understand the factors involved. We aimed to evaluate the associations of birthweight (BW) and newborn weight change (NWC) during the first 96 h of life and childhood longitudinal weight trajectories with dietary intake at age 4. Methods: As part of the Generation XXI birth cohort (G21), children were recruited in 2005 and 2006 at all public units providing obstetrical and neonatal care in Porto, Portugal. Information was collected by face-to-face interview and abstracted from clinical records. At age 4, weight measurements recorded from birth to current age were abstracted and weight trajectories estimated. Food frequency questionnaires were applied, and three dietary patterns (DPs) were identified: “Energy-dense food (EDF)+Dairy,” “Lower in Healthy Food,” and “Healthier.” Logistic regression models were used to compute the odds ratio (OR) and 95% confidence intervals (CIs) (OR [95% CI]) in a sample of 775 children. Results: Children with higher BW were less frequently in the “EDF+Dairy” DP (0.94 [0.89–0.98] per 100 g increase in BW). Children with higher NWC had lower odds of eating fruit ≥3/d (0.93 [0.87–0.99] per 1% increase in NWC). Children with higher weight during childhood had higher odds of belonging to the “EDF+Dairy” DP (1.90 [1.04–3.47]) and lower odds of eating vegetable soup ≥2/d (0.56 [0.34–0.91]). Children showing catch-up grow in the first year of life had higher odds of eating dairy products ≥3/d (3.76 [1.31–10.80]). Conclusions: The way that children grow during childhood played a major role on dietary intake at age 4

What catches the eye in class observation? Observers' perspectives in a multidisciplinary peer observation of teaching program

Peer Observation of Teaching has raised a lot of interest as a device for quality enhancement of teaching. While much research has focused on its models, implementation schemes and feedback to the observed, little attention has been paid to what the observer actually sees and can learn from the observation. A multidisciplinary peer observation of teaching program is described, and its data is used to identify the pedagogical aspects to which lecturers pay more attention to when observing classes. The discussion addresses the valuable learning opportunities for observers provided by this program, as well as its usefulness in disseminating, sharing and clarifying quality teaching practices. The need for further research concerning teacher-student relationships and students' engagement is also suggested

The influence of item order of the Household Food Security Survey Module on the assessment of food insecurity in households with children

Abstract Objective: Changes in the item order of the US Household Food Security Survey Module (USHFSSM) were performed throughout time. This study aimed to compare the psychometric properties of the general and specific factors of the 2000 and 2012 versions of the USHFSSM to measure the construct of food insecurity in two Portuguese samples of households with children. Design: Cross-sectional. Setting: Portugal. Participants: An adaptation of the 2000 version was applied to 839 adults (from households with children aged 7-17 years) from the National Food, Nutrition and Physical Activity Survey 2015-2016, while the 2012 version was used among 2855 families from the Generation XXI birth cohort. Results: The 2000 version showed to have a stronger ωh than the 2012 version (0·89 v. 0·78 for the general factor), as well as eigenvalues higher than 1 for the general factor (eigenvalues equal to 9·54, 0·97 and 0·80, for the general factor, specific factor 1 and specific factor 2, respectively), while the 2012 version had also the contribution of specific factors to explain food insecurity (eigenvalues equal to 9·40, 2·40 and 1·20, for general factor and specific factors 1 and 2, respectively). Good internal consistency (ωt = 0·99, for both versions) was obtained. Conclusions: In conclusion, the 2000 and 2012 versions of the USHFSSM showed good psychometric properties; however, the 2000 version has stronger general factor, while the 2012 version also has the contribution of specific factors.