Conformational dynamics and stability of u-shaped and s-shaped amyloid β assemblies

Alzheimer’s disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ1–40 and Aβ1–42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ1–40 peptides can only assume U-shaped conformations while Aβ1–42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped Aβ17–42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils

Methods for the analysis of histone H3 and H4 acetylation in blood

LBH589 is one of the many histone deacetylase inhibitors (HDACi) that are currently in clinical trial. Despite their wide-spread use, there is little literature available describing the typical levels of histone acetylation in untreated peripheral blood, the treatment and storage of samples to retain optimal measurement of histone acetylation nor methods by which histone acetylation analysis may be monitored and measured during the course of a patient’s treatment. In this study, we have used cord or peripheral blood as a source of human leukocytes, performed a comparative analysis of sample processing methods and developed a flow cytometric method suitable for monitoring histone acetylation in isolated lymphocytes and liquid tumors. Western blotting and immunohistochemistry techniques have also been addressed. We have tested these methods on blood samples collected from four patients treated with LBH589 as part of an Australian Children’s Cancer Clinical Trial (CLBH589AAU03T) and show comparable results when comparing in vitro and in vivo data. This paper does not seek to correlate histone acetylation levels in peripheral blood with clinical outcome but describes methods of analysis that will be of interest to clinicians and scientists monitoring the effects of HDACi on histone acetylation in blood samples in clinical trials or in related research studies

MASRI-HEADSET: A Maltese Corpus for Speech Recognition

Maltese, the national language of Malta, is spoken by approximately 500,000 people. Speech processing for Maltese is still in its early stages of development. In this paper, we present the first spoken Maltese corpus designed purposely for Automatic Speech Recognition (ASR). The MASRI-HEADSET corpus was developed by the MASRI project at the University of Malta. It consists of 8 hours of speech paired with text, recorded by using short text snippets in a laboratory environment. The speakers were recruited from different geographical locations all over the Maltese islands, and were roughly evenly distributed by gender. This paper also presents some initial results achieved in baseline experiments for Maltese ASR using Sphinx and Kaldi. The MASRI-HEADSET Corpus is publicly available for research/academic purposes.Comment: 8 pages, 2 figures, 4 tables, 1 appendix. Appears in Proceedings of the 12th edition of the Language Resources and Evaluation Conference (LREC'20

Treatment effect variability in brain stimulation across psychiatric disorders: A meta-analysis of variance

Noninvasive brain stimulation methods such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are promising add-on treatments for a number of psychiatric conditions. Yet, some of the initial excitement is wearing off. Randomized controlled trials (RCT) have found inconsistent results. This inconsistency is suspected to be the consequence of variation in treatment effects and solvable by identifying responders in RCTs and individualizing treatment. However, is there enough evidence from RCTs that patients respond differently to treatment? This question can be addressed by comparing the variability in the active stimulation group with the variability in the sham group. We searched MEDLINE/PubMed and included all double-blinded, sham-controlled RCTs and crossover trials that used TMS or tDCS in adults with a unipolar or bipolar depression, bipolar disorder, schizophrenia spectrum disorder, or obsessive compulsive disorder. In accordance with the PRISMA guidelines to ensure data quality and validity, we extracted a measure of variability of the primary outcome. A total of 130 studies with 5748 patients were considered in the analysis. We calculated variance-weighted variability ratios for each comparison of active stimulation vs sham and entered them into a random-effects model. We hypothesized that treatment effect variability in TMS or tDCS would be reflected by increased variability after active compared with sham stimulation, or in other words, a variability ratio greater than one. Across diagnoses, we found only a minimal increase in variability after active stimulation compared with sham that did not reach statistical significance (variability ratio = 1.03; 95% CI, 0.97, 1.08, P = 0.358). In conclusion, this study found little evidence for treatment effect variability in brain stimulation, suggesting that the need for personalized or stratified medicine is still an open questio

Treatment effect variability in brain stimulation across psychiatric disorders: A meta-analysis of variance

Noninvasive brain stimulation methods such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are promising add-on treatments for a number of psychiatric conditions. Yet, some of the initial excitement is wearing off. Randomized controlled trials (RCT) have found inconsistent results. This inconsistency is suspected to be the consequence of variation in treatment effects and solvable by identifying responders in RCTs and individualizing treatment. However, is there enough evidence from RCTs that patients respond differently to treatment? This question can be addressed by comparing the variability in the active stimulation group with the variability in the sham group. We searched MEDLINE/PubMed and included all double-blinded, sham-controlled RCTs and crossover trials that used TMS or tDCS in adults with a unipolar or bipolar depression, bipolar disorder, schizophrenia spectrum disorder, or obsessive compulsive disorder. In accordance with the PRISMA guidelines to ensure data quality and validity, we extracted a measure of variability of the primary outcome. A total of 130 studies with 5748 patients were considered in the analysis. We calculated variance-weighted variability ratios for each comparison of active stimulation vs sham and entered them into a random-effects model. We hypothesized that treatment effect variability in TMS or tDCS would be reflected by increased variability after active compared with sham stimulation, or in other words, a variability ratio greater than one. Across diagnoses, we found only a minimal increase in variability after active stimulation compared with sham that did not reach statistical significance (variability ratio = 1.03; 95% CI, 0.97, 1.08, P = 0.358). In conclusion, this study found little evidence for treatment effect variability in brain stimulation, suggesting that the need for personalized or stratified medicine is still an open question

Reaching Hard-to-Reach Individuals: Nonselective Versus Targeted Outbreak Response Vaccination for Measles

Current mass vaccination campaigns in measles outbreak response are nonselective with respect to the immune status of individuals. However, the heterogeneity in immunity, due to previous vaccination coverage or infection, may lead to potential bias of such campaigns toward those with previous high access to vaccination and may result in a lower-than-expected effective impact. During the 2010 measles outbreak in Malawi, only 3 of the 8 districts where vaccination occurred achieved a measureable effective campaign impact (i.e., a reduction in measles cases in the targeted age groups greater than that observed in nonvaccinated districts). Simulation models suggest that selective campaigns targeting hard-to-reach individuals are of greater benefit, particularly in highly vaccinated populations, even for low target coverage and with late implementation. However, the choice between targeted and nonselective campaigns should be context specific, achieving a reasonable balance of feasibility, cost, and expected impact. In addition, it is critical to develop operational strategies to identify and target hard-to-reach individuals

The evolutionary pattern of mutations in glioblastoma reveals therapy-mediated selection

Glioblastoma presents as a heterogeneous disease with poor prognosis despite the use of multimodal therapy. Analysis of genomic DNA changes between initial diagnosis and recurrence in response to standard treatment protocols would enhance understanding of disease progression and better inform new treatment strategies. A cohort of 21 patients with primary glioblastoma were examined between diagnosis and first recurrence. This study presented a rare opportunity to characterize molecular alterations in tumors observed in three patients who received no therapeutic intervention, other than surgery, offering a unique control. We focused this study by comparing the dynamic mutation profiles between the primary tumors and their matched recurrent counterparts. Molecular profiling of tumors was performed using multiplexed targeted deep sequencing of 409 well characterized cancer-associated genes, achieving a mean read depth of 1272 x. Three levels of evidence suggested an evolutionary pattern consistent with a response to therapy-mediated selection pressures exists in treated patients: 1) variant burden was reduced in recurrent tumors, 2) neutral evolutionary dynamics apparent in untreated tumors shifted toward a non-neutral mode of evolution in treated patients at recurrence, and 3) the recurrent tumor of one patient displayed an increased mutation rate attributable to a temozolomide-associated hypermutator phenotype. Our observations suggest that current treatment modalities are likely to fail in achieving long term remission with the majority of relapse samples containing distinct mutations when compared to primary diagnostic samples. Oncotarget 2018 9(8):7844-7858

Case-control study on uveal melanoma (RIFA): rational and design

BACKGROUND: Although a rare disease, uveal melanoma is the most common primary intraocular malignancy in adults, with an incidence rate of up to 1.0 per 100,000 persons per year in Europe. Only a few consistent risk factors have been identified for this disease. We present the study design of an ongoing incident case-control study on uveal melanoma (acronym: RIFA study) that focuses on radiofrequency radiation as transmitted by radio sets and wireless telephones, occupational risk factors, phenotypical characteristics, and UV radiation. METHODS/DESIGN: We conduct a case-control study to identify the role of different exposures in the development of uveal melanoma. The cases of uveal melanoma were identified at the Division of Ophthalmology, University of Essen, a referral centre for tumours of the eye. We recruit three control groups: population controls, controls sampled from those ophthalmologists who referred cases to the Division of Ophthalmology, University of Duisburg-Essen, and sibling controls. For each case the controls are matched on sex and age (five year groups), except for sibling controls. The data are collected from the study participants by short self-administered questionnaire and by telephone interview. During and at the end of the field phase, the data are quality-checked. To estimate the effect of exposures on uveal melanoma risk, we will use conditional logistic regression that accounts for the matching factors and allows to control for potential confounding

Tobacco smoking and gastric cancer: meta-analyses of published data versus pooled analyses of individual participant data (StoP Project).

Tobacco smoking is one of the main risk factors for gastric cancer, but the magnitude of the association estimated by conventional systematic reviews and meta-analyses might be inaccurate, due to heterogeneous reporting of data and publication bias. We aimed to quantify the combined impact of publication-related biases, and heterogeneity in data analysis or presentation, in the summary estimates obtained from conventional meta-analyses. We compared results from individual participant data pooled-analyses, including the studies in the Stomach Cancer Pooling (StoP) Project, with conventional meta-analyses carried out using only data available in previously published reports from the same studies. From the 23 studies in the StoP Project, 20 had published reports with information on smoking and gastric cancer, but only six had specific data for gastric cardia cancer and seven had data on the daily number of cigarettes smoked. Compared to the results obtained with the StoP database, conventional meta-analyses overvalued the relation between ever smoking (summary odds ratios ranging from 7% higher for all studies to 22% higher for the risk of gastric cardia cancer) and yielded less precise summary estimates (SE ≤2.4 times higher). Additionally, funnel plot asymmetry and corresponding hypotheses tests were suggestive of publication bias. Conventional meta-analyses and individual participant data pooled-analyses reached similar conclusions on the direction of the association between smoking and gastric cancer. However, published data tended to overestimate the magnitude of the effects, possibly due to publication biases and limited the analyses by different levels of exposure or cancer subtypes