The microscopic environment inside a metazoan organism is highly crowded. Whether individual cells can tailor their behavior to the limited space remains unclear. In this study, we found that cells ...measure the degree of spatial confinement by using their largest and stiffest organelle, the nucleus. Cell confinement below a resting nucleus size deforms the nucleus, which expands and stretches its envelope. This activates signaling to the actomyosin cortex via nuclear envelope stretch-sensitive proteins, up-regulating cell contractility. We established that the tailored contractile response constitutes a nuclear ruler-based signaling pathway involved in migratory cell behaviors. Cells rely on the nuclear ruler to modulate the motive force that enables their passage through restrictive pores in complex three-dimensional environments, a process relevant to cancer cell invasion, immune responses, and embryonic development.
Introduction
Molecular testing of Inherited bleeding coagulation disorders (IBCDs) not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and in certain ...cases genotype–phenotype correlations are important for predicting the clinical course of the disease and to allow tailor‐made follow‐up of individuals. Until recently, genotyping has been mainly performed by Sanger sequencing, a technique known to be time consuming and expensive. Currently, next‐generation sequencing (NGS) offers a new potential approach that enables the simultaneous investigation of multiple genes at manageable cost.
Aim
The aim of this study was to design and to analyse the applicability of a 23‐gene NGS panel in the molecular diagnosis of patients with IBCDs.
Methods
A custom target enrichment library was designed to capture 31 genes known to be associated with IBCDs. Probes were generated for 296 targets to cover 86.3 kb regions (all exons and flanking regions) of these genes. Twenty patients with an IBCDs phenotype were studied using NGS technology.
Results
In all patients, our NGS approach detected causative mutations. Twenty‐one pathogenic variants were found; while most of them were missense (18), three deletions were also identified. Six novel mutations affecting F8, FGA, F11, F10 and VWF genes, and 15 previously reported variants were detected. NGS and Sanger sequencing were 100% concordant.
Conclusion
Our results demonstrate that this approach could be an accurate, reproducible and reliable tool in the rapid genetic diagnosis of IBCDs.
Highlights • We report real-world data from 464 patients treated with perampanel over 1 year. • Efficacy and tolerability of perampanel were comparable with clinical trial data. • Patients ≥65 years, ...vascular aetiology or fewer prior AEDs had a superior response. • Patients with psychiatric comorbidities (hyperactivity and personality disorder) were more likely to experience psychiatric AEs. • Patients with slower titration schedules were less likely to experience an AE
Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of multiple myeloma (MM) after ...therapy. However, current flow-MRD has lower sensitivity than molecular methods and lacks standardization. Here we report on a novel next generation flow (NGF) approach for highly sensitive and standardized MRD detection in MM. An optimized 2-tube 8-color antibody panel was constructed in five cycles of design-evaluation-redesign. In addition, a bulk-lysis procedure was established for acquisition of ⩾10
cells/sample, and novel software tools were constructed for automatic plasma cell gating. Multicenter evaluation of 110 follow-up BM from MM patients in very good partial response (VGPR) or CR showed a higher sensitivity for NGF-MRD vs conventional 8-color flow-MRD -MRD-positive rate of 47 vs 34% (P=0.003)-. Thus, 25% of patients classified as MRD-negative by conventional 8-color flow were MRD-positive by NGF, translating into a significantly longer progression-free survival for MRD-negative vs MRD-positive CR patients by NGF (75% progression-free survival not reached vs 7 months; P=0.02). This study establishes EuroFlow-based NGF as a highly sensitive, fully standardized approach for MRD detection in MM which overcomes the major limitations of conventional flow-MRD methods and is ready for implementation in routine diagnostics.
Essentials
Diagnosis of sitosterolemia, a rare recessive or syndromic disorder, is usually delayed.
Peripheral blood smear is extremely useful for establishing the suspicion of sitosterolemia.
...High‐throughput sequencing technology enables the molecular diagnosis of inherited thrombocytopenias.
Accurate characterization of sitosterolemia helps us determine appropriate management.
Summary
Background
Sitosterolemia (STSL) is a recessive inherited disorder caused by pathogenic variants in the ABCG5 and ABCG8 genes. Increased levels of plasma plant sterols (PSs) usually result in xanthomas and premature coronary atherosclerosis, although hematologic abnormalities may occasionally be present. This clinical picture is unfamiliar to many physicians, and patients may be at high risk of misdiagnosis.
Objectives
To report two novel ABCG5 variants causing STSL in a Spanish patient, and review the clinical and mutational landscape of STSL.
Patient/Methods
A 46‐year‐old female was referred to us with lifelong macrothrombocytopenia. She showed familial hypercholesterolemia‐related xanthomas. Molecular analysis was performed with high‐throughput sequencing. Plasma PS levels were evaluated with gas–liquid chromatography. The STSL landscape was reviewed with respect to specific online databases and all reports published since 1974.
Results
A blood smear revealed giant platelets and stomatocytes. Novel compound heterozygous variants were detected in exons 7 (c.914C>G) and 13 (c.1890delT) of ABCG5. The patient showed an increased plasma level of sitosterol. These findings support the diagnosis of STSL. In our review, we identified only 25 unrelated STLS patients who presented with hematologic abnormalities including macrothrombocytopenia. It remains unknown why only some patients develop hematologic abnormalities.
Conclusions
This is the first Spanish STSL patient to be reported and molecularly characterized. The early diagnosis of STLS is strongly supported by the presence of stomatocytes in blood smears. The definitive diagnosis of STSL by measurement of serum PS levels and molecular analyses prompted the use of ezetimibe therapy.
Objective
To identify risk factors associated with suicide of patients with schizophrenia and provide clinical recommendations, which integrate research findings into a consensus based on clinical ...experience and evidence.
Method
A task force formed of experts and clinicians iteratively developed consensus through serial revisions using the Delphi method. Initial survey items were based on systematic literature review published up to June 2013.
Results
Various risk factors were reported to be implicated in suicide in schizophrenia. Our findings indicate that suicide risk in schizophrenia is mainly related to affective symptoms, history of a suicide attempt and number of psychiatric admissions. Other risk factors identified are given by younger age, closeness to illness onset, older age at illness onset, male sex, substance abuse and period during or following psychiatric discharge. Integrating the evidence and the experience of the task force members, a consensus was reached on 14 clinical recommendations.
Conclusion
Identification of risk factors for suicide in individuals diagnosed with schizophrenia is imperative to improve clinical management and develop strategies to reduce the incidence of suicide in this population. This study provides the critical overview of available data and clinical recommendations on recognition and management of the above‐mentioned risk factors.
Composting has been traditionally considered a process in which a succession of mesophilic and thermophilic microbial populations occurs due to temperature changes. In order to deepen in this model, ...1380 bacterial and fungal strains (the entire culturable microbiota isolated from a composting process) were investigated for their ability to grow across a wide range of temperatures (20 to 60 °C). First, qualitative tests were performed to establish a thermal profile for each strain. Then, quantitative tests allowed ascertaining the extent of growth for each strain at each of the tested temperatures. The identity of the isolates enabled to position them taxonomically and permitted tracking the strains throughout the process. Results showed that 90% of the isolates were classified as thermotolerant (they grew at all tested temperatures). Only 9% and 1% of the studied strains showed to be strictly mesophilic or thermophilic, respectively. Firmicutes exhibited the greatest thermal plasticity, followed by Actinobacteria and Ascomycota. Most of the Proteobacteria and all Basidiomycota strains were also able to grow at all the assayed temperatures. Thermotolerance was clearly demonstrated among the composting microbiota, suggesting that the idea of the succession of mesophilic and thermophilic populations throughout the process might need a reassessment.
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•The temperature-driven succession of the composting microbial populations was revisited.•Thermotolerance was demonstrated for a vast majority of the composting microbiota.•Thermotolerant strains were repeatedly identified in most of the composting stages.•Firmicutes and Ascomycota accounted for the best represented thermotolerant phyla.•Thermal plasticity is a microbial reply to the ever changing composting conditions.
Prostate Cancer (PC) is commonly known as one of the most frequent tumors among males. A significant problem of this tumor is that in early stages most of the cases course as indolent forms, so an ...active surveillance will anticipate the appearance of aggressive stages. One of the main strategies in medical and biomedical research is to find non-invasive biomarkers for improving monitoring and performing a more precise follow-up of diseases like PC. Here we report the relevant role of
and miR-93-5p as non-invasive biomarker for PC. This event could improve current medical strategies in PC.
The quality of the retrieved temperature-versus-pressure (or T(p)) profiles is described for the middle atmosphere for the publicly available Sounding of the Atmosphere using Broadband Emission ...Radiometry (SABER) Version 1.07 (V1.07) data set. The primary sources of systematic error for the SABER results below about 70 km are (1) errors in the measured radiances, (2) biases in the forward model, and (3) uncertainties in the corrections for ozone and in the determination of the reference pressure for the retrieved profiles. Comparisons with other correlative data sets indicate that SABER T(p) is too high by 1-3 K in the lower stratosphere but then too low by 1 K near the stratopause and by 2 K in the middle mesosphere. There is little difference between the local thermodynamic equilibrium (LTE) algorithm results below about 70 km from V1.07 and V1.06, but there are substantial improvements/differences for the non-LTE results of V1.07 for the upper mesosphere and lower thermosphere (UMLT) region. In particular, the V1.07 algorithm uses monthly, diurnally averaged CO2 profiles versus latitude from the Whole Atmosphere Community Climate Model. This change has improved the consistency of the character of the tides in its kinetic temperature (T(sub k)). The T(sub k) profiles agree with UMLT values obtained from ground-based measurements of column-averaged OH and O2 emissions and of the Na lidar returns, at least within their mutual uncertainties. SABER T(sub k) values obtained near the mesopause with its daytime algorithm also agree well with the falling sphere climatology at high northern latitudes in summer. It is concluded that the SABER data set can be the basis for improved, diurnal-to-interannual-scale temperatures for the middle atmosphere and especially for its UMLT region.
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