Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome.

Background & Aims: Approximately 75% of patients with suspected Lynch syndrome carry variants in MLH1 or MSH2, proteins encoded by these genes are required for DNA mismatch repair (MMR). However, 30% of these are variants of unknown significance (VUS). A assay that measures cell response to the cytotoxic effects of a methylating agent can determine the effects of VUS in MMR genes and identify patients with constitutional MMR-deficiency syndrome.

The dynamin-like protein Fzl promotes thylakoid fusion and resistance to light stress in Chlamydomonas reinhardtii.

Large GTPases of the Dynamin Related Proteins (DRP) family shape lipid bilayers through membrane fission or fusion processes. Despite the highly organized photosynthetic membranes of thylakoids, a single DRP is known to be targeted inside the chloroplast. Fzl from the land plant Arabidopsis thaliana is inserted in the inner envelope and thylakoid membranes to regulate their morphology.

"Decoding hereditary breast cancer" benefits and questions from multigene panel testing.

Multigene panel testing for breast and ovarian cancer predisposition diagnosis is a useful tool as it makes possible to sequence a considerable number of genes in a large number of individuals. More than 200 different multigene panels in which the two major BRCA1 and BRCA2 breast cancer predisposing genes are included are proposed by public or commercial laboratories. We review the clinical validity and clinical utility of the 26 genes most oftenly included in these panels.

mutations in metastatic lobular breast cancer patients.

Invasive lobular breast cancer (ILC) represents the second most common histology of breast cancer after invasive ductal breast cancer (IDC), accounts for up to 15% of all invasive cases and generally express the estrogen receptor (ER, coded by the gene). mutations have been associated with resistance to endocrine therapy, however these have not been specifically evaluated in ILC. We assessed the frequency of mutations by droplet digital PCR in a retrospective multi-centric series of matched primary tumor and recurrence samples ( = 279) from 80 metastatic ER-positive ILC patients.

The PIKfyve complex regulates the early melanosome homeostasis required for physiological amyloid formation.

The metabolism of PI(3,5)P2 is regulated by the PIKfyve, VAC14 and FIG4 complex, mutations in which are associated with hypopigmentation in mice. These pigmentation defects indicate a key, but as yet unexplored, physiological relevance of this complex in the biogenesis of melanosomes. Here, we show that PIKfyve activity regulates formation of amyloid matrix composed of PMEL protein within the early endosomes in melanocytes, called stage I melanosomes.

Distal extremities soft tissue sarcomas: Are they so different from other limb localizations?

Background And Objectives: Soft tissue sarcoma localization in distal extremities (DESTS) of the limbs (hand/fingers, and foot/toes) is unusual. The literature is scarce about their behavior and this study was designed to assess their epidemiological characteristics, outcomes, and prognosis compared to other limb localizations (OLSTS).

Methods: From 1980 to 2010, adult DESTS and OLSTS in 22 centers were included.

[Constitutional MMR deficiency: Genetic bases and clinical implications].

Inherited mono-allelic mutation in one of the 4 major MMR genes results in Lynch syndrome which predisposes, in adulthood, mainly to colorectal and endometrial tumors characterized by microsatellite instability (MSI phenotype). Individuals with bi-allelic mutations of one of these genes developed early and multiple malignancies, most often in childhood. This recessively inherited condition is named CMMRD for Constitutional Mismatch Repair Deficiency.

Non-Coding Variants in and Genes: Potential Impact on Breast and Ovarian Cancer Predisposition.

and are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to / exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein.

Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy.

Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome caused by biallelic germline mutations in one of four mismatch-repair genes. Besides very high tumour risks, CMMRD phenotypes are often characterised by the presence of signs reminiscent of neurofibromatosis type 1 (NF1). Because NF1 signs may be present prior to tumour onset, CMMRD is a legitimate differential diagnosis in an otherwise healthy child suspected to have NF1/Legius syndrome without a detectable underlying / germline mutation.

Multi-parametric functional ultrasound imaging of cerebral hemodynamics in a cardiopulmonary resuscitation model.

Patient mortality at one year reaches 90% after out-of-hospital cardiac arrest and resuscitation. Temperature management is one of the main strategies proposed to improve patient outcome after resuscitation and preclinical studies have shown neuroprotective effects when hypothermia is achieved rapidly, although the underlying mechanisms have not yet been elucidated. State-of-the-art brain imaging technologies can bring new insights into the early cerebral events taking place post cardiac arrest and resuscitation.

Adaptation and Inhibition Control Pathological Synchronization in a Model of Focal Epileptic Seizure.

Pharmacoresistant epilepsy is a common neurological disorder in which increased neuronal intrinsic excitability and synaptic excitation lead to pathologically synchronous behavior in the brain. In the majority of experimental and theoretical epilepsy models, epilepsy is associated with reduced inhibition in the pathological neural circuits, yet effects of intrinsic excitability are usually not explicitly analyzed. Here we present a novel neural mass model that includes intrinsic excitability in the form of spike-frequency adaptation in the excitatory population.

Myosin VI and branched actin filaments mediate membrane constriction and fission of melanosomal tubule carriers.

Vesicular and tubular transport intermediates regulate organellar cargo dynamics. Transport carrier release involves local and profound membrane remodeling before fission. Pinching the neck of a budding tubule or vesicle requires mechanical forces, likely exerted by the action of molecular motors on the cytoskeleton.

Higher-order topological insulators.

Three-dimensional topological (crystalline) insulators are materials with an insulating bulk but conducting surface states that are topologically protected by time-reversal (or spatial) symmetries. We extend the notion of three-dimensional topological insulators to systems that host no gapless surface states but exhibit topologically protected gapless hinge states. Their topological character is protected by spatiotemporal symmetries of which we present two cases: (i) Chiral higher-order topological insulators protected by the combination of time-reversal and a fourfold rotation symmetry.

Publisher Correction: RING tetramerization is required for nuclear body biogenesis and PML sumoylation.

In the originally published version of this Article, the authors Sai-Juan Chen and Zhu Chen were incorrectly listed as being affiliated with 'University Paris Diderot, Sorbonne Paris Cité, INSERM U944, CNRS UMR7212, Equipe labellisée LNCC, Hôpital St. Louis 1, Paris 75475, France', and the affiliation 'Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China' was inadvertently omitted. These errors have now been corrected in both the PDF and HTML versions of the Article.

The paradoxical extinction of the most charismatic animals.

A widespread opinion is that conservation efforts disproportionately benefit charismatic species. However, this doesn't mean that they are not threatened, and which species are "charismatic" remains unclear. Here, we identify the 10 most charismatic animals and show that they are at high risk of imminent extinction in the wild.

RING tetramerization is required for nuclear body biogenesis and PML sumoylation.

ProMyelocyticLeukemia nuclear bodies (PML NBs) are stress-regulated domains directly implicated in acute promyelocytic leukemia eradication. Most TRIM family members bind ubiquitin E2s and many acquire ligase activity upon RING dimerization. In contrast, PML binds UBC9, the SUMO E2 enzyme.

High rate of PIK3CA mutations but no TP53 mutations in low-grade adenosquamous carcinoma of the breast.

Aims: Low-grade adenosquamous carcinoma of the breast (LGASC) is a rare variant of metaplastic carcinoma characterised by a favourable outcome and histologically composed of glandular and squamous elements in a spindle cell background typically associated with a lymphocytic stromal reaction. Because of its rarity, the immunophenotypic and genetic profile of LGASC has not been sufficiently characterised. The aim of this study was to gain insights into the molecular and phenotypic characteristics of LGASC.

Genotypic variability enhances the reproducibility of an ecological study.

Many scientific disciplines are currently experiencing a 'reproducibility crisis' because numerous scientific findings cannot be repeated consistently. A novel but controversial hypothesis postulates that stringent levels of environmental and biotic standardization in experimental studies reduce reproducibility by amplifying the impacts of laboratory-specific environmental factors not accounted for in study designs. A corollary to this hypothesis is that a deliberate introduction of controlled systematic variability (CSV) in experimental designs may lead to increased reproducibility.

Robust Neuronal Discrimination in Primary Auditory Cortex Despite Degradations of Spectro-temporal Acoustic Details: Comparison Between Guinea Pigs with Normal Hearing and Mild Age-Related Hearing Loss.

This study investigated to which extent the primary auditory cortex of young normal-hearing and mild hearing-impaired aged animals is able to maintain invariant representation of critical temporal-modulation features when sounds are submitted to degradations of fine spectro-temporal acoustic details. This was achieved by recording ensemble of cortical responses to conspecific vocalizations in guinea pigs with either normal hearing or mild age-related sensorineural hearing loss. The vocalizations were degraded using a tone vocoder.

Pan-arthropod analysis reveals somatic piRNAs as an ancestral defence against transposable elements.

In animals, small RNA molecules termed PIWI-interacting RNAs (piRNAs) silence transposable elements (TEs), protecting the germline from genomic instability and mutation. piRNAs have been detected in the soma in a few animals, but these are believed to be specific adaptations of individual species. Here, we report that somatic piRNAs were probably present in the ancestral arthropod more than 500 million years ago.

Lysosome signaling controls the migration of dendritic cells.

Dendritic cells (DCs) patrol their environment by linking antigen acquisition by macropinocytosis to cell locomotion. DC activation upon bacterial sensing inhibits macropinocytosis and increases DC migration, thus promoting the arrival of DCs to lymph nodes for antigen presentation to T cells. The signaling events that trigger such changes are not fully understood.

Survival and divergence in a small group: The extraordinary genomic history of the endangered Apennine brown bear stragglers.

About 100 km east of Rome, in the central Apennine Mountains, a critically endangered population of ∼50 brown bears live in complete isolation. Mating outside this population is prevented by several 100 km of bear-free territories. We exploited this natural experiment to better understand the gene and genomic consequences of surviving at extremely small population size.