Powerhahn0553

Polar and tropical intertidal data were sparse, and more sampling is required to improve knowledge of marine biodiversity.G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/IGF signalling is reduced in fly models of C9orf72 repeat expansion using RNA sequencing of adult brain. We further demonstrate that activation of insulin/IGF signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/IGF signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/IGF signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.Asymmetric and self-renewing divisions build and pattern tissues. In the Arabidopsis stomatal lineage, asymmetric cell divisions, guided by polarly localized cortical proteins, generate most cells on the leaf surface. Systemic and environmental signals modify tissue development, but the mechanisms by which plants incorporate such cues to regulate asymmetric divisions are elusive. In a screen for modulators of cell polarity, we identified CONSTITUTIVE TRIPLE RESPONSE1, a negative regulator of ethylene signaling. We subsequently revealed antagonistic impacts of ethylene and glucose signaling on the self-renewing capacity of stomatal lineage stem cells. Quantitative analysis of cell polarity and fate dynamics showed that developmental information may be encoded in both the spatial and temporal asymmetries of polarity proteins. These results provide a framework for a mechanistic understanding of how nutritional status and environmental factors tune stem-cell behavior in the stomatal lineage, ultimately enabling flexibility in leaf size and cell-type composition.Helicases utilize nucleotide triphosphate (NTP) hydrolysis to translocate along single-stranded nucleic acids (NA) and unwind the duplex. In the cell, helicases function in the context of other NA-associated proteins such as single-stranded DNA binding proteins. Such encounters regulate helicase function, although the underlying mechanisms remain largely unknown. Ferroplasma acidarmanus xeroderma pigmentosum group D (XPD) helicase serves as a model for understanding the molecular mechanisms of superfamily 2B helicases, and its activity is enhanced by the cognate single-stranded DNA binding protein replication protein A 2 (RPA2). Here, optical trap measurements of the unwinding activity of a single XPD helicase in the presence of RPA2 reveal a mechanism in which XPD interconverts between two states with different processivities and transient RPA2 interactions stabilize the more processive state, activating a latent 'processivity switch' in XPD. A point mutation at a regulatory DNA binding site on XPD similarly activates this switch. These findings provide new insights on mechanisms of helicase regulation by accessory proteins.Face shape is genetically determined, but the underlying genetic architecture is complex, and precise definition of facial structures is essential for any serious study. Recent work, based on objective definition of facial segments and GWAS analyses of thousands of participants, defines a large number of loci (> 100) influencing face shape and begin to allow in-depth analysis of this complex morphological structure.Obesity or insulin resistance are the major non-infectious diseases that continue to progress worldwide. They promote diabetes and cardiovascular diseases, but also lead to a decrease in fertility in both sexes. FGF21, discovered in the 2000s, is a hormone closely linked to the energy status and has the ability to decrease insulin resistance. Its action through the FGFR1c, 3c & 4 receptors modulates tissues involved in energy-related metabolism but also the brain and the gonads. Recent data favor a role of FGF21 in female and male fertility, but raise the question about the role of FGF21 on reproductive function. In this review, we have scanned the different FGF21 actions on the reproductive axis, suggesting a potential therapeutic role in case of infertility.DNA methylation is an epigenetic mechanism that has been largely probed regarding eukaryotic nuclear genome and bacteria, and its role is especially crucial in the regulation of gene expression. In mammals, it is almost exclusively acting on a cytosine preceding a guanine (CpG), whereas it presents itself mainly in a non-CpG context in bacteria's DNA. Conversely to nuclear and bacterial genomes, the existence of methylation in the mitochondrial genome is still widely debated. This controversy has been attributed to structural differences between the nuclear and mitochondrial genomes, and to the techniques used to study methylation of cytosines, which were rather optimized for the study of nuclear DNA. However, novel studies suggest that cytosine methylation is truly existing in mitochondria, and that it is mostly found in a non-CpG context, just like in their evolutionary relative, the bacteria.The advent of the molecular biology and the completion of the human genome sequencing prompted the pharmaceutical industry to progressively implement target-centric drug discovery strategies. However, concerns regarding the research and development productivity during the last ten years, combined with technological developments in high-content screening, automation, image analysis and artificial intelligence triggered a renewed interest for the phenotypic drug discovery approaches. Target-centric and phenotypic approaches are more and more considered complementary, hence, positioning the target deconvolution on the critical path. This review analyzes the evolution of the target-centric and phenotypic approaches, focusing more specifically on the high-content screening and the target deconvolution technologies currently available.In this article, we present the latest innovations to generate in vitro models of the glomerular filtration barrier. There is currently a growing interest for such model systems that allow to reduce the use of animal models. Methodologies to improve their physiological relevance have taken advantage of the development of induced pluripotent stem cells and of bioengineering, particularly tissue engineering. Here, we first introduce the methods to overcome the limitations of the currently used glomerular cells based on the use of stem cells. The different approaches to obtain podocytes, the most important cells in the glomerulus, are presented. Finally, we emphasize the importance of the glomerular microenvironment in maintaining the glomerular cell phenotype, which can be achieved by co-culturing different glomerular cells, integration of biomaterials mimicking the extracellular matrix and introduction of flows with microfluidics.The liver ensures a large part of xenobiotics metabolism thanks to its sizeable enzymatic equipment, its anatomical localization and its abundant vascularization. However, these various characteristics also make it a privileged target for toxic compounds, particularly in the case of a toxic metabolism. Xenobiotics-induced hepatotoxicity is a major cause of liver damage and a real challenge for clinicians, pharmaceutical industry, and health agencies. Intrinsic, i.e. predictable and reproducible hepatotoxicities occurring at threshold doses are distinguished from idiosyncratic hepatotoxicities, occurring in an unpredictable manner in people with individual susceptibilities. Among them, idiosyncratic immune-mediated hepatotoxicity pathophysiology is still unclear. However, the development of tools to improve the prediction and understanding of these disorders may open avenues to the identification of risk factors and new mechanisms of toxicity.For a few years now, the One Health concept has appeared to go hand in hand with the issue of antibiotic resistance as the most comprehensive and global solution. As part of a study comparing the publicization process of the links between antibiotic resistance and food in France and in the United States, this paper retraces the One Health concept's trajectory in terms of significations and (re)definitions, according to the actors adopting this approach as a viable solution. Furthermore, this paper questions the concept's take over impact in antibiotic resistance reframing as well as its expansion in terms of functioning and applicability. Within social sciences research, interest in the issue of antibiotic resistance and the One Health approach has largely been established in recent years by a growing number of studies examining its different and multiple aspects. The specificity of this research lies in its two different levels of questioning the One Health concept. Firstly, the concept seems to be referred to by various formulas, from its oldest form, One Medicine-1984, to One World, One Health. Secondly, the concept is being redefined as links between a plurality of domains are recognized (human health, animal health, the environment, and food), following the emergence of international health and food crises and as their multi-level consequences are being addressed by various stakeholders, including public authorities, political leaders, and economic actors.

In multiple system atrophy (MSA), sleep-disordered breathing has a broad spectrum of phenotypes, among them inspiratory stridor and obstructive sleep apnea being most frequent. KU-0063794 molecular weight We present a case of 59-year old female with cerebellar-type MSA, who showed transient paradoxical breathing effort during non-REM sleep on diagnostic polysomnography. Since this thoraco-abdominal paradox was atypical for and did not coincide with upper airway obstruction it most likely indicated central dysregulation of the diaphragm. Continuous positive airway pressure therapy with low pressure (5 cmH₂O) was sufficient to completely resolve this type of respiratory dysregulation. This case extends the clinical spectrum of sleep-disordered breathing in MSA.

In multiple system atrophy (MSA), sleep-disordered breathing has a broad spectrum of phenotypes, among them inspiratory stridor and obstructive sleep apnea being most frequent. We present a case of 59-year old female with cerebellar-type MSA, who showed transient paradoxical breathing effort during non-REM sleep on diagnostic polysomnography. Since this thoraco-abdominal paradox was atypical for and did not coincide with upper airway obstruction it most likely indicated central dysregulation of the diaphragm. Continuous positive airway pressure therapy with low pressure (5 cmH₂O) was sufficient to completely resolve this type of respiratory dysregulation. This case extends the clinical spectrum of sleep-disordered breathing in MSA.

Sleep-disordered breathing (SDB) is common in patients with neuromuscular disorders (NMD), developing before chronic hypercapnia appears. Polysomnography (PSG) is the diagnostic gold standard but is often impractical and poorly accessible for individuals with NMD. We sought to determine diagnostic accuracy, feasibility and patient preference of Home Sleep Apnea Testing (HSAT) compared with PSG for detection of SDB in NMD.

Participants with NMD at risk for SDB, aged ≥13 years, underwent HSAT followed by overnight PSG with concomitant Laboratory Sleep Apnea Testing (same device as HSAT). Sensitivity and specificity were calculated for standard Apnea-Hypopnea Index (AHI) cut-offs for mild (≥5/h), moderate (≥15/h) and severe SDB (≥30/h), and for Oxygen Desaturation Index (ODI) ≥5/h. Receiver operating characteristic (ROC) curves were built. A questionnaire assessed patient preference.

Of 38 participants, 73% had moderate-severe SDB and 79% had technically acceptable HSAT. For AHI ≥15/h, HSAT sensitivity and specificity were 50% and 88% respectively.