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Symptoms in the urogenital organs are common in multiple system atrophy (MSA), also in the years preceding the MSA diagnosis. It is unknown how MSA is triggered and these observations in prodromal MSA led us to hypothesize that synucleinopathy could be triggered by infection of the genitourinary tract causing ɑ-synuclein (ɑSyn) to aggregate in peripheral nerves innervating these organs. As a first proof that peripheral infections could act as a trigger in MSA, this study focused on lower urinary tract infections (UTIs), given the relevance and high frequency of UTIs in prodromal MSA, although other types of infection might also be important triggers of MSA. We performed an epidemiological nested-case control study in the Danish population showing that UTIs are associated with future diagnosis of MSA several years after infection and that it impacts risk in both men and women. Bacterial infection of the urinary bladder triggers synucleinopathy in mice and we propose a novel role of ɑSyn in the innate immune system response to bacteria. Urinary tract infection with uropathogenic E. coli results in the de novo aggregation of ɑSyn during neutrophil infiltration. During the infection, ɑSyn is released extracellularly from neutrophils as part of their extracellular traps. Injection of MSA aggregates into the urinary bladder leads to motor deficits and propagation of ɑSyn pathology to the central nervous system in mice overexpressing oligodendroglial ɑSyn. Repeated UTIs lead to progressive development of synucleinopathy with oligodendroglial involvement in vivo. Our results link bacterial infections with synucleinopathy and show that a host response to environmental triggers can result in ɑSyn pathology that bears semblance to MSA. ispartof: ACTA NEUROPATHOLOGICA vol:145 issue:5 pages:541-559 ispartof: location:Germany status: published

Dans le cadre de travaux de recherche prénormatifs qui ont été engagés par le CEN/TC137 afin d'étudier l'application des micro-capteurs d'aérosols pour l'évaluation de l'exposition professionnelle aux NOAA, nous avons exposé six types de micro-capteurs à des aérosols produits à partir de neuf poudres différentes composées de composées de Nano-Objets, Aggrégats et Agglomérats (NOAA). Une grande variabilité des réponses en fonction des aérosols générés est observée, quel que soit le type de micro-capteur, ne permettant pas de garantir une détermination précise des concentrations massiques (PMx) et numériques (PNx). Néanmoins, ces capteurs possèdent tous des réponses linéaires qui pourraient être calibrées vis-à-vis des aérosols mesurés., As part of prenormative research that was initiated by CEN / TC137 to study the application of aerosol micro-sensors for the assessment of occupational exposure to NOAAs, we have exposed six types of sensors to nine different powders constituted by Nano-Objects, Aggregates and Agglomerates (NOAA). A great variability of the responses in function of the powders generated was observed, whatever the type of sensor. It does not make it possible to guarantee a precise determination of the PMx and PNx. However, all these sensors have linear responses that can be calibrated regarding the measured aerosols.

International audience; Results from the Sample Analysis at Mars (SAM)-evolved gas analyzer (EGA) on board the Mars Science Laboratory Curiosity rover constrained the alteration history and habitability potential of rocks sampled across the Siccar Point unconformity in Gale crater.The Glasgow member (Gm) mudstone just below the unconformity had evidence of acid sulfate or Si-poor brine alteration of Fe-smectite to Fe amorphous phases, leaching loss of Fe-Mg-sulfate and exchange of unfractionated sulfur 34S (δ34S=2±7‰) with enriched 34S (20±5‰, V-CDT). Carbon abundances did not significantly change (322-661 μgC/g) consistent with carbon stabilization by amorphous Al- and Fe-hydroxide phases. The Gm mudstone had no detectable oxychlorine and extremely low nitrate. Nitrate (0.06 wt.% NO3), oxychlorine (0.13 wt% ClO4), high C (1472 μg C/g), and low Fe/Mg-sulfate concentration (0.24 wt.% SO3) depleted in 34S (δ34S = -27‰ ± 7), were detected in the Stimson formation (Sf) eolian sandstone above the unconformity. Redox disequilibrium through the detections of iron sulfide and sulfate supported limited aqueous processes in the Sf sandstone. Si-poor brines or acidic fluids altered the Gm mudstone just below the unconformity but did not alter underlying Gm mudstones further from the contact. Chemical differences between the Sf and Gm rocks suggested that fluid interaction was minimal between the Sf and Gm rocks. These results suggested that the Gm rocks were altered by subsurface fluids after the Sf placement. Aqueous processes along the unconformity could have provided habitable conditions and in some cases, C and N levels could have supported heterotrophic microbial populations.

Dans cet article, nous présentons un nouveau dispositif de Prélèvement Personnel des Aérosols Semi-volatils (PPAS), inspiré du principe de l'impacteur virtuel. Le dispositif permet de mesurer séparément la concentration massique des phases particulaire et vapeur d'un aérosol semi-volatil. Les performances du PPAS ont été évaluées par simulation numérique et validées par des tests expérimentaux menés dans un banc de génération d'aérosols organiques. L'efficacité de transmission du dispositif est supérieure à 86 % pour des particules de diamètre aérodynamique supérieur à 0,05 µm et atteint une valeur de 100 % pour les particules de diamètre aérodynamique compris entre 2 et 20 µm. Le dispositif est portatif avec une perte de charge maximale de 160 Pa compatible avec les capacités des pompes de prélèvement individuelles, permettant ainsi de réaliser des prélèvements de 8 h sur les lieux de travail., In this article, we present a new device for sampling semi-volatile aerosols (PPAS), inspired by the virtual impactor concept. The device allows measuring separately the concentration of the particulate and vapour phases of a semi-volatile aerosol. The performances of the device were evaluated by numerical simulation and validated by experiments conducted in an organic aerosol generation test rig. The transmission efficiency of the device is higher than 86 % for particle aerodynamic diameters superior to 0.05 µm and reaches a value of 100% for particles aerodynamic diameters between 2 and 20 µm. The PPAS device is portable with a maximum pressure drop of 160 Pa adapted to the performances of individual sampling pumps, thus allowing 8-hour sampling at the workplace.

Repeat-associated non-AUG (RAN) translation is a noncanonical translation initiation event that occurs at nucleotide-repeat expansion mutations that are associated with several neurodegenerative diseases, including fragile X-associated tremor ataxia syndrome (FXTAS), ALS, and frontotemporal dementia (FTD). Translation of expanded repeats produces toxic proteins that accumulate in human brains and contribute to disease pathogenesis. Consequently, RAN translation constitutes a potentially important therapeutic target for managing multiple neurodegenerative disorders. Here, we adapted a previously developed RAN translation assay to a high-throughput format to screen 3,253 bioactive compounds for inhibition of RAN translation of expanded CGG repeats associated with FXTAS. We identified five diverse small molecules that dose-dependently inhibited CGG RAN translation, while relatively sparing canonical translation. All five compounds also inhibited RAN translation of expanded GGGGCC repeats associated with ALS and FTD. Using CD and native gel analyses, we found evidence that three of these compounds, BIX01294, CP-31398, and propidium iodide, bind directly to the repeat RNAs. These findings provide proof-of-principle supporting the development of selective small-molecule RAN translation inhibitors that act across multiple disease-causing repeats.

RationaleInterleukin-6 (IL-6) is a pleiotropic cytokine essential in the development of acute respiratory distress syndrome (ARDS) associated with Coronavirus disease 2019 (COVID-19). IL-6 is produced by immune cells and is instrumental in the up-regulation of acute phase reactants and helper T cell differentiation needed for B lymphocyte and antibody production. Inhibitors of IL-6 may result in down-regulation of immunoglobulin formation, predisposing patients to superinfections. Tocilizumab is a recombinant monoclonal antibody that targets the IL-6 receptor and is used in the management of rheumatologic diseases. More recently, tocilizumab has been used to treat patients with COVID-19. Based on results of retrospective cohort studies, tocilizumab may shorten time to clinical improvement and duration of invasive mechanical ventilation (IMV);however, the relationship between tocilizumab and development of secondary infections is uncertain due to limited and conflicting data. Our study aims to evaluate the use of tocilizumab in critically ill patients with COVID-19 who develop bacterial superinfections with or without bronchopleural fistulas (BPF). MethodsWe conducted a retrospective observational case series utilizing data from 50 patients admitted to the intensive care units at Lankenau Medical Center and Paoli Hospital, two large academic suburban hospitals. All patients were diagnosed with confirmed COVID-19 between February and July 2020 and received tocilizumab. ResultsTwenty-three (46%) patients who received tocilizumab developed secondary bacterial infections. Isolated organisms are outlined in Figure 1. The most common pathogens were MSSA and MRSA. Two of these patients developed a BPF. Of the 50 patients, 90% required invasive mechanical ventilation and 10% required non-invasive ventilation. Nine patients underwent extracorporeal membrane oxygenation. Illness severity ranged from mild to severe ARDS. ConclusionDespite its theoretical benefits, exposure to tocilizumab may predispose certain individuals to secondary infections, which may induce structural damage and cellular death. In our study, 46% of patients developed confirmed bacterial infection after receiving tocilizumab. Two of these patients went on to develop a BPF. The results of our study are in contrast to the results recently published in the NEJM, which reported that 8.1% of patients developed serious infection after receiving tocilizumab. The increased rate of bacterial superinfections noted in our study population may be in part due to illness severity, as all of our patients were critically ill and most of them required IMV. Additional randomized controlled trials of critically ill patients with COVID-19 are needed to determine if treatment with tocilizumab is directly correlated with the development of secondary bacterial infections.

In August 2015, the Curiosity Mars rover discovered tridymite, a high‐temperature silica polymorph, in Gale crater. The existing model for its occurrence suggests erosion and detrital sedimentation from silicic volcanic rocks in the crater rim or central peak. The chemistry and mineralogy of the tridymite‐bearing rocks, however, are not consistent with silicic volcanic material. Using data from Curiosity, including chemical composition from the Alpha Particle X‐ray Spectrometer, mineralogy from the CheMin instrument, and evolved gas and isotopic analyses from the Sample Analysis at Mars instrument, we show that the tridymite‐bearing rocks exhibit similar chemical patterns with silica‐rich alteration halos which crosscut the stratigraphy. We infer that the tridymite formed in‐place through hydrothermal processes and show additional chemical and mineralogical results from Gale crater consistent with hydrothermal activity occurring after sediment deposition and lithification.

The brain-expressed ubiquilins, UBQLNs 1, 2 and 4, are highly homologous proteins that participate in multiple aspects of protein homeostasis and are implicated in neurodegenerative diseases. Studies have established that UBQLN2 forms liquid-like condensates and accumulates in pathogenic aggregates, much like other proteins linked to neurodegenerative diseases. However, the relative condensate and aggregate formation of the three brain-expressed ubiquilins is unknown.We report that the three ubiquilins differ in aggregation propensity, revealed by in-vitro experiments, cellular models, and analysis of human brain tissue. UBQLN4 displays heightened aggregation propensity over the other ubiquilins and, like amyloids, UBQLN4 forms ThioflavinT-positive fibrils in vitro. Measuring fluorescence recovery after photobleaching (FRAP) of puncta in cells, we report that all three ubiquilins undergo liquid-liquid phase transition. UBQLN2 and 4 exhibit slower recovery than UBQLN1, suggesting the condensates formed by the brain-expressed ubiquilins have different compositions and undergo distinct internal rearrangements.We conclude that while all brain-expressed ubiquilins exhibit self-association behavior manifesting as condensates, they follow distinct courses of phase-separation and levels of aggregation. This variability among ubiquilins along the continuum from liquid-like to solid likely informs both the normal ubiquitin-linked functions of ubiquilins and their accumulation and potential contribution to toxicity in various neurodegenerative diseases.

Partant du constat que les définitions existantes des composés organiques semi-volatils sont insuffisantes et qu'elles induisent en erreur les concepteurs et utilisateurs des méthodes de prélèvement, les auteurs ont eu pour objectif de redéfinir la propriété semi-volatile de ces composés avec le point de vue du préleveur. La limite entre non volatilité et semi-volatilité et la limite entre semi-volatilité et volatilité ont été précisées par ce travail bibliographique et théorique., Based on the observation that the existing definitions of semi-volatile organic compounds are insufficient and that they mislead the designers and users of sampling methods, the authors aimed to redefine the semi-volatile property of these compounds with the point of view of the sampler. The limit between non-volatility and semi-volatility and the limit between semi-volatility and volatility have been clarified by this bibliographic and theoretical work.

Ce travail a pour objectif de présenter le travail de recherche prénormative qui ont été engagés par le CEN/TC137 afin d'étudier l'application des micro-capteurs d'aérosols pour l'évaluation de l'exposition professionnelle aux nano-objets, leurs agrégats et agglomérats (NOAA). Le projet « NOAA LCS » mobilise plusieurs partenaires européens (DGUV, INRS, IUTA, LNE et TNO). Six micro-capteurs différents, présélectionnés suite à une revue de littérature, sont actuellement en cours d'étude dans les laboratoires et leurs performances seront évaluées sur des lieux de travail où sont manipulés des NOAA. Les résultats permettront d'établir une stratégie d'évaluation des expositions professionnelles qui prendra la forme d'un rapport technique (TS) dont la publication est prévue en 2023., The objective of this work is to present the prenormative research work that has been undertaken by CEN / TC137 in order to study the application of low-cost aerosol sensors for the assessment of occupational exposure to nano-objects, their aggregates and agglomerates (NOAA). The "NOAA LCS" project mobilizes several European partners (DGUV, INRS, IUTA, LNE and TNO). Six different low-cost sensors, preselected following a literature review, are currently being studied in laboratories and their performance will be evaluated in workplaces where NOAA is handled. The results will make it possible to establish an occupational exposure assessment strategy that will take the form of a technical specification (TS) scheduled for publication in 2023.

Dans cet article, nous présentons les tests de performance d'un dispositif de prélèvement appelé SADS, basé sur le principe de l'impacteur virtuel, lorsqu'il est utilisé pour échantillonner la phase particulaire d'un aérosol semi-volatil. Les tests sont réalisés dans un banc de génération d'aérosols organiques. Les résultats des tests mettent en lumière certains facteurs réduisant l'efficacité de collecte de la phase particulaire, tels que le dépôt très important des particules dans le dispositif. Agir sur ces facteurs permettrait de concevoir un dispositif plus performant., In this paper, we present the performance tests of a sampling device called SADS, based on the virtual impactor principle, when used to sample the particle phase of a semi-volatile aerosol. The tests are performed in an organic aerosol generation bench. The results of the tests highlight some factors reducing the collection efficiency of the particle phase, such as an important deposit inside the device. Acting on these factors would make it possible to design a more efficient device.

BackgroundMessenger RNA 3’ untranslated regions (3’UTRs) control many aspects of gene expression and determine where the transcript will terminate. The polyadenylation signal (PAS) AAUAAA is a key regulator of transcript termination and this hexamer, or a similar sequence, is very frequently found within 30 bp of 3’UTR ends. Short interspersed element (SINE) retrotransposons are found throughout genomes in high copy number. When inserted into genes they can disrupt expression, alter splicing, or cause nuclear retention of mRNAs. The genomes of the domestic dog and other carnivores carry hundreds of thousands Can-SINEs, a tRNA-related SINE with transcription termination potential. Because of this we asked whether Can-SINEs may help terminate transcript in some dog genes.ResultsDog 3’UTRs have several peaks of AATAAA PAS frequency within 40 bp of the 3’UTR end, including four bp-interval peaks at 28, 32, and 36 bp from the end. The periodicity is partly explained by TAAA(n) repeats within Can-SINE AT-rich tails. While density of antisense-oriented Can-SINEs in 3’UTRs is fairly constant with distances from 3’end, sense-oriented Can-SINEs are common at the 3’end but nearly absent farther upstream. There are nine Can-SINE sub-types in the dog genome and the consensus sequence sense strands (head to tail) all carry at least three PASs while antisense strands usually have none. We annotated all repeat-masked Can-SINE copies in the Boxer reference genome and found that the young SINEC_Cf type has a mode of 15 bp for target site duplications (TSDs). We find that all Can-SINE types favor integration at TSDs beginning with A(4). The count of AATAAA PASs differs significantly between sense and antisense-oriented retrotransposons in transcripts. Can-SINEs near 3’UTR ends are very likely to carry AATAAA on the mRNA sense strand while those farther upstream are not. We also identified loci where Can-SINE insertion has truncated or altered a dog 3’UTR compared to the human ortholog.ConclusionDog Can-SINE activity has imported AATAAA PASs into gene transcripts and led to alteration of 3’UTRs. AATAAA sequences are selectively removed from Can-SINEs in introns and upstream 3’UTR regions but are retained at the far downstream end of 3’UTRs, which we infer reflects their role as termination sequences for these transcripts.

Supporting information file for Journal of Geophysical Research - Planets article.

International audience

The dog is an exciting genetic system in which many simple and complex traits have now been mapped. For many traits the causal mutation is a polymorphic SINE. To investigate the genome-wide pattern of young SINEC_Cf insertions, we sampled 62 dogs representing 59 breeds and sequenced libraries enriched for SINE flanks. In each dog we detect an average of 10,423 polymorphic loci and all together the libraries identify 81,747 putative polymorphic SINEs. We validated 184 SINEs inserted in protein-coding exons, untranslated regions, introns and intergenic sequence. In dogs both SINEC_Cf and LINEs exhibit a strand bias in introns where antisense copies are more frequent. Antisense polymorphic SINEs also have a higher density in introns. Both SINEs and LINEs drop to very low density near exons. Both sense and antisense polymorphic SINEs also drop to low density upstream of coding exons but not downstream. Antisense polymorphic SINEC_Cfs upstream of coding exons are known to cause narcolepsy, merle, and progressive retinal atrophy in dogs. In other mammals SINE pairs in inverted orientation disrupt gene expression. We find inverted pairs of SINEC_Cf are rare in both introns and intergenic sequence when the two SINEs are separated by less than 100 bp. The lack of inverted pairs is even more pronounced when the SINEs have high sequence identity. Intronic and intergenic LINE pairs show similar patterns. Polymorphic SINEs rarely pair with either SINEC_Cf or SINEC_Cf2. Overall, the high insertion rate of SINEC_Cf provides a natural mutagenesis screen in the dog genome.

Vera Rubin ridge (VRR) is an erosion‐resistant feature on the northwestern slope of Mount Sharp in Gale crater, Mars, and orbital visible/short‐wave infrared measurements indicate it contains red‐colored hematite. The Mars Science Laboratory Curiosity rover performed an extensive campaign on VRR to study its mineralogy, geochemistry, and sedimentology to determine the depositional and diagenetic history of the ridge and constrain the processes by which the hematite could have formed. X‐ray diffraction (XRD) data from the CheMin instrument of four samples drilled on and below VRR demonstrate differences in iron, phyllosilicate, and sulfate mineralogy and hematite grain size. Hematite is common across the ridge, and its detection in a gray‐colored outcrop suggested localized regions with coarse‐grained hematite, which commonly forms from warm fluids. Broad XRD peaks for hematite in one sample below VRR and the abundance of FeO_T in the amorphous component suggest the presence of nano‐crystalline hematite and amorphous Fe oxides/oxyhydroxides. Well‐crystalline akaganeite and jarosite are present in two samples drilled from VRR, indicating at least limited alteration by acid‐saline fluids. Collapsed nontronite is present below VRR, but samples from VRR contain phyllosilicate with d(001) = 9.6 A, possibly from ferripyrophyllite or an acid‐altered smectite. The most likely cementing agents creating the ridge are hematite and opaline silica. We hypothesize late diagenesis can explain much of the mineralogical variation on the ridge, where multiple fluid episodes with variable pH, salinity, and temperature altered the rocks, causing the precipitation and crystallization of phases that are not otherwise in equilibrium.

The aggregation of amyloidogenic polypeptides is strongly linked to several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Conformational antibodies that selectively recognize protein aggregates are leading therapeutic agents for selectively neutralizing toxic aggregates, diagnostic and imaging agents for detecting disease, and biomedical reagents for elucidating disease mechanisms. Despite their importance, it is challenging to generate high-quality conformational antibodies in a systematic and site-specific manner due to the properties of protein aggregates (hydrophobic, multivalent, and heterogeneous) and limitations of immunization (uncontrolled antigen presentation and immunodominant epitopes). Toward addressing these challenges, we have developed a systematic directed evolution procedure for affinity maturing antibodies against Alzheimer's Aβ fibrils and selecting variants with strict conformational and sequence specificity. We first designed a library based on a lead conformational antibody by sampling combinations of amino acids in the antigen-binding site predicted to mediate high antibody specificity. Next, we displayed this library on the surface of yeast, sorted it against Aβ42 aggregates, and identified promising clones using deep sequencing. The resulting antibodies displayed similar or higher affinities than clinical-stage Aβ antibodies (aducanumab and crenezumab). Moreover, the affinity-matured antibodies retained high conformational specificity for Aβ aggregates, as observed for aducanumab and unlike crenezumab. Notably, the affinity-maturated antibodies displayed extremely low levels of nonspecific interactions, as observed for crenezumab and unlike aducanumab. We expect that our systematic methods for generating antibodies with unique combinations of desirable properties will improve the generation of high-quality conformational antibodies specific for diverse types of aggregated conformers.

Within developing embryos, tissues flow and reorganize dramatically on timescales as short as minutes. This includes epithelial tissues, which often narrow and elongate in convergent extension movements due to anisotropies in external forces or in internal cell-generated forces. However, the mechanisms that allow or prevent tissue reorganization, especially in the presence of strongly anisotropic forces, remain unclear. We study this question in the converging and extending Drosophila germband epithelium, which displays planar-polarized myosin II and experiences anisotropic forces from neighboring tissues. We show that, in contrast to isotropic tissues, cell shape alone is not sufficient to predict the onset of rapid cell rearrangement. From theoretical considerations and vertex model simulations, we predict that in anisotropic tissues, two experimentally accessible metrics of cell patterns—the cell shape index and a cell alignment index—are required to determine whether an anisotropic tissue is in a solid-like or fluid-like state. We show that changes in cell shape and alignment over time in the Drosophila germband predict the onset of rapid cell rearrangement in both wild-type and snail twist mutant embryos, where our theoretical prediction is further improved when we also account for cell packing disorder. These findings suggest that convergent extension is associated with a transition to more fluid-like tissue behavior, which may help accommodate tissue-shape changes during rapid developmental events.

Les aérosols semi-volatils sont simultanément présents dans l'air sous forme particulaire et gazeuse et sont de nature chimique très diverse. Supposant des effets sur la santé différents des phases particulaires et gazeuses, l'évaluation de l'exposition des salariés nécessite le prélèvement et la collecte séparée de chaque phase. Cet article rapporte les résultats de simulations numériques 2D axisymétriques et 3D réalisées sur un nouveau dispositif de prélèvement appelé SADS, et basé sur le principe de l'impacteur virtuel. Ces simulations ont permis de mettre en lumière les phénomènes physiques réduisant l'efficacité de séparation des deux phases., Semi-volatile aerosols are simultaneously present in the particle and vapour phase, and have a high chemical diversity. Considering different effects of the phases on human health, the exposure assessment of the workers requires to sample theses phases separately. This article reports numerical 2D axisymmetric and 3D numerical simulation results carried on a new sampler called SADS (Semi-volatile Aerosol Dichotomous Sampler), based on the virtual impactor principle. These numerical simulations highlighted the physical phenomena decreasing the separation efficiency of the device.

OBJECTIVE To identify the genetic cause for congenital photosensitivity and hyperbilirubinemia (CPH) in Southdown sheep. ANIMALS 73 Southdown sheep from a CPH research flock and 48 sheep of various breeds from commercial flocks without CPH. PROCEDURES Whole-genome sequencing was performed for a phenotypically normal Southdown sheep heterozygous for CPH. Heterozygous variants within Slco1b3 coding exons were identified, and exons that contained candidate mutations were amplified by PCR assay methods for Sanger sequencing. Blood samples from the other 72 Southdown sheep of the CPH research flock were used to determine plasma direct and indirect bilirubin concentrations. Southdown sheep with a plasma total bilirubin concentration < 0.3 mg/dL were classified as controls, and those with a total bilirubin concentration ≥ 0.3 mg/dL and signs of photosensitivity were classified as mutants. Sanger sequencing was used to determine the Slco1b3 genotype for all sheep. Genotypes were compared between mutants and controls of the CPH research flock and among all sheep. Protein homology was measured across 8 species to detect evolutionary conservation of Slco1b. RESULTS A nonsynonymous mutation at ovine Chr3:193,691,195, which generated a glycine-to-arginine amino acid change within the predicted Slco1b3 protein, was significantly associated with hyperbilirubinemia and predicted to be deleterious. That amino acid was conserved across 7 other mammalian species. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested a nonsynonymous mutation in Slco1b3 causes CPH in Southdown sheep. This disease appears to be similar to Rotor syndrome in humans. Sheep with CPH might be useful animals for Rotor syndrome research.

Within developing embryos, tissues flow and reorganize dramatically on timescales as short as minutes. This includes epithelial tissues, which often narrow and elongate in convergent extension movements due to anisotropies in external forces or in internal cell-generated forces. However, the mechanisms that allow or prevent tissue reorganization, especially in the presence of strongly anisotropic forces, remain unclear. We study this question in the converging and extendingDrosophilagermband epithelium, which displays planar polarized myosin II and experiences anisotropic forces from neighboring tissues, and we show that in contrast to isotropic tissues, cell shape alone is not sufficient to predict the onset of rapid cell rearrangement. From theoretical considerations and vertex model simulations, we predict that in anisotropic tissues two experimentally accessible metrics of cell patterns—the cell shape index and a cell alignment index—are required to determine whether an anisotropic tissue is in a solid-like or fluid-like state. We show that changes in cell shape and alignment over time in theDrosophilagermband indicate a solid-to-fluid transition that corresponds to the onset of cell rearrangement and convergent extension in wild-type embryos and are also consistent with more solid-like behavior inbntmutant embryos. Thus, the onset of cell rearrangement in the germband can be predicted by a combination of cell shape and alignment. These findings suggest that convergent extension is associated with a transition to more fluid-like tissue behavior, which may help accommodate tissue shape changes during rapid developmental events.

This study provides novel insights into the mechanisms by which presence of polyP alters the formation, structural properties, and cytotoxic effects of α-synuclein fibers., The universally abundant polyphosphate (polyP) accelerates fibril formation of disease-related amyloids and protects against amyloid cytotoxicity. To gain insights into the mechanism(s) by which polyP exerts these effects, we focused on α-synuclein, a well-studied amyloid protein, which constitutes the major component of Lewy bodies found in Parkinson’s disease. Here, we demonstrate that polyP is unable to accelerate the rate-limiting step of α-synuclein fibril formation but effectively nucleates fibril assembly once α-synuclein oligomers are formed. Binding of polyP to α-synuclein either during fibril formation or upon fibril maturation substantially alters fibril morphology and effectively reduces the ability of α-synuclein fibrils to interact with cell membranes. The effect of polyP appears to be α-synuclein fibril specific and successfully prevents the uptake of fibrils into neuronal cells. These results suggest that altering the polyP levels in the extracellular space might be a potential therapeutic strategy to prevent the spreading of the disease.

The domesticated horse has played a unique role in human history, serving not just as a source of animal protein, but also as a catalyst for long-distance migration and military conquest. As a result, the horse developed unique physiological adaptations to meet the demands of both their climatic environment and their relationship with man. Completed in 2009, the first domesticated horse reference genome assembly (EquCab 2.0) produced most of the publicly available genetic variations annotations in this species. Yet, there are around 400 geographically and physiologically diverse breeds of horse. To enrich the current collection of genetic variants in the horse, we sequenced whole genomes from six horses of six different breeds: an American Miniature, a Percheron, an Arabian, a Mangalarga Marchador, a Native Mongolian Chakouyi, and a Tennessee Walking Horse, and mapped them to EquCab3.0 genome. Aside from extreme contrasts in body size, these breeds originate from diverse global locations and each possess unique adaptive physiology. A total of 1.3 billion reads were generated for the six horses with coverage between 15x to 24x per horse. After applying rigorous filtration, we identified and functionally annotated 17,514,723 Single Nucleotide Polymorphisms (SNPs), and 1,923,693 Insertions/Deletions (INDELs), as well as an average of 1,540 Copy Number Variations (CNVs) and 3,321 Structural Variations (SVs) per horse. Our results revealed putative functional variants including genes associated with size variation like LCORL gene (found in all horses), ZFAT in the Arabian, American Miniature and Percheron horses and ANKRD1 in the Native Mongolian Chakouyi horse. We detected a copy number variation in the Latherin gene that may be the result of evolutionary selection impacting thermoregulation by sweating, an important component of athleticism and heat tolerance. The newly discovered variants were formatted into user-friendly browser tracks and will provide a foundational database for future studies of the genetic underpinnings of diverse phenotypes within the horse., Author summary The domesticated horse played a unique role in human history, serving not just as a source of dietary animal protein, but also as a catalyst for long-distance migration and military conquest. As a result, the horse developed unique physiological adaptations to meet the demands of both their climatic environment and their relationship with man. Although the completion of the horse reference genome allowed for the discovery of many genetic variants, the remarkable diversity across breeds of horse calls for additional effort to quantify the complete span of genetic polymorphism within this unique species. In this work, we present genome re-sequencing and variant detection analysis for six horses belonging to six different breeds representing different morphology, origins and vary in their physiological demands and response. We identified and annotated not just single nucleotide polymorphisms (SNPs), but also insertions and deletions (INDELs), copy number variations (CNVs) and structural variations (SVs). Our results illustrate novel sources of polymorphism and highlight potentially impactful variations for phenotypes of body size and conformation. We also detected a copy number loss in the Latherin gene that could be the result of an evolutionary selection affecting thermoregulation through sweating. Our newly discovered variants were formatted into easy-to-use tracks that can be easily accessed by researchers around the globe.