215 research outputs found

    Pedigree‐management‐flight interaction for temporal phenotype analysis and temporal phenomic prediction

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    Abstract Unoccupied aerial systems (UAS, aka drones) provide high dimensional temporal phenotype data for predictive plant breeding and genetic dissection. Methods to assess temporal phenotype data are an emerging need to predict temporal breeding values of genotypes. Here a novel interaction design was developed and evaluated to include drone flight dates as a component into the mixed model; allowing the temporal changes of drone image derived traits of maize hybrids across different flight dates as well as different management conditions to be monitored. Across 2017 and 2019 respectively, 228 and 100 maize hybrids were grown under two types of management (optimal and late plantings). Seven drone surveys were conducted over each management in 2017 while five drone surveys were conducted over each management in 2019. Temporal plant height (canopy height measurements, CHM) and normalized green‐red difference index (NGRDI) were extracted from each drone survey and used as phenotype data to evaluate the interaction design. Day of flight effects explained the highest amount of total variation for grain yield in the interaction model, meaning the majority of phenotypic variation of CHM and NGRDI occurred across growth with a unique temporal trajectory in each management system. Temporal repeatability values remained higher than 0.5 for CHM and NGRDI in each year. Temporal CHM and NGRDI breeding values of maize hybrids were combined in ridge and lasso regression prediction models. Yield prediction ability of untested genotypes in untested environments were predicted higher by using pedigree × management × flight (PMF) and pedigree× management (PM) interaction results (∌0.34 and 0.52 in 2017 and 2019). Combining environment specific phenomic data (PMF plus PM) gave a larger improvement in yield prediction when the tested and untested environments were less similar. Overall, combined temporal phenomic data could moderately predict grain yield under the most challenging predictive breeding scenario, untested and unrelated genotypes in untested environments

    Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts

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    Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient–parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10−33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease.<br/

    Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts

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    Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10-33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease

    Effect of Nitric Oxide Pathway Inhibition on the Evolution of Anaphylactic Shock in Animal Models: A Systematic Review

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    Nitric oxide (NO) induces vasodilation in various types of shock. The effect of pharmacological modulation of the NO pathway in anaphylactic shock (AS) remains poorly understood. Our objective was to assess, through a systematic review, whether inhibition of NO pathways (INOP) was beneficial for the prevention and/or treatment of AS. A predesigned protocol for this systematic review was published in PROSPERO (CRD42019132273). A systematic literature search was conducted till March 2022 in the electronic databases PubMed, EMBASE, Scopus, Cochrane and Web of Science. Heterogeneity of the studies did not allow meta-analysis. Nine hundred ninety unique studies were identified. Of 135 studies screened in full text, 17 were included in the review. Among six inhibitors of NO pathways identified, four blocked NO synthase activity and two blocked guanylate cyclase downstream activity. Pre-treatment was used in nine studies and post-treatment in three studies. Five studies included both pre-treatment and post-treatment models. Overall, seven pre-treatment studies from fourteen showed improvement of survival and/or arterial blood pressure. Four post-treatment studies from eight showed positive outcomes. Overall, there was no strong evidence to conclude that isolated blockade of the NO/cGMP pathway is sufficient to prevent or restore anaphylactic hypotension. Further studies are needed to analyze the effect of drug combinations in the treatment of AS

    Dysregulated Erythroid Mg2+ Efflux in Type 2 Diabetes

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    CEECIND/01053/2017 UIDB/04647/2020 UIDP/04647/2020Hyperglycemia is associated with decreased Mg2+ content in red blood cells (RBC), but mechanisms remain unclear. We characterized the regulation of Mg2+ efflux by glucose in ex vivo human RBC. We observed that hemoglobin A1C (HbA1C) values correlated with Na+-dependent Mg2+ efflux (Na+/Mg2+ exchange) and inversely correlated with cellular Mg content. Treatment of cells with 50 mM D-glucose, but not with sorbitol, lowered total cellular Mg (2.2 ± 0.1 to 2.0 ± 0.1 mM, p < 0.01) and enhanced Na+/Mg2+ exchange activity [0.60 ± 0.09 to 1.12 ± 0.09 mmol/1013 cell × h (flux units, FU), p < 0.05]. In contrast, incubation with selective Src family kinase inhibitors PP2 or SU6656 reduced glucose-stimulated exchange activation (p < 0.01). Na+/Mg2+ exchange activity was also higher in RBC from individuals with type 2 diabetes (T2D, 1.19 ± 0.13 FU) than from non-diabetic individuals (0.58 ± 0.05 FU, p < 0.01). Increased Na+/Mg2+ exchange activity in RBC from T2D subjects was associated with lower intracellular Mg content. Similarly increased exchange activity was evident in RBC from the diabetic db/db mouse model as compared to its non-diabetic control (p < 0.03). Extracellular exposure of intact RBC from T2D subjects to recombinant peptidyl-N-glycosidase F (PNGase F) reduced Na+/Mg2+ exchange activity from 0.98 ± 0.14 to 0.59 ± 0.13 FU (p < 0.05) and increased baseline intracellular Mg content (1.8 ± 0.1 mM) to normal values (2.1 ± 0.1 mM, p < 0.05). These data suggest that the reduced RBC Mg content of T2D RBC reflects enhanced RBC Na+/Mg2+ exchange subject to regulation by Src family kinases and by the N-glycosylation state of one or more membrane proteins. The data extend our understanding of dysregulated RBC Mg2+ homeostasis in T2D.publishersversionpublishe

    Activation of 2‐oxoglutarate receptor 1 (OXGR1) by α‐ketoglutarate (αKG) does not detectably stimulate Pendrin‐mediated anion exchange in Xenopus oocytes

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    Abstract SLC26A4/Pendrin is the major electroneutral Cl−/HCO3− exchanger of the apical membrane of the Type B intercalated cell (IC) of the connecting segment (CNT) and cortical collecting duct (CCD). Pendrin mediates both base secretion in response to systemic base load and Cl− reabsorption in response to systemic volume depletion, manifested as decreased nephron salt and water delivery to the distal nephron. Pendrin‐mediated Cl−/HCO3− exchange in the apical membrane is upregulated through stimulation of the ÎČ‐IC apical membrane G protein‐coupled receptor, 2‐oxoglutarate receptor 1 (OXGR1/GPR99), by its ligand α‐ketoglutarate (αKG). αKG is both filtered by the glomerulus and lumenally secreted by proximal tubule apical membrane organic anion transporters (OATs). OXGR1‐mediated regulation of Pendrin by αKG has been documented in transgenic mice and in isolated perfused CCD. However, aspects of the OXGR1 signaling pathway have remained little investigated since its original discovery in lymphocytes. Moreover, no ex vivo cellular system has been reported in which to study the OXGR1 signaling pathway of Type B‐IC, a cell type refractory to survival in culture in its differentiated state. As Xenopus oocytes express robust heterologous Pendrin activity, we investigated OXGR1 regulation of Pendrin in oocytes. Despite functional expression of OXGR1 in oocytes, co‐expression of Pendrin and OXGR1 failed to exhibit αKG‐sensitive stimulation of Pendrin‐mediated Cl−/anion exchange under a wide range of conditions. We conclude that Xenopus oocytes lack one or more essential molecular components or physical conditions required for OXGR1 to regulate Pendrin activity

    Combined Treatment with KV Channel Inhibitor 4-Aminopyridine and either Îł-Cystathionine Lyase Inhibitor ÎČ-Cyanoalanine or Epinephrine Restores Blood Pressure, and Improves Survival in the Wistar Rat Model of Anaphylactic Shock

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    The mechanism of anaphylactic shock (AS) remains incompletely understood. The potassium channel blocker 4-aminopyridine (4-AP), the inhibitors of cystathionine Îł-lyase (ICSE), dl-propargylglycine (DPG) or ÎČ-cyanoalanine (BCA), and the nitric oxide (NO) synthase produce vasoconstriction and could be an alternative for the treatment of AS. The aim of this study was to demonstrate the ability of L-NAME, ICSE alone or in combination with 4-AP to restore blood pressure (BP) and improve survival in ovalbumin (OVA) rats AS. Experimental groups included non-sensitized Wistar rats (n = 6); AS (n = 6); AS (n = 10 per group) treated i.v. with 4-AP (AS+4-AP), epinephrine (AS+EPI), AS+DPG, AS+BCA, or with L-NAME (AS+L-NAME); or AS treated with drug combinations 4-AP+DPG, 4-AP+BCA, 4-AP+L-NAME, or 4-AP+EPI. AS was induced by i.v. OVA (1 mg). Treatments were administered i.v. one minute after AS induction. Mean arterial BP (MAP), heart rate (HR), and survival were monitored for 60 min. Plasma levels of histamine, prostaglandin E2 (PGE2) and F2 (PGF2α), leukotriene B4 and C4, angiotensin II, vasopressin, oxidative stress markers, pH, HCO3, PaO2, PaCO2, and K+ were measured. OVA induced severe hypotension and all AS rats died. Moreover, 4-AP, 4-AP+EPI, or 4-AP+BCA normalized both MAP and HR and increased survival. All sensitized rats treated with 4-AP alone or with 4-AP+BCA survived. The time-integrated MAP “area under the curve” was significantly higher after combined 4-AP treatment with ICSE. Metabolic acidosis was not rescued and NO, ICSE, and Kv inhibitors differentially alter oxidative stress and plasma levels of anaphylactic mediators. The AS-induced reduction of serum angiotensin II levels was prevented by 4-AP treatment alone or in combination with other drugs. Further, 4-AP treatment combined with EPI or with BCA also increased serum PGF2α, whereas only the 4-AP+EPI combination increased serum LTB4. Serum vasopressin and angiotensin II levels were increased by 4-AP treatment alone or in combination with other drugs. Moreover, 4-AP alone and in combination with inhibition of cystathionine Îł-lyase or EPI normalizes BP, increases serum vasoconstrictor levels, and improves survival in the Wistar rat model of AS. These findings suggest possible investigative treatment pathways for research into epinephrine-refractory anaphylactic shock in patients

    Temporal Vegetation Indices and Plant Height from Remotely Sensed Imagery Can Predict Grain Yield and Flowering Time Breeding Value in Maize via Machine Learning Regression

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    Unoccupied aerial system (UAS; i.e., drone equipped with sensors) field-based high-throughput phenotyping (HTP) platforms are used to collect high quality images of plant nurseries to screen genetic materials (e.g., hybrids and inbreds) throughout plant growth at relatively low cost. In this study, a set of 100 advanced breeding maize (Zea mays L.) hybrids were planted at optimal (OHOT trial) and delayed planting dates (DHOT trial). Twelve UAS surveys were conducted over the trials throughout the growing season. Fifteen vegetative indices (VIs) and the 99th percentile canopy height measurement (CHMs) were extracted from processed UAS imagery (orthomosaics and point clouds) which were used to predict plot-level grain yield, days to anthesis (DTA), and silking (DTS). A novel statistical approach utilizing a nested design was fit to predict temporal best linear unbiased predictors (TBLUP) for the combined temporal UAS data. Our results demonstrated machine learning-based regressions (ridge, lasso, and elastic net) had from 4- to 9-fold increases in the prediction accuracies and from 13- to 73-fold reductions in root mean squared error (RMSE) compared to classical linear regression in prediction of grain yield or flowering time. Ridge regression performed best in predicting grain yield (prediction accuracy = ~0.6), while lasso and elastic net regressions performed best in predicting DTA and DTS (prediction accuracy = ~0.8) consistently in both trials. We demonstrated that predictor variable importance descended towards the terminal stages of growth, signifying the importance of phenotype collection beyond classical terminal growth stages. This study is among the first to demonstrate an ability to predict yield in elite hybrid maize breeding trials using temporal UAS image-based phenotypes and supports the potential benefit of phenomic selection approaches in estimating breeding values before harvest

    Adaptative Up-Regulation of PRX2 and PRX5 Expression Characterizes Brain from a Mouse Model of Chorea-Acanthocytosis

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    The peroxiredoxins (PRXs) constitute a ubiquitous antioxidant. Growing evidence in neurodegenerative disorders such as Parkinson&rsquo;s disease (PD) or Alzheimer&rsquo;s disease (AD) has highlighted a crucial role for PRXs against neuro-oxidation. Chorea-acanthocytosis/Vps13A disease (ChAc) is a devastating, life-shortening disorder characterized by acanthocytosis, neurodegeneration and abnormal proteostasis. We recently developed a Vps13a&minus;/&minus; ChAc-mouse model, showing acanthocytosis, neurodegeneration and neuroinflammation which could be restored by LYN inactivation. Here, we show in our Vps13a&minus;/&minus; mice protein oxidation, NRF2 activation and upregulation of downstream cytoprotective systems NQO1, SRXN1 and TRXR in basal ganglia. This was associated with upregulation of PRX2/5 expression compared to wild-type mice. PRX2 expression was age-dependent in both mouse strains, whereas only Vps13a&minus;/&minus; PRX5 expression was increased independent of age. LYN deficiency or nilotinib-mediated LYN inhibition improved autophagy in Vps13a&minus;/&minus; mice. In Vps13a&minus;/&minus;; Lyn&minus;/&minus; basal ganglia, absence of LYN resulted in reduced NRF2 activation and down-regulated expression of PRX2/5, SRXN1 and TRXR. Nilotinib treatment of Vps13a&minus;/&minus; mice reduced basal ganglia oxidation, and plasma PRX5 levels, suggesting plasma PRX5 as a possible ChAc biomarker. Our data support initiation of therapeutic Lyn inhibition as promptly as possible after ChAc diagnosis to minimize development of irreversible neuronal damage during otherwise inevitable ChAc progression

    Countermeasures against COVID-19: how to navigate medical practice through a nascent, evolving evidence base — a European multicentre mixed methods study

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    Objectives In a previously published Delphi exercise the European Pediatric Dialysis Working Group (EPDWG) reported widely variable counteractive responses to COVID-19 during the first week of statutory public curfews in 12 European countries with case loads of 4–680 infected patients per million. To better understand these wide variations, we assessed different factors affecting countermeasure implementation rates and applied the capability, opportunity, motivation model of behaviour to describe their determinants.Design We undertook this international mixed methods study of increased depth and breadth to obtain more complete data and to better understand the resulting complex evidence.Setting This study was conducted in 14 paediatric nephrology centres across 12 European countries during the COVID-19 pandemic.Participants The 14 participants were paediatric nephrologists and EPDWG members from 12 European centres.Main outcome measures 52 countermeasures clustered into eight response domains (access control, patient testing, personnel testing, personal protective equipment policy, patient cohorting, personnel cohorting, suspension of routine care, remote work) were categorised by implementation status, drivers (expert opinion, hospital regulations) and resource dependency. Governmental strictness and media attitude were independently assessed for each country and correlated with relevant countermeasure implementation factors.Results Implementation rates varied widely among response domains (median 49.5%, range 20%–71%) and centres (median 46%, range 31%–62%). Case loads were insufficient to explain response rate variability. Increasing case loads resulted in shifts from expert opinion-based to hospital regulation-based decisions to implement additional countermeasures despite increased resource dependency. Higher governmental strictness and positive media attitude towards countermeasure implementation were associated with higher implementation rates.Conclusions COVID-19 countermeasure implementation by paediatric tertiary care centres did not reflect case loads but rather reflected heterogeneity of local rules and of perceived resources. These data highlight the need of ongoing reassessment of current practices, facilitating rapid change in ‘institutional behavior’ in response to emerging evidence of countermeasure efficacy
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