ResearchPad - studies https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[A MYB transcription factor, <i>BnMYB2</i>, cloned from ramie (<i>Boehmeria nivea</i>) is involved in cadmium tolerance and accumulation]]> https://www.researchpad.co/article/elastic_article_15762 MYB-related transcription factors play important roles in plant development and response to various environmental stresses. In the present study, a novel MYB gene, designated as BnMYB2 (GenBank accession number: MF741319.1), was isolated from Boehmeria nivea using rapid amplification of cDNA ends (RACE) and RT-PCR on a sequence fragment from a ramie transcriptome. BnMYB2 has a 945 bp open reading frame encoding a 314 amino acid protein that contains a DNA-binding domain and shares high sequence identity with MYB proteins from other plant species. The BnMYB2 promoter contains several putative cis-acting elements involved in stress or phytohormone responses. A translational fusion of BnMYB2 with enhanced green fluorescent protein (eGFP) showed nuclear and cytosolic subcellular localization. Real-time PCR results indicated that BnMYB2 expression was induced by Cadmium (Cd) stress. Overexpression of BnMYB2 in Arabidopsis thaliana resulted in a significant increase of Cd tolerance and accumulation. Thus, BnMYB2 positively regulated Cd tolerance and accumulation in Arabidopsis, and could be used to enhance the efficiency of Cd removal with plants.

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<![CDATA[Levosimendan reduces segmental pulmonary vascular resistance in isolated perfused rat lungs and relaxes human pulmonary vessels]]> https://www.researchpad.co/article/elastic_article_15739 Levosimendan is approved for acute heart failure. Within this context, pulmonary hypertension represents a frequent co-morbidity. Hence, the effects of levosimendan on segmental pulmonary vascular resistance (PVR) are relevant. So far, this issue has been not studied. Beyond that the relaxant effects of levosimendan in human pulmonary vessel are unknown. We addressed these topics in rats’ isolated perfused lungs (IPL) and human precision-cut lung slices (PCLS).Material and methodsIn IPL, levosimendan (10 μM) was perfused in untreated and endothelin-1 pre-contracted lungs. The pulmonary arterial pressure (PPA) was continuously recorded and the capillary pressure (Pcap) was determined by the double-occlusion method. Thereafter, segmental PVR, expressed as precapillary (Rpre) and postcapillary resistance (Rpost) and PVR were calculated. Human PCLS were prepared from patients undergoing lobectomy. Levosimendan-induced relaxation was studied in naïve and endothelin-1 pre-contracted PAs and PVs. In endothelin-1 pre-contracted PAs, the role of K+-channels was studied by inhibition of KATP-channels (glibenclamide), BKCa2+-channels (iberiotoxin) and Kv-channels (4-aminopyridine). All changes of the vascular tone were measured by videomicroscopy. In addition, the increase of cAMP/GMP due to levosimendan was measured by ELISA.ResultsLevosimendan did not relax untreated lungs or naïve PAs and PVs. In IPL, levosimendan attenuated the endothelin-1 induced increase of PPA, PVR, Rpre and Rpost. In human PCLS, levosimendan relaxed pre-contracted PAs or PVs to 137% or 127%, respectively. In pre-contracted PAs, the relaxant effect of levosimendan was reduced, if KATP- and Kv-channels were inhibited. Further, levosimendan increased cGMP in PAs/PVs, but cAMP only in PVs.DiscussionLevosimendan reduces rats’ segmental PVR and relaxes human PAs or PVs, if the pulmonary vascular tone is enhanced by endothelin-1. Regarding levosimendan-induced relaxation, the activation of KATP- and Kv-channels is of impact, as well as the formation of cAMP and cGMP. In conclusion, our results suggest that levosimendan improves pulmonary haemodynamics, if PVR is increased as it is the case in pulmonary hypertension. ]]> <![CDATA[The <i>G123</i> rice mutant, carrying a mutation in <i>SE13</i>, presents alterations in the expression patterns of photosynthetic and major flowering regulatory genes]]> https://www.researchpad.co/article/elastic_article_15737 Day length is a determinant of flowering time in rice. Phytochromes participate in flowering regulation by measuring the number of daylight hours to which the plant is exposed. Here we describe G123, a rice mutant generated by irradiation, which displays insensitivity to the photoperiod and early flowering under both long day and short day conditions. To detect the mutation responsible for the early flowering phenotype exhibited by G123, we generated an F2 population, derived from crossing with the wild-type, and used a pipeline to detect genomic structural variation, initially developed for human genomes. We detected a deletion in the G123 genome that affects the PHOTOPERIOD SENSITIVITY13 (SE13) gene, which encodes a phytochromobilin synthase, an enzyme implicated in phytochrome chromophore biosynthesis. The transcriptomic analysis, performed by RNA-seq, in the G123 plants indicated an alteration in photosynthesis and other processes related to response to light. The expression patterns of the main flowering regulatory genes, such as Ghd7, Ghd8 and PRR37, were altered in the plants grown under both long day and short day conditions. These findings indicate that phytochromes are also involved in the regulation of these genes under short day conditions, and extend the role of phytochromes in flowering regulation in rice.

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<![CDATA[Factors associated with the job satisfaction of certified nurses and nurse specialists in cancer care in Japan: Analysis based on the Basic Plan to Promote Cancer Control Programs]]> https://www.researchpad.co/article/elastic_article_15727 As the Japanese population ages, the number of cancer patients will likely increase. Therefore, qualified cancer health care providers should be recruited and retained. Nurse job satisfaction is influenced by numerous factors and may affect staff turnover and patient outcomes.ObjectivesTo evaluate the job satisfaction of certified nurses and nurse specialists in Japanese cancer care and elucidate factors associated with job satisfaction.MethodsParticipants in this cross-sectional study comprised 200 certified nurse specialists and 1,472 certified nurses working in Japanese cancer care. A chi-square test and logistic regression analysis were conducted to identify job satisfaction factors.ResultsJob satisfaction was present in 38.45% and 49.00% of certified nurses and nurse specialists, respectively. Certified nurses associated job satisfaction with cross-departmental activities (OR 2.24, p<0.001), positive evaluation from senior stuff (OR 4.58, p<0.001), appropriate staff allocation (OR 1.75, p<0.001), more than five years certified nurse experience (OR 1.91, p<0.001), and positive evaluation of the development of certified nurses (OR 2.13, p<0.01) and nurse specialists (OR 1.37, p<0.05). Low job satisfaction was associated with working on a ward (OR 0.51, p<0.001) and a capacity of more than 200 beds (OR 0.33, p = 0.00). Certified nurse specialists associated job satisfaction with palliative care team participation (OR 2.64, p<0.05), cross–sectional activities (OR 7.06, p<0.01), positive evaluation from senior stuff (OR 13.15, p<0.001), presence of certified nurses in radiation therapy (OR 2.91, p<0.05), positive certified nurse specialist development evaluation (OR 7.35, p<0.001), medical service fees (OR 3.78, p<0.01), and independent activities (OR 11.34, p<0.01).ConclusionsWe identified factors related to activities, facilities, and the cancer care team associated with job satisfaction of certified nurses and nurse specialists in Japanese cancer care. Suggestions are provided to enhance job satisfaction through Japan’s Basic Plan to Promote Cancer Control, which may help hospital administrators retain nursing staff. ]]> <![CDATA[Genome-wide association study of partial resistance to sclerotinia stem rot of cultivated soybean based on the detached leaf method]]> https://www.researchpad.co/article/elastic_article_15721 Sclerotinia stem rot (SSR) is a devastating fungal disease that causes severe yield losses of soybean worldwide. In the present study, a representative population of 185 soybean accessions was selected and utilized to identify the quantitative trait nucleotide (QTN) of partial resistance to soybean SSR via a genome-wide association study (GWAS). A total of 22,048 single-nucleotide polymorphisms (SNPs) with minor allele frequencies (MAF) > 5% and missing data < 3% were used to assess linkage disequilibrium (LD) levels. Association signals associated with SSR partial resistance were identified by two models, including compressed mixed linear model (CMLM) and multi-locus random-SNP-effect mixed linear model (mrMLM). Finally, seven QTNs with major effects (a known locus and six novel loci) via CMLM and nine novel QTNs with minor effects via mrMLM were detected in relation to partial resistance to SSR, respectively. One of all the novel loci (Gm05:14834789 on Chr.05), which was co-located by these two methods, might be a stable one that showed high significance in SSR partial resistance. Additionally, a total of 71 major and 85 minor candidate genes located in the 200-kb genomic region of each peak SNP detected by CMLM and mrMLM were found, respectively. By using a gene-based association, a total of six SNPs from three major effects genes and eight SNPs from four minor effects genes were identified. Of them, Glyma.18G012200 has been characterized as a significant element in controlling fungal disease in plants.

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<![CDATA[Road development in Asia: Assessing the range-wide risks to tigers]]> https://www.researchpad.co/article/elastic_article_15426 Roads are proliferating worldwide at an unprecedented rate, with potentially severe impacts on wildlife. We calculated the extent and potential impacts of road networks across the 1,160,000-km2, 13-country range of the globally endangered tiger (Panthera tigris)—a conservation umbrella species. We found that roads were pervasive, totaling 134,000 km across tiger conservation landscapes (TCLs), even in tiger priority sites and protected areas. Approximately 43% of the area where tiger breeding occurs and 57% of the area in TCLs fell within the road-effect zone. Consequently, current road networks may be decreasing tiger and prey abundances by more than 20%. Nearly 24,000 km of new roads will be built in TCLs by 2050, stimulated through major investment projects such as China’s Belt and Road Initiative. Given that roads will be a pervasive challenge to tiger recovery in the future, we urge decision-makers to make sustainable road development a top priority.

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<![CDATA[Global agricultural economic water scarcity]]> https://www.researchpad.co/article/elastic_article_15415 Water scarcity raises major concerns on the sustainable future of humanity and the conservation of important ecosystem functions. To meet the increasing food demand without expanding cultivated areas, agriculture will likely need to introduce irrigation in croplands that are currently rain-fed but where enough water would be available for irrigation. “Agricultural economic water scarcity” is, here, defined as lack of irrigation due to limited institutional and economic capacity instead of hydrologic constraints. To date, the location and productivity potential of economically water scarce croplands remain unknown. We develop a monthly agrohydrological analysis to map agricultural regions affected by agricultural economic water scarcity. We find these regions account for up to 25% of the global croplands, mostly across Sub-Saharan Africa, Eastern Europe, and Central Asia. Sustainable irrigation of economically water scarce croplands could feed an additional 840 million people while preventing further aggravation of blue water scarcity.

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<![CDATA[Quantifying methane emissions from the largest oil-producing basin in the United States from space]]> https://www.researchpad.co/article/elastic_article_15393 Using new satellite observations and atmospheric inverse modeling, we report methane emissions from the Permian Basin, which is among the world’s most prolific oil-producing regions and accounts for >30% of total U.S. oil production. Based on satellite measurements from May 2018 to March 2019, Permian methane emissions from oil and natural gas production are estimated to be 2.7 ± 0.5 Tg a−1, representing the largest methane flux ever reported from a U.S. oil/gas-producing region and are more than two times higher than bottom-up inventory-based estimates. This magnitude of emissions is 3.7% of the gross gas extracted in the Permian, i.e., ~60% higher than the national average leakage rate. The high methane leakage rate is likely contributed by extensive venting and flaring, resulting from insufficient infrastructure to process and transport natural gas. This work demonstrates a high-resolution satellite data–based atmospheric inversion framework, providing a robust top-down analytical tool for quantifying and evaluating subregional methane emissions.

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<![CDATA[Anthropogenic alteration of nutrient supply increases the global freshwater carbon sink]]> https://www.researchpad.co/article/elastic_article_15361 Lakes have a disproportionate effect on the global carbon (C) cycle relative to their area, mediating C transfer from land to atmosphere, and burying organic-C in their sediments. The magnitude and temporal variability of C burial is, however, poorly constrained, and the degree to which humans have influenced lake C cycling through landscape alteration has not been systematically assessed. Here, we report global and biome specific trajectories of lake C sequestration based on 516 lakes and show that some lake C burial rates (i.e., those in tropical forest and grassland biomes) have quadrupled over the last 100 years. Global lake C-sequestration (~0.12 Pg year−1) has increased by ~72 Tg year−1 since 1900, offsetting 20% of annual CO2 freshwater emissions rising to ~30% if reservoirs are included and contributing to the residual continental C sink. Nutrient availability explains ~70% of the observed increase, while rising temperatures have a minimal effect.

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<![CDATA[Consulting with a folk deity before making decisions: spiritual practices in parents facing end-of-life decisions for their child on life support with brain stem dysfunction]]> https://www.researchpad.co/article/elastic_article_15175 Adolescents with brain stem dysfunction may undergo many invasive treatments, and parents are often faced with making the decision to withdraw treatment. However, in the face of their child’s death, the spiritual practices of parents dealing with end-of-life decision-making remain under investigated.PurposeThis study explores the spiritual practices in parents making end-of-life decisions for adolescents on life support with brain stem dysfunction.MethodA descriptive phenomenological study was conducted through in-depth interviews with three parents of two adolescents in Taiwan. Data were analysed using Colaizzi’s seven-step protocol.ResultsThree main themes emerged: (1) faith during decision-making, (2) struggles during decision-making, (3) transformation during decision-making. The findings indicate that “transforming the nature of hope” is the essence of the experience.ConclusionFamily-centred care, gaining insight into parental spiritual practices, and developing culturally-appropriate care are recommended. ]]> <![CDATA[The <i>Caenorhabditis elegans</i> CUB-like-domain containing protein RBT-1 functions as a receptor for <i>Bacillus thuringiensis</i> Cry6Aa toxin]]> https://www.researchpad.co/article/elastic_article_14753 Bacillus thuringiensis (Bt) crystal proteins belong to pore-forming toxins (PFTs), which display virulence against target hosts by forming holes in the cell membrane. Cry6A is a nematicidal PFT, which exhibits unique protein structure and different mode of action than Cry5B, another nematicidal PFT. However, little is known about the mode of action of Cry6A. Although an intracellular nematicidal necrosis pathway of Cry6A was reported, its extracellular mode of action remains unknown. We here demonstrate that the CUB-like-domain containing protein RBT-1 acts as a functional receptor of Cry6A, which mediates the intestinal cell interaction and nematicidal activity of this toxin. RBT-1 represents a new class of crystal protein receptors. RBT-1 is dispensable for Cry5B toxicity against nematodes, consistent with that Cry6A and Cry5B have different nematicidal mechanisms. We also find that Cry6A kills nematodes by complex mechanism since rbt-1 mutation did not affect Cry6A-mediated necrosis signaling pathway. This work not only enhances the understanding of Bt crystal protein-nematode mechanism, but is also in favor for the application of Cry6A in nematode control.

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<![CDATA[iterb-PPse: Identification of transcriptional terminators in bacterial by incorporating nucleotide properties into PseKNC]]> https://www.researchpad.co/article/elastic_article_14750 Terminator is a DNA sequence that gives the RNA polymerase the transcriptional termination signal. Identifying terminators correctly can optimize the genome annotation, more importantly, it has considerable application value in disease diagnosis and therapies. However, accurate prediction methods are deficient and in urgent need. Therefore, we proposed a prediction method “iterb-PPse” for terminators by incorporating 47 nucleotide properties into PseKNC-Ⅰ and PseKNC-Ⅱ and utilizing Extreme Gradient Boosting to predict terminators based on Escherichia coli and Bacillus subtilis. Combing with the preceding methods, we employed three new feature extraction methods K-pwm, Base-content, Nucleotidepro to formulate raw samples. The two-step method was applied to select features. When identifying terminators based on optimized features, we compared five single models as well as 16 ensemble models. As a result, the accuracy of our method on benchmark dataset achieved 99.88%, higher than the existing state-of-the-art predictor iTerm-PseKNC in 100 times five-fold cross-validation test. Its prediction accuracy for two independent datasets reached 94.24% and 99.45% respectively. For the convenience of users, we developed a software on the basis of “iterb-PPse” with the same name. The open software and source code of “iterb-PPse” are available at https://github.com/Sarahyouzi/iterb-PPse.

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<![CDATA[Influence of total western diet on docosahexaenoic acid suppression of silica-triggered lupus flaring in NZBWF1 mice]]> https://www.researchpad.co/article/elastic_article_14732 Lupus is a debilitating multi-organ autoimmune disease clinically typified by periods of flare and remission. Exposing lupus-prone female NZBWF1 mice to crystalline silica (cSiO2), a known human autoimmune trigger, mimics flaring by inducing interferon-related gene (IRG) expression, inflammation, ectopic lymphoid structure (ELS) development, and autoantibody production in the lung that collectively accelerate glomerulonephritis. cSiO2-triggered flaring in this model can be prevented by supplementing mouse diet with the ω-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA). A limitation of previous studies was the use of purified diet that, although optimized for rodent health, does not reflect the high American intake of saturated fatty acid (SFA), ω-6 PUFAs, and total fat. To address this, we employed here a modified Total Western Diet (mTWD) emulating the 50th percentile U.S. macronutrient distribution to discern how DHA supplementation and/or SFA and ω-6 reduction influences cSiO2-triggered lupus flaring in female NZBWF1 mice. Six-week-old mice were fed isocaloric experimental diets for 2 wks, intranasally instilled with cSiO2 or saline vehicle weekly for 4 wks, and tissues assessed for lupus endpoints 11 wks following cSiO2 instillation. In mice fed basal mTWD, cSiO2 induced robust IRG expression, proinflammatory cytokine and chemokine elevation, leukocyte infiltration, ELS neogenesis, and autoantibody production in the lung, as well as early kidney nephritis onset compared to vehicle-treated mice fed mTWD. Consumption of mTWD containing DHA at the caloric equivalent to a human dose of 5 g/day dramatically suppressed induction of all lupus-associated endpoints. While decreasing SFA and ω-6 in mTWD modestly inhibited some disease markers, DHA addition to this diet was required for maximal protection against lupus development. Taken together, DHA supplementation at a translationally relevant dose was highly effective in preventing cSiO2-triggered lupus flaring in NZBWF1 mice, even against the background of a typical Western diet.

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<![CDATA[Modulation of T helper 1 and T helper 2 immune balance in a murine stress model during <i>Chlamydia muridarum</i> genital infection]]> https://www.researchpad.co/article/elastic_article_14727 A murine model to study the effect of cold-induced stress (CIS) on Chlamydia muridarum genital infection and immune response has been developed in our laboratory. Previous results in the lab show that CIS increases the intensity of chlamydia genital infection, but little is known about the effects and mechanisms of CIS on the differentiation and activities of CD4+ T cell subpopulations and bone marrow-derived dendritic cells (BMDCs). The factors that regulate the production of T helper 1 (Th1) or T helper 2 (Th2) cytokines are not well defined. In this study, we examined whether CIS modulates the expressions of beta-adrenergic receptor (β-AR), transcription factors, hallmark cytokines of Th1 and Th2, and differentiation of BMDCs during C. muridarum genital infection in the murine model. Our results show that the mRNA level of the beta2-adrenergic receptor (β2-AR) compared to β1-AR and β3-AR was high in the mixed populations of CD4+ T cells and BMDCs. Furthermore, we observed decreased expression of T-bet, low level of Interferon-gamma (IFN-γ) production, increased expression of GATA-3, and Interleukin-4 (IL-4) production in CD4+ T cells of stressed mice. Exposure of BMDCs to Fenoterol, β2-AR agonist, or ICI118,551, β2-AR antagonist, revealed significant β2-AR stimulation or inhibition, respectively, in stressed mice. Moreover, co-culturing of mature BMDCs and naïve CD4+ T cells increased the production of IL-4, IL-10, L-17, and IL-23 cytokines, suggesting that stimulation of β2-AR leads to the increased production of Th2 cytokines. Overall, our results show for the first time that CIS promotes the switching from a Th1 to Th2 cytokine environment. This was evidenced in the murine stress model by the overexpression of GATA-3 concurrent with elevated IL-4 production, reduced T-bet expression, and IFN-γ secretion.

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<![CDATA[Odiparcil, a potential glycosaminoglycans clearance therapy in mucopolysaccharidosis VI—Evidence from <i>in vitro</i> and <i>in vivo</i> models]]> https://www.researchpad.co/article/elastic_article_14726 Mucopolysaccharidoses are a class of lysosomal storage diseases, characterized by enzymatic deficiency in the degradation of specific glycosaminoglycans (GAG). Pathological accumulation of excess GAG leads to multiple clinical symptoms with systemic character, most severely affecting bones, muscles and connective tissues. Current therapies include periodic intravenous infusion of supplementary recombinant enzyme (Enzyme Replacement Therapy–ERT) or bone marrow transplantation. However, ERT has limited efficacy due to poor penetration in some organs and tissues. Here, we investigated the potential of the β-D-xyloside derivative odiparcil as an oral GAG clearance therapy for Maroteaux–Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). In vitro, in bovine aortic endothelial cells, odiparcil stimulated the secretion of sulphated GAG into culture media, mainly of chondroitin sulphate (CS) /dermatan sulphate (DS) type. Efficacy of odiparcil in reducing intracellular GAG content was investigated in skin fibroblasts from MPS VI patients where odiparcil was shown to reduce efficiently the accumulation of intracellular CS with an EC50 in the range of 1 μM. In vivo, in wild type rats, after oral administrations, odiparcil was well distributed, achieving μM concentrations in MPS VI disease-relevant tissues and organs (bone, cartilage, heart and cornea). In MPS VI Arylsulphatase B deficient mice (Arsb-), after chronic oral administration, odiparcil consistently stimulated the urinary excretion of sulphated GAG throughout the treatment period and significantly reduced tissue GAG accumulation in liver and kidney. Furthermore, odiparcil diminished the pathological cartilage thickening observed in trachea and femoral growth plates of MPS VI mice. The therapeutic efficacy of odiparcil was similar in models of early (treatment starting in juvenile, 4 weeks old mice) or established disease (treatment starting in adult, 3 months old mice). Our data demonstrate that odiparcil effectively diverts the synthesis of cellular glycosaminoglycans into secreted soluble species and this effect can be used for reducing cellular and tissue GAG accumulation in MPS VI models. Therefore, our data reveal the potential of odiparcil as an oral GAG clearance therapy for MPS VI patients.

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<![CDATA[Confidential, accessible point-of-care sexual health services to support the participation of key populations in biobehavioural surveys: Lessons for Papua New Guinea and other settings where reach of key populations is limited]]> https://www.researchpad.co/article/elastic_article_14720 To achieve the UNAIDS 90-90-90 targets at a national level, many countries must accelerate service coverage among key populations. To do this, key population programs have adopted methods similar to those used in respondent-driven sampling (RDS) to expand reach. A deeper understanding of factors from RDS surveys that enhance health service engagement can improve key population programs. To understand the in-depth lives of key populations, acceptance of expanded point-of-care biological testing and determine drivers of participation in RDS surveys, we conducted semi-structured interviews with 111 key population participants (12–65 years) were purposefully selected from six biobehavioral surveys (BBS) in three cities in Papua New Guinea. Key populations were female sex workers, men who have sex with men, and transgender women. Four reasons motivated individuals to participate in the BBS: peer referrals; private, confidential, and stigma-free study facilities; “one-stop shop” services that provided multiple tests and with same-day results, sexually transmitted infection treatment, and referrals; and the desire to know ones’ health status. Biobehavioral surveys, and programs offering key population services can incorporate the approach we used to facilitate key population engagement in the HIV cascade.

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<![CDATA[A genome-wide association study of deafness in three canine breeds]]> https://www.researchpad.co/article/elastic_article_14705 Congenital deafness in the domestic dog is usually related to the presence of white pigmentation, which is controlled primarily by the piebald locus on chromosome 20 and also by merle on chromosome 10. Pigment-associated deafness is also seen in other species, including cats, mice, sheep, alpacas, horses, cows, pigs, and humans, but the genetic factors determining why some piebald or merle dogs develop deafness while others do not have yet to be determined. Here we perform a genome-wide association study (GWAS) to identify regions of the canine genome significantly associated with deafness in three dog breeds carrying piebald: Dalmatian, Australian cattle dog, and English setter. We include bilaterally deaf, unilaterally deaf, and matched control dogs from the same litter, phenotyped using the brainstem auditory evoked response (BAER) hearing test. Principal component analysis showed that we have different distributions of cases and controls in genetically distinct Dalmatian populations, therefore GWAS was performed separately for North American and UK samples. We identified one genome-wide significant association and 14 suggestive (chromosome-wide) associations using the GWAS design of bilaterally deaf vs. control Australian cattle dogs. However, these associations were not located on the same chromosome as the piebald locus, indicating the complexity of the genetics underlying this disease in the domestic dog. Because of this apparent complex genetic architecture, larger sample sizes may be needed to detect the genetic loci modulating risk in piebald dogs.

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<![CDATA[Design of composite measure schemes for comparative severity assessment in animal-based neuroscience research: A case study focussed on rat epilepsy models]]> https://www.researchpad.co/article/elastic_article_14687 Comparative severity assessment of animal models and experimental interventions is of utmost relevance for harm-benefit analysis during ethical evaluation, an animal welfare-based model prioritization as well as the validation of refinement measures. Unfortunately, there is a lack of evidence-based approaches to grade an animal’s burden in a sensitive, robust, precise, and objective manner. Particular challenges need to be considered in the context of animal-based neuroscientific research because models of neurological disorders can be characterized by relevant changes in the affective state of an animal. Here, we report about an approach for parameter selection and development of a composite measure scheme designed for precise analysis of the distress of animals in a specific model category. Data sets from the analysis of several behavioral and biochemical parameters in three different epilepsy models were subjected to a principal component analysis to select the most informative parameters. The top-ranking parameters included burrowing, open field locomotion, social interaction, and saccharin preference. These were combined to create a composite measure scheme (CMS). CMS data were subjected to cluster analysis enabling the allocation of severity levels to individual animals. The results provided information for a direct comparison between models indicating a comparable severity of the electrical and chemical post-status epilepticus models, and a lower severity of the kindling model. The new CMS can be directly applied for comparison of other rat models with seizure activity or for assessment of novel refinement approaches in the respective research field. The respective online tool for direct application of the CMS or for creating a new CMS based on other parameters from different models is available at https://github.com/mytalbot/cms. However, the robustness and generalizability needs to be further assessed in future studies. More importantly, our concept of parameter selection can serve as a practice example providing the basis for comparable approaches applicable to the development and validation of CMS for all kinds of disease models or interventions.

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<![CDATA[Simultaneous SNP selection and adjustment for population structure in high dimensional prediction models]]> https://www.researchpad.co/article/elastic_article_14653 This work addresses a recurring challenge in the analysis and interpretation of genetic association studies: which genetic variants can best predict and are independently associated with a given phenotype in the presence of population structure? Not controlling confounding due to geographic population structure, family and/or cryptic relatedness can lead to spurious associations. Much of the existing research has therefore focused on modeling the association between a phenotype and a single genetic variant in a linear mixed model with a random effect. However, this univariate approach may miss true associations due to the stringent significance thresholds required to reduce the number of false positives and also ignores the correlations between markers. We propose an alternative method for fitting high-dimensional multivariable models, which selects SNPs that are independently associated with the phenotype while also accounting for population structure. We provide an efficient implementation of our algorithm and show through simulation studies and real data examples that our method outperforms existing methods in terms of prediction accuracy and controlling the false discovery rate.

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<![CDATA[SPOP promotes ubiquitination and degradation of MyD88 to suppress the innate immune response]]> https://www.researchpad.co/article/elastic_article_14645 MyD88 is a central adaptor that mediates initiation of the innate immune response and production of the proinflammatory cytokines that restrain pathogens and activate adaptive immunity. Although MyD88 is crucial for a host to prevent pathogenic infection, misregulation of its abundance might lead to autoimmune diseases. Thus, degradation of MyD88 is a key canonical mechanism for terminating cytokine production. Here, we characterized a novel E3 ligase, SPOP, that targets MyD88 for degradation. ChSPOP attenuated IL-1β production through K48-linked polyubiquitination and degradation of chMyD88, and thus impaired immune responses. Spop deficient mice showed more susceptibility to infection by Salmonella typhimurium. These findings demonstrate that SPOP is a negative regulator of MyD88-dependent pathway activation triggered by LPS and Salmonella typhimurium, which helps the host to maintain immune homeostasis.

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