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Introduction: Scoliosis is a pathological spine structure deformation, predominantly classified as "idiopathic" due to its unknown etiology. However, it has been suggested that scoliosis may be linked to polygenic backgrounds. It is crucial to identify potential Adolescent Idiopathic Scoliosis (AIS)-related genetic backgrounds before scoliosis onset. Methods: The present study was designed to intelligently parse, decompose and predict AIS-related variants in ClinVar database. Possible AIS-related variant records downloaded from ClinVar were parsed for various labels, decomposed for Dinucleotide Compositional Representation (DCR) and other traits, screened for high-risk genes with statistical analysis, and then learned intelligently with deep learning to predict high-risk AIS genotypes. Results: Results demonstrated that the present framework is composed of all technical sections of data parsing, scoliosis genotyping, genome encoding, machine learning (ML)/deep learning (DL) and scoliosis genotype predicting. 58,000 scoliosis-related records were automatically parsed and statistically analyzed for high-risk genes and genotypes, such as FBN1 , LAMA2 and SPG11. All variant genes were decomposed for DCR and other traits. Unsupervised ML indicated marked inter-group separation and intra-group clustering of the DCR of FBN1 , LAMA2 or SPG11 for the five types of variants (Pathogenic, Pathogeniclikely, Benign, Benignlikely and Uncertain). A FBN1 DCR-based Convolutional Neural Network (CNN) was trained for Pathogenic and Benign/ Benignlikely variants performed accurately on validation data and predicted 179 high-risk scoliosis variants. The trained predictor was interpretable for the similar distribution of variant types and variant locations within 2D structure units in the predicted 3D structure of FBN1. Discussion: In summary, scoliosis risk is predictable by deep learning based on genomic decomposed features of DCR. DCR-based classifier has predicted more scoliosis risk FBN1 variants in ClinVar database. DCR-based models would be promising for genotype-to-phenotype prediction for more disease types. [ABSTRACT FROM AUTHOR]

• Multi-trait selection revealed the strengths and weaknesses of the genotypes. • Significant genotype-environment interaction was observed for yield traits. • Genotypes with high commercial tuberous root yield and stability were selected. Few purple-fleshed sweet potato (PFSP) cultivars are available for Brazilian growers, urging for the development of new and adapted cultivars. PFSP breeding programs should include multiple traits during the selection process to increase the chances of developing an adequate genotype, specially yield-related and quality-related traits. The objective was to select promising PFSP genotypes based on yield and tuberous-roots-related traits exploring genotype x environment interaction (GEI). Four experiments were carried out, in which 23 pre-selected PFSP genotypes were evaluated based on yield and quality traits, after screening among 2500 experimental genotypes. The first experiment adopted an augmented block design, with 'Luiza' interspersed as a control. From this first experiment, the 19 experimental genotypes with the best performance were selected for the following three experiments, which were conducted in a randomized block experimental design, with three replications each, including 'Luiza' as control. The best genotypes were selected in the first experiment using the multi-trait genotype-ideotype distance index (MGIDI). For the following experiments, the performance of the genotypes was assessed using deviance analysis, genotypic stability through weighted average of absolute scores (WAASB) index, and the multi-trait stability index (MTSI). In the first experiment, three factors were retained, being associated to commercial production of tuberous roots ('K-104′, 'K-25′ and 'U1–29′), total production of tuberous roots ('K-110′, 'C-42′, 'F-16′, and 'U1–29′), and quality of tuberous roots ('F-22′), respectively. Desired gains were observed for all traits. For the experiments II, III, and IV five factors were retained, being four related to quality of tuberous roots and one to yield components. The GEI was significant for yield-related traits and desired gains were observed for most traits. Due to high commercial tuberous root yield and low WAASB values, the genotypes 'U1–29′, 'K-98′, 'F-22′, 'K-57′, 'C-36′, 'U1–15′, 'K-25′, and 'U2–12′ were highly productive and stable. The genotypes selected by the MTSI index were 'U1–15′, 'U2–10′, 'U1–29′, 'K-98′, and 'K-78′. The multi-trait selection enabled the identification of promising genotypes highlighting their strengths and weaknesses. [ABSTRACT FROM AUTHOR]

• Results indicated that the F 2 plants had wide variations in most characteristics. • Multivariate methods successfully determined selection criteria. • The decision tree successfully predicted the PN and SW range for superior genotypes. • Selecting PN 87 – 119 per plant and SW ≥ 14.55 g can obtain superior genotypes. The existence of sufficient genetic variability and knowing the suitable selection criterion ranges are indispensable requirements of breeding studies. This study aimed to explore genetic diversity in ten F 2 populations (heterozygous–heterogeneous), five parents, and three commercial check cultivars by multivariate methods and to predict useful selection ranges using a decision tree model for further breeding studies. Hybridizations were made in 2019, F 1 populations were grown, and F 2 seeds were obtained in 2020. Genotypes were grown according to an Augmented Randomized Complete-Block Design in 2021 at Aydın Adnan Menderes University Faculty of Agriculture. Results revealed considerable genetic diversity and transgressive segregation in key characteristics across the F 2 populations. Seed yields of F 2 plants are higher than those of the parents. The seed protein and oil content of the F 2 plants were not different from the parents and commercial checks. Higher phenotypic than genotypic variance indicated a high influence of environment on the inheritance of all studied characteristics. The highest broad heritability was observed in the number of shattered pods per plant (94.81 %) and the lowest in infertile pods per plant (2.16 %). Seed yield showed a significant and positive genotypic correlation with the number of fertile pods per plant (0.61**) and a significant negative association with the number of fertile branches per plant (−0.53**). Principal component analysis (PCA) of 14 quantitative characteristics showed that soybean genotypes separated by the first four components contributed 71.12 % of total genetic variation, with important yield-attributing characteristics present in PC1 and PC3, while important seed quality characteristics were noted in PC2. The decision tree model indicated that genotypes with high yield and optimum quality could be obtained by selecting the number of fertile pods 87–119 per plant and a hundred-seed weight greater than 14.55 g. [ABSTRACT FROM AUTHOR]

Tooth agenesis (TA) occurs when tooth development is disrupted at the initiation stage. It can be classified into non-syndromic and syndromic forms (named NSTA and STA), depending on whether it is accompanied by abnormalities of other organs and systems. Genetic factors play a predominant role in the pathogenesis of tooth agenesis, with dozens of genes implicated in both forms. Several genes have been identified, mutations in which can lead to both forms of TA. Among these, WNT10A and EDA are frequently mutated genes in this context, representing extensively researched and documented genes in human non-syndromic selective agenesis of permanent teeth and their association with ectodermal dysplasia syndromes. In this review, we present an overview of the current knowledge regarding genes associated with NSTA and STA, focusing on the distribution and nature of WNT10A and EDA gene mutations. We also explore how these mutations relate to the condition's both forms, including their association with the number of missing permanent teeth. [ABSTRACT FROM AUTHOR]

Objective: The aim was to investigate the relationship between metabolic indices and abnormal bone mass (ABM), analyse the association between osteoprotegerin (OPG) gene mutations and ABM, and explore the interaction effect of type 2 diabetes mellitus (T2DM) and OPG gene mutations on bone mineral density (BMD) in postmenopausal women to provide a new supplementary index and a reliable basis for the early identification of osteoporosis (OP) in postmenopausal women in the clinical setting. Methods: Postmenopausal women hospitalized within the Department of Endocrinology of the First Affiliated Sanatorium of Shihezi University from June 2021 to March 2023 were retrospectively analysed, and the bone mineral density of lumbar vertebrae 1–4 (BMD (L1-4)) of the studied subjects was measured once via twin-energy X-ray absorptiometry. The studied subjects were divided into a normal bone mass (NBM) group and an ABM group according to their bone mineral density, and the general data of the studied subjects were recorded once. Blood biochemical indices were determined, and genotyping of the rs4355801 locus of the OPG gene was performed. Differences in the overall data and biochemical indices of the two groups were evaluated via the rank-sum test, and the relationship between blood glucose levels and mutations of the rs4355801 locus of the OPG gene and ABM or BMD (L1-4) was evaluated via binary logistic regression analysis or linear regression analysis. A bootstrap test was performed to test whether uric acid (UA) levels mediate the association between blood glucose levels and BMD (L1-4). Simple effect analysis was performed to analyse the interaction between T2DM and mutations at the rs4355801 locus of the OPG gene on BMD (L1-4). Results: ① After adjusting for confounding factors, the risk of ABM increased by 50% (95% CI 21–85%) for each unit increase in fasting plasma glucose (FPG) levels and 31% (95% CI 2–69%) for each unit increase in glycosylated haemoglobin (HbA1c) levels (both P < 0.05). FPG levels were negatively correlated with BMD (L1-4) (both P < 0.05), and uric acid in blood sugar and BMD (L1-4) played a significant mediating role in the model; this mediation accounted for 21% of the variance. ② After adjusting for confounding factors, women with the mutant genotypes GA and GG + GA of the OPG gene rs4355801 locus had a lower risk of ABM than did those with the wild-type genotype AA (OR = 0.71, 95% CI = 0.52–1.00; OR = 0.51, 95% CI = 0.28–0.92, P < 0.05). The mutant genotypes GG, GA and GG + GA were positively correlated with BMD (L1–4) (all P < 0.05). The interaction between T2DM and mutations in the OPG gene rs4355801 locus had an effect on BMD (L1-4), and this site mutation weakened the increase in blood glucose levels and led to an increase in the risk of ABM (P < 0.05). Conclusion: Elevated blood glucose levels in postmenopausal women were associated with an increased risk of ABM, and UA played a mediating role in the relationship FPG levels and BMD (L1-4), accounting for 21% of the variance. Mutations at the rs4355801 locus of the OPG gene were associated with a reduced risk of ABM in postmenopausal women. The interaction between T2DM and mutations at the rs4355801 locus of the OPG gene in postmenopausal women affects BMD (L1-4), and mutations at this locus attenuate the increased risk of ABM due to elevated blood glucose levels. [ABSTRACT FROM AUTHOR]

Low soil nitrogen (N) is a significant challenge to maize (Zea mays L.) production in Sub-Saharan Africa, particularly for small-scale farmers. Developing maize hybrids tolerant to low N is crucial for improving yields under such conditions. This study examined the genetic basis of agronomic traits in intermediate/late maturing maize inbred lines under contrasting N conditions, focusing on general combining ability (GCA) and specific combining ability (SCA) effects. Two hundred and thirty-seven F1 hybrids from 79 inbred lines crossed with three testers in a line x tester mating design, were evaluated across eight environments in Nigeria. Line x tester analysis revealed that GCA effects, primarily from lines, predominantly influenced grain yield and other traits across both N conditions, except for ear height and plant aspect under low N, where SCA effects also had significant impact. A significant (p ≤ 0.01) positive correlation was observed between GCA and SCA effects, suggesting a positive relationship between additive and non-additive genetic components. Lines SMLW146 and SMLW147 were identified as valuable resources for breeding low-N tolerant hybrids. Additionally, considering non-additive effects, hybrids SMLW22 × SAM50M and SMLW106 × SAM50M (under low-N) and SMLW3 × IITA1876, SMLW84 × IITA1876, and SMLW165 × IITA1876 (under optimum-N) were promising combinations for high grain yield. Morphological traits like plant height and ear height, phenological traits like days to anthesis and silking, and qualitative traits like ear aspect and plant aspect were identified as important for selecting genotypes with improved grain yield under low-N conditions. [ABSTRACT FROM AUTHOR]

Late leaf spot (LLS), caused by the fungus Nothopassalora personata, is an important foliar disease in groundnut (Arachis hypogaea L.) production. The present study used previously reported three single nucleotide polymorphism (SNP) markers to screen a set of groundnut germplasm and compared them with phenotypic values of three hotspot locations. The results indicated that marker-identified genotypes had LLS-resistant or moderately resistant phenotypes. About 56% of the phenotypically confirmed genotypes were confirmed with the SNP genotype. Some of the phenotypically resistant genotypes were not confirmed with marker genotypes, indicating some other quantitative trait locus (QTL) responsible for the LLS resistance might have been involved. The findings in this study are relevant to future LLS resistance breeding programs. [ABSTRACT FROM AUTHOR]

Albinism is a phenotypically and genetically heterogeneous condition characterized by a variable degree of hypopigmentation and by ocular features leading to reduced visual acuity. Whereas numerous genotypic studies have been conducted throughout the world, very little is known about the genotypic spectrum of albinism in Africa and especially in sub‐Saharan Western Africa. Here we report the analysis of all known albinism genes in a series a 23 patients originating from Mali. Four were diagnosed with OCA 1 (oculocutaneous albinism type 1), 17 with OCA 2, and two with OCA 4. OCA2 variant NM_000275.3:c.819_822delinsGGTC was most frequently encountered. Four novel variants were identified (two in TYR, two in OCA2). A deep intronic variant was found to alter splicing of the OCA2 RNA by inclusion of a pseudo exon. Of note, the OCA2 exon 7 deletion commonly found in eastern, central, and southern Africa was absent from this series. African patients with OCA 1 and OCA 4 had only been reported twice and once, respectively, in previous publications. This study constitutes the first report of the genotypic spectrum of albinism in a western sub‐Saharan country. [ABSTRACT FROM AUTHOR]

Fluconazole-resistant clade 4 Candida tropicalis causing candidemia in humans has been detected in tropical/subtropical areas, including those in China, Singapore, and Australia. We analyzed 704 individual yeasts isolated from fruits, soil, water, and farmers at 80 orchards in Taiwan. The most common pathogenic yeast species among 251 isolates recovered from farmers were Candida albicans (14.7%) and C. parapsilosis (11.6%). In contrast, C. tropicalis (13.0%), C. palmioleophila (6.6%), and Pichia kudriavzevii (6.0%) were prevalent among 453 environmental isolates. Approximately 18.6% (11/59) of C. tropicalis from the environment were resistant to fluconazole, and 81.8% (9/11) of those belonged to the clade 4 genotype. C. tropicalis susceptibility to fluconazole correlated with susceptibilities to the agricultural azole fungicides, difenoconazole, tebuconazole, and triadimenol. Tandem gene duplications of mutated ERG11 contributed to azole resistance. Agriculture environments are a reservoir for azole-resistant C. tropicalis; discontinuing agricultural use of azoles might reduce emergence of azole-resistant Candida spp. strains in humans. [ABSTRACT FROM AUTHOR]

As detailed information on the pharmacokinetics (PK) of labetalol in pregnant people are lacking, the aims of this study were: (1) to build a physiologically based PK (PBPK) model of labetalol in non‐pregnant individuals that incorporates different CYP2C19 genotypes (specifically, *1/*1, *1/*2 or *3, *2/*2, and *17/*17); (2) to translate this model to the second and third trimester of pregnancy; and (3) to combine the model with a previously published direct pharmacodynamic (PD) model to predict the blood pressure lowering effect of labetalol in the third trimester. Clinical data for model evaluation was obtained from the scientific literature. In non‐pregnant populations, the mean ratios of simulated versus observed peak concentration (Cmax), time to reach Cmax (Tmax), and exposure (area under the plasma concentration–time curve, AUC) were 0.94, 0.82, and 1.16, respectively. The pregnancy PBPK model captured the observed PK adequately, but clearance was slightly underestimated with mean ratios of simulated versus observed Cmax, Tmax, and AUC of 1.28, 1.30, and 1.39, respectively. The results suggested that pregnant people with CYP2C19 *2/*2 alleles have similar labetalol exposure and trough levels compared to non‐pregnant controls, whereas those with other alleles were found to have increased exposure and trough concentrations. Importantly, the pregnancy PBPK/PD model predicted that, despite increased exposure in some genotypes, the blood pressure lowering effect was broadly comparable across all genotypes. In view of the large inter‐individual variability and the potentially increasing blood pressure during pregnancy, patients may need to be closely monitored for achieving optimal therapeutic effects and avoiding adverse events. [ABSTRACT FROM AUTHOR]

The overuse of β-lactam drugs as the primary approach to antibiotic treatment for Enterobacteria-related infections has led to the selection of β-lactam-resistant isolates, so resistance to β-lactams has become a serious concern worldwide today. This study aimed to examine the patterns of antibacterial resistance and the prevalence of extended-spectrum β-lactamases (ESBLs) genes. A total of 100 Escherichia coli isolates were collected from stool samples of children with diarrhea between December 2020 and August 2021 from three different hospitals in Mashhad, Iran. Antibacterial resistance patterns and frequency of ESBL genes including blaTEM, blaSHV, blaCTX-M and blaOXA were investigated using the Polymerase chain reaction (PCR) technique and phenotypic method. Overall, the highest resistance was towards erythromycin (100%), followed by amoxicillin-clavulanic acid (69%), trimethoprim-sulfamethoxazole (63%), and cefixime (63%). On the other hand, the highest susceptibility was detected to amikacin (98%), gentamicin (98%), nitrofurantoin (97%), and ciprofloxacin (74%), respectively. Moreover, 75% of all isolates were multi-drug resistant (MDR), and the majority of ESBL-positive isolates showed considerably higher resistance rates, especially to cephalosporins, compared to ESBL-negative isolates. PCR screening revealed that the most prevalent ESBL gene was blaTEM at 93%, followed by blaCTX-M at 55%, while blaOXA and blaSHV were the least common, at 10% and 6%, respectively. The results emphasized the increased number of ESBL resistance gene carriers and their global dissemination. In addition, the high rate of MDR bacteria highlights the importance of continuously assessing antimicrobials to achieve effective antibiotic treatments. [ABSTRACT FROM AUTHOR]

The prevalence of mixed hepatitis C virus (HCV) genotype infection in a representative Canadian HCV cohort is reported and virological response with direct acting antiviral (DAA) treatment was evaluated. 3272 HCV‐positive participants were enrolled, of which 2945 (90.0%) initiated DAA therapy. 0.8% were identified with mixed genotype infection. Overall sustained virological response (SVR) was 99.1% and did not differ based on mixed genotype status. Any historical disadvantage to achieving cure with HCV treatment in mixed genotype infection has been overcome by current DAA regimens. [ABSTRACT FROM AUTHOR]

Despite the improvements in forensic DNA quantification methods that allow for the early detection of low template/challenged DNA samples, complicating stochastic effects are not revealed until the final stage of the DNA analysis workflow. An assay that would provide genotyping information at the earlier stage of quantification would allow examiners to make critical adjustments prior to STR amplification allowing for potentially exclusionary information to be immediately reported. Specifically, qPCR instruments often have dissociation curve and/or high-resolution melt curve (HRM) capabilities; this, coupled with statistical prediction analysis, could provide additional information regarding STR genotypes present. Thus, this study aimed to evaluate Qiagen's principal component analysis (PCA)-based ScreenClust® HRM® software and a linear discriminant analysis (LDA)-based technique for their abilities to accurately predict genotypes and similar groups of genotypes from HRM data. Melt curves from single source samples were generated from STR D5S818 and D18S51 amplicons using a Rotor-Gene® Q qPCR instrument and EvaGreen® intercalating dye. When used to predict D5S818 genotypes for unknown samples, LDA analysis outperformed the PCA-based method whether predictions were for individual genotypes (58.92% accuracy) or for geno-groups (81.00% accuracy). However, when a locus with increased heterogeneity was tested (D18S51), PCA-based prediction accuracy rates improved to rates similar to those obtained using LDA (45.10% and 63.46%, respectively). This study provides foundational data documenting the performance of prediction modeling for STR genotyping based on qPCR-HRM data. In order to expand the forensic applicability of this HRM assay, the method could be tested with a more commonly utilized qPCR platform. [ABSTRACT FROM AUTHOR]

Background: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Temporomandibular joint (TMJ) is among the most commonly affected joints in JIA patients. When JIA involves the TMJ, it may affect condylar growth in the joint; therefore, JIA patients are at risk of unfavourable long‐term outcomes from associated joint damage. If undetected, TMJ involvement can lead to various functional disabilities such as reduced mandibular mobility and disorders of the mastication muscles. Limitations in sagittal and vertical mandibular growth can result in micrognathia and anterior open bite with aesthetic and functional restrictions. Objective: Genetic factors may play a role in determining which individuals are more prone to develop TMJ disorders or in predicting the severity of the disease process. Therefore, we applied a GWAS approach to identify loci associated with TMJ involvement in a sample of Estonian patients with JIA. Our aim was to address the potential role of genetic susceptibility factors in TMJ‐JIA, a condition not previously studied in this context. Methods: The case group consisted of 55 JIA patients with TMJ involvement and 208 patients without TMJ involvement comprised the control group. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. Imputation was performed using a nationwide reference panel obtained of 2240 individuals whose data were obtained from the Estonian Biobank. Results: We identified six loci as being associated with the risk of TMJ‐JIA in Estonian JIA patients. The strongest associations were identified at CD6 rs3019551 (P = 3.80 × 10−6), SLC26A8/MAPK14 rs9470191 (P = 6.15 × 10−6), NLRP3 rs2056795 (P = 8.91 × 10−6) and MAP2K4 rs7225328 (P = 1.64 × 10−5). Conclusion: This study provides first insights into the risk‐associated loci between JIA and its manifestation in the TMJ. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that render the TMJ susceptible to involvement by JIA in Estonian patients. [ABSTRACT FROM AUTHOR]

We propose fast and accurate molecular detection of the Y132F ERG11p substitution directly on pure-cultured Candida parapsilosis isolates. We also assessed a discriminative genotyping scheme to track circulating genotypes. A total of 223 C. parapsilosis isolates (one patient each) from 20 hospitals, located in Spain and Italy were selected. Isolates were fluconazole-resistant (n = 94; harbouring the Y132F ERG11p substitution [ n = 85], the G458S substitution [ n = 6], the R398I substitution [ n = 2], or the wild-type ERG11 gene sequence) or fluconazole-susceptible (n = 129). Two targeted-A395T-mutation PCR formats (conventional and real-time) were engineered and optimized on fluconazole-susceptible and fluconazole-resistant pure-cultured isolates, thus skipping DNA extraction. Two genotyping schemes were compared: Scheme 1 (CP1, CP4a, CP6, and B markers), and Scheme 2 (6A, 6B, 6C, CP1, CP4a, and CP6 markers). The screening performed using both PCR formats showed 100% specificity (fluconazole-susceptible isolates; n = 129/129) and sensitivity (Y132F isolates; n = 85/85) values; however, results were available in 3 and 1.5 hours with the conventional and real-time PCR formats, respectively. Overall, Scheme 1 showed higher genetic diversity than Scheme 2, as shown by the number of alleles detected (n = 98; mean 23, range 13–38), the significantly higher observed and expected heterozygosity, and the probability of identity index (2.5 × 10−6). Scheme 2 markers did not provide further genotypic discrimination of Y132F fluconazole-resistant genotypes. Both proposed PCR formats allow us to speed up the accurate detection of substitution Y132F ERG11p in C. parapsilosis isolates with 100% specificity and sensitivity. In addition, we recommend CP1, CP4a, CP6, and B microsatellite markers for genotyping fluconazole-resistant isolates. [ABSTRACT FROM AUTHOR]

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient patients is still not defined. The EMA recommends targeted DPYD genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches. This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted DPYD genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015–2022). Mean U was 9.9 ± 10.1 ng/mL (median 8.7, range 1.6–856). According to French recommendations, 7.3 % of patients were partially deficient (U 16–150 ng/mL) and 0.02 % completely deficient (U≥150 ng/mL). DPYD variant frequencies were *2A: 0.83 %, *13: 0.17 %, D949V: 1.16 %, *7: 0.05 % (2 homozygous patients with U at 22 and 856 ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6 ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U2 (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16 ng/mL, challenging correct identification of DPD deficiency based on U. The sensitivity (% patients with a deficient phenotype among variant carriers) of U threshold at 16 ng/mL was 34 %. The best discriminant marker for identifying variant carriers was UH2/U2. UH2/U2<0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U. These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted DPYD genotyping is not sufficiently reliable to identify all patients with complete deficiency. [ABSTRACT FROM AUTHOR]

Background: There is insufficient replicated data to establish a relationship between the polymorphisms of SLC6A2 and CYP2D6 and the treatment responses of atomoxetine (ATX) in ADHD. We focused on evaluating the effect of top-line single nucleotide polymorphisms (SNPs) in SLC6A2 and CYP2D6 on the ATX treatment response in attention deficit and hyperactivity disorder (ADHD). Methods: Of 160 patient records, 34 patients who met the inclusion criteria were evaluated to determine the relationship between genotypes of ten SNPs (six of SLC6A2 and four of CYP2D6) and ATX treatment response. Additionally, the connection between SNPs of CYP2D6 and the severity of side effects associated with ATX was analyzed in 37 patients, including the 34 study patients, and three patients discontinued because of ATX-dependent side effects. Results: All six polymorphisms we studied in SLC6A2 were associated with the treatment response of ATX. Clinical improvement in oppositional defiant disorder symptoms of patients with ADHD was only observed in carriers of the homozygous "C" allele of rs3785143 (podd = 0.026). We detected an association between higher CGI-side-effect severity scores and the "TT" genotype of rs1065852 polymorphism in CYP2D6 (p = 0.043). Conclusions: The findings of this study suggest that genotypes of polymorphisms within the SLC6A2 and CYP2D6 may play an influential role in treatment response or the severity of side effects associated with ATX in ADHD patients. [ABSTRACT FROM AUTHOR]

Pseudomonas syringae pv. actinidiae biovar 3 (Psa3) causes a devastating canker disease in yellow‐fleshed kiwifruit (Actinidia chinensis). The effector HopZ5, which is present in all isolates of Psa3 causing global outbreaks of pandemic kiwifruit canker disease, triggers immunity in Nicotiana benthamiana and is not recognised in susceptible A. chinensis cultivars. In a search for N. benthamiana nonhost resistance genes against HopZ5, we found that the nucleotide‐binding leucine‐rich repeat receptor NbPTR1 recognised HopZ5. RPM1‐interacting protein 4 orthologues from N. benthamiana and A. chinensis formed a complex with NbPTR1 and HopZ5 activity was able to disrupt this interaction. No functional orthologues of NbPTR1 were found in A. chinensis. NbPTR1 transformed into Psa3‐susceptible A. chinensis var. chinensis 'Hort16A' plants introduced HopZ5‐specific resistance against Psa3. Altogether, this study suggested that expressing NbPTR1 in Psa3‐susceptible kiwifruit is a viable approach to acquiring resistance to Psa3 and it provides valuable information for engineering resistance in otherwise susceptible kiwifruit genotypes. Summary Statement: The NLR protein PTR1 from Nicotiana benthamiana is involved in the recognition of P. syringae pv. actinidiae (Psa) effector HopZ5, possibly through the plant immunity hub RPM1‐interacting protein 4. Transgenic expression of NbPTR1 in kiwifruit plants conferred immunity to Psa in a HopZ5‐specific manner. [ABSTRACT FROM AUTHOR]

Infectious Bursal Disease (IBD) is an infectious and immunosuppressive disease primarily affecting young chickens. Despite stringent biosecurity and vaccination for control measures, the effective management of IBD remains challenging. The disparity in observed clinical symptoms in the field infections further complicates matters for breeders. The study aims to perform molecular characterization of VP2 gene fragments to identify the latest genotype of field IBD viruses. Twentytwo samples of bursa of Fabricius were collected from broilers suspected of IBD in commercial farms located in Central Java and The Yogyakarta Special Region from 2021 to 2022. Viral RNA was extracted from these samples, and after amplification, a 743 bp PCR product was obtained and subjected to sequencing. The obtained sequences were analyzed in Mega X for multiple alignments, amino acid prediction, homology, and phylogenetic tree construction. Lesion, i.e., Bursa of Fabricius enlargement, oedema, swelling of plica bursa, gelatinous mass, hemorrhage, atrophy, and thigh muscles petechiae to hemorrhage, were considered indicative of IBD. Out of 22 samples tested by RT-PCR, 19 were positive, and 13 samples were selected for sequencing. All sequenced samples [ABSTRACT FROM AUTHOR]

Measles is a highly contagious viral illness mainly affecting the younger population worldwide despite the availability of a safe and effective vaccine. The disease is caused by measles virus, a member of the Paramyxoviridea family, which is transmitted through aerosols and respiratory droplets. Widespread vaccination has led to a significant decline in morbidity and mortality worldwide; however, recent years have witnessed a resurgence of outbreaks in the United States, highlighting barriers in achieving and sustaining elimination goals. The measles and rubella elimination initiative, under Immunization Agenda 2030, required at least 5 World Health Organization regions to achieve measles elimination by 2020, but none of the regions met these goals. Vaccine hesitancy, virus importation via international travel, and waning immunity are considered contributing factors to the recent surge of measles outbreaks. This review highlights the challenges in the pursuit of measles eradication and the importance of a multidimensional approach involving public health interventions. [ABSTRACT FROM AUTHOR]

Objective: To establish the dynamic treatment strategy of Chinese medicine (CM) for metastatic colorectal cancer (mCRC) by machine learning algorithm, in order to provide a reference for the selection of CM treatment strategies for mCRC. Methods: From the outpatient cases of mCRC in the Department of Oncology at Xiyuan Hospital, China Academy of Chinese Medical Sciences, 197 cases that met the inclusion criteria were screened. According to different CM intervention strategies, the patients were divided into 3 groups: CM treatment alone, equal emphasis on Chinese and Western medicine treatment (CM combined with local treatment of tumors, oral chemotherapy, or targeted drugs), and CM assisted Western medicine treatment (CM combined with intravenous regimen of Western medicine). The survival time of patients undergoing CM intervention was taken as the final evaluation index. Factors affecting the choice of CM intervention scheme were screened as decision variables. The dynamic CM intervention and treatment strategy for mCRC was explored based on the cost-sensitive classification learning algorithm for survival (CSCLSurv). Patients' survival was estimated using the Kaplan-Meier method, and the survival time of patients who received the model-recommended treatment plan were compared with those who received actual treatment plan. Results: Using the survival time of patients undergoing CM intervention as the evaluation index, a dynamic CM intervention therapy strategy for mCRC was established based on CSCLSurv. Different CM intervention strategies for mCRC can be selected according to dynamic decision variables, such as gender, age, Eastern Cooperative Oncology Group score, tumor site, metastatic site, genotyping, and the stage of Western medicine treatment at the patient's first visit. The median survival time of patients who received the model-recommended treatment plan was 35 months, while those who receive the actual treatment plan was 26.0 months (P=0.06). Conclusions: The dynamic treatment strategy of CM, based on CSCLSurv for mCRC, plays a certain role in providing clinical hints in CM. It can be further improved in future prospective studies with larger sample sizes. [ABSTRACT FROM AUTHOR]

Microbiota living in the rhizosphere influences plant growth and fitness, from the opposite perspective; whether host genotypes control its root microbiota is of great interest to forest breeders and microbiologists. To improve lowyield plantations and promote sustainable management of Camellia oleifera, high-throughput sequencing was used to study the chemical properties and microbiome in rhizosphere soil of Camellia forests under three genotypes (common C. oleifera, local C. gauchowensis, and C. chekiangoleosa) and three growth stages (sapling stage at 4-year-old, primary fruit stage at 7-year-old, and full fruiting stage at 11-year-old). The results showed that the rhizosphere soil organic matter (OM), nutrient concentrations, diversity, and community composition of the microbiome were significantly varied among different Camellia genotypes. The relative abundance of symbiotic and pathotrophic fungi in the rhizosphere soil of C. chekiangoleosa was significantly higher than that of C. gauchowensis. Concentrations of OM, available phosphorus (AP), and bacterial alpha diversity increased with tree age. Fungi of Saitozyma, Mortierella, and Glomeromycota and bacteria of Burkholderia–Caballeronia–Paraburkholderia and Vicinamibacterales had potential for fertilizer development for Camellia plantation. Camellia genotypes and growth stages were significantly correlated with the rhizosphere soil pH, OM, and available potassium (AK). Soil pH and OM were key factors that affected the microbiome in the Camellia rhizosphere soils. In conclusion, tree genotypes and growth stages shaped microbial communities in Camellia rhizosphere soils, and some plant growth-promoting rhizobacteria were identified as preliminary candidates for improving Camellia plantation growth. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (KOA) is an important cause of disability in the world and it denotes a public health defiance of the upcoming years. Aim To examine the connection between ADAMTS14 gene rs4747096 polymorphism and KOA and to assess risk factors associated with KOA. Methods A case control study was conducted on 158 patients with KOA and 120 controls with comparable age and sex randomly recruited from National Research Centre employees. All participants were subjected to full history taking, assessment of KOA severity using WOMAC scoring system, and thorough clinical examination. Blood sample was collected for detection of ADAMTS14/rs4747096 gene polymorphism. Results The frequency of ADAMTS14 gene rs4747096 genotypes among patients with KOA was 73.5% for AA, 25.7% for AG, and 0.7% for GG compared to controls 963%, 31.3%, and 5.6% respectively and the frequency of alleles among patients was 86.4% for A and 78.7% for G compared to controls (78.7% and 21.3% respectively, P < 0.05. The study found that the median levels of total WOMAC score and its domains were significantly higher among KOA patients than controls. The logistic regression analysis revealed that age ≥ 50 years, BMI ≥ 35, and long standing at work were predictive factors for KOA (P < 0.05). Regarding different genetic patterns, only the A recessive pattern of inheritance was found to be a predictive risk factor for KOA. Conclusion For ADAMTS14 rs4747096 genotype, the AA and AG genotypes significantly increased the risk of KOA. The recessive pattern of inheritance, older age, morbid obesity, and prolonged standing at work were the predictive risk factors for KOA. Further studies with larger sample size are encouraged to investigate the mechanism by which this genotype can affect the development of KOA. [ABSTRACT FROM AUTHOR]

Genotype–environment interaction (GEI) information is essential in plant breeding programs. The objectives of this study were to select high‐yielding and stable yellow‐fleshed sweet potato (YFSP) genotypes in different environments and identify the favorable environment for testing. The trials were conducted in four different locations in West Java, Indonesia, using randomized complete block design (RCBD) with three replications. The results showed that yield was the primary source of variation, accounting for 46.947% of the total variation, followed by GE effect (29.938%) and genotype (23.115%). Additive Main Effect and Multiplicative Interaction (AMMI) Stability Value (ASV) analysis showed Prai (838) and high‐yielding KMDR were the genotypes with the most stability performance in all environments. Parametric and nonparametric stability analysis showed that Prai (838) produced high yields with stability performance in all environments. AMMI showed that Prai (838) and 264 were stable in all environments. Genotype + genotype by environment (GGE) biplot analysis identified Prai (838), 8(11), and Rancing, of which 8(11) and Rancing were the best performing vertex genotypes in Jatinangor. Prai (838) was the stable genotype in all stability analyses used. AC Putih was categorized as having a high level of stability (73.663%) according to coefficient of variability (CVi) with the sustainability index (SI) ranked first. Stable genotypes can be recommended as new genotypes, while Jatinangor can be used in favorable environment for testing. [ABSTRACT FROM AUTHOR]

SUMMARY Plant height can be an indicator of plant health across environments and used to identify superior genotypes. Typically plant height is measured at a single timepoint when plants reach terminal height. Evaluating plant height using unoccupied aerial vehicles allows for measurements throughout the growing season, facilitating a better understanding of plant‐environment interactions and the genetic basis of this complex trait. To assess variation throughout development, plant height data was collected from planting until terminal height at anthesis (14 flights 2018, 27 in 2019, 12 in 2020, and 11 in 2021) for a panel of ~500 diverse maize inbred lines. The percent variance explained in plant height throughout the season was significantly explained by genotype (9–48%), year (4–52%), and genotype‐by‐year interactions (14–36%) to varying extents throughout development. Genome‐wide association studies revealed 717 significant single nucleotide polymorphisms associated with plant height and growth rate at different parts of the growing season specific to certain phases of vegetative growth. When plant height growth curves were compared to growth curves estimated from canopy cover, greater Fréchet distance stability was observed in plant height growth curves than for canopy cover. This indicated canopy cover may be more useful for understanding environmental modulation of overall plant growth and plant height better for understanding genotypic modulation of overall plant growth. This study demonstrated that substantial information can be gained from high temporal resolution data to understand how plants differentially interact with the environment and can enhance our understanding of the genetic basis of complex polygenic traits. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusions Several studies have reported that chronic hepatitis B (CHB) patients with low hepatitis B surface antigen (HBsAg) levels (100 or 10 IU/mL) at the cessation of nucleot(s)ide analogs (NA) have a favorable prognosis. In this retrospective study, we evaluated the duration of NA treatment and the factors associated with achieving these low HBsAg levels. We also examined the relationship between HBsAg and hepatitis B core‐related antigen (HBcrAg) levels at the time of NA discontinuation and subsequent clinical outcomes.This study included 153 CHB patients who initiated NA therapy at our hospital, received treatment, and were followed up for over 1 year.The cumulative incidence rates of achieving low HBsAg levels at 5 and 10 years post‐NA administration were as follows: 19.0% and 29.2% for HBsAg <100 IU/mL, 13.8% and 17.6% for HBsAg <10 IU/mL, and 9.5% and 13.5% for HBsAg <0.05 IU/mL, respectively. Hepatitis B virus genotypes other than genotype C (hazard ratio [HR] 3.47; p < 0.001) and an HBsAg level <1000 IU/mL at the start of NA therapy (HR 2.49; p = 0.008) were significantly associated with achieving HBsAg levels <100 IU/mL. Among 27 patients who discontinued NA therapy, 5 patients with HBsAg levels <100 IU/mL and HBcrAg levels <3 log U/mL at the time of discontinuation did not experience virological relapse.The cumulative rates of achieving HBsAg levels <100 IU/mL were relatively high. Discontinuation of NA may be considered based on HBsAg and HBcrAg levels during the course of NA therapy. [ABSTRACT FROM AUTHOR]

Introduction: Sorghum anthracnose, caused by Colletotrichum sublineola, is the most destructive disease of sorghum, which causes up to 80% grain yield loss in susceptible varieties. The use of resistance varieties is an effective, durable, and eco-friendly strategy for anthracnose control. Knowledge of the phenotypic and genetic variation in C. sublineola is vital for designing appropriate anthracnose management strategies. Methods: The present study examined the morphology and virulence of 25 C. sublineola isolates recovered from various sorghum-producing regions of Ethiopia against 18 known sorghum anthracnose differentials, 6 Ethiopian sorghum landraces, and a variety of Bonsa. Results: Analysis of variance (ANOVA) revealed significant differences among sorghum genotypes, C. sublineola isolates, and their interactions. There was a significant difference between the isolates in virulence, with each isolate exhibiting virulence in 8-72% of the sorghum genotypes tested. Among the 25 tested isolates, the top four most virulent isolates were from Pawe, suggesting that this area is suitable for pathogen diversity studies and host plant resistance screening. The sorghum genotypes IS_18760, Brandes, and Bonsa showed resistance to all tested isolates. Consequently, they may provide potential sources of resistance genes for sorghum breeding programs to develop cultivars resistant to different C. sublineola pathotypes. However, the resistant check SC748-5 was susceptible to isolates NK73_F37, while another resistant check SC112-14 was susceptible to isolates PW123_F47 and PW122_F47. Cluster analysis grouped 22 isolates into seven clusters based on their morphological characters, whereas 24 pathotypes were identified among 25 isolates that were tested on 25 sorghum genotypes. Discussion: Hence, this study revealed high variation in C. sublineola in Ethiopia suggesting the need for broad-spectrum resistance to control the disease. Sorghum genotypes resistant to various C. sublineola isolates were identified in this study, which can be used in sorghum breeding programs aiming to develop resistant cultivars to anthracnose. Highly virulent C. sublineola isolates were also identified which could be used in sorghum germplasm resistance screening. The report is the first to show the existence of C. sublineola pathotypes in Ethiopia. [ABSTRACT FROM AUTHOR]

Background: Freezing of gait (FOG) is an important milestone in the individual disease trajectory of people with Parkinson's disease (PD). Based on the cognitive model of FOG etiology, the mechanism behind FOG implies higher executive dysfunction in PDFOG+. To test this model, we investigated the FOGrelated phenotype and cognitive subdomains in idiopathic PD (iPD) patients without genetic variants linked to PD from the Luxembourg Parkinson's study. Methods: A cross-sectional analysis comparing iPDFOG+ (n = 118) and iPDFOG- (n = 378) individuals was performed, followed by the application of logistic regression models. Consequently, regression models were fitted for a subset of iPDFOG+ (n = 35) vs. iPDFOG- (n = 126), utilizing a detailed neuropsychological battery to assess the association between FOG and cognitive subdomains. Both regression models were adjusted for sociodemographic confounders and disease severity. Results: iPDFOG+ individuals presented with more motor complications (MDSUPDRS IV) compared to iPDFOG- individuals. Moreover, iPDFOG+ individuals exhibited a higher non-motor burden, including a higher frequency of hallucinations, higher MDS-UPDRS I scores, and more pronounced autonomic dysfunction as measured by the SCOPA-AUT. In addition, iPDFOG+ individuals showed lower sleep quality along with lower quality of life (measured by PDSS and PDQ-39, respectively). The cognitive subdomain analysis in iPDFOG+ vs. iPDFOG- indicated lower scores in Benton's Judgment of Line Orientation test and CERAD word recognition, reflecting higher impairment in visuospatial, executive function, and memory encoding. Conclusion: We determined a significant association between FOG and a clinical endophenotype of PD with higher non-motor burden. While our results supported the cognitive model of FOG, our findings point to a more widespread cortical impairment across cognitive subdomains beyond the executive domain in PDFOG+ with additional higher impairment in visuospatial function and memory encoding. [ABSTRACT FROM AUTHOR]

Objective: To analyze the genotypes of VZV in Jiangsu province to identify vaccine strains and wild strains, providing a molecular biological background for the effective prevention and control of varicella. Method: Stratified sampling was used to collect herpes fluid or throat swab from patients diagnosed with varicella. ORF22 was carried out, and the restriction enzyme site of ORF38, ORF54 and ORF62 were detected. Results: All 207 virus strains were Clade 2 type by sequencing the PCR products of ORF22. The sequencing results showed that five SNP sites changed compared to the Dumas reference strain(Clade 1). From A to G at 37,902, from T to c at 38,055, from A to C at 38,081, and from G to A at 38,177, from G to A at 39,394. The prevalent VZV genotypes in Jiangsu is consistent with the P-Oka. The restriction enzyme site analysis of PCR amplification products from ORF38 (PstI), ORF54 (BglI), ORF62 (SmaI) showed that all 207 virus strains were wild-type. There were two different types of the wild strains, and 183 strains (88.4%) were PstI (+), BglI (+), SmaI (-). The wild strains between different regions showed no significant differences (χ2 = 0.05, P = 0.982). Conclusions: The prevalent VZV genotypes are Clade 2 and the prevalent virus strains are wild strains in Jiangsu Province, the primary wild strain observed is mainly PstI (+), BglI (+), SmaI (-). [ABSTRACT FROM AUTHOR]

AbstractIn the actual context of climate change and increasing oil and nitrogen prices, oil crops varieties with high nitrogen use efficiency (NUE) will be highly appreciated. As no studies on NUE in spring rapeseed have been carried out in Mediterranean area, including Morocco, this work aimed to assess responses of six rapeseed varieties to six nitrogen levels (0, 30, 60, 90, 120, and 150 Kg N/ha) and their NUE for grain and oil yields. The experiment was conducted according to a split-plot design with three replications, during two cropping seasons. Results showed that increasing nitrogen rate from 0 to 120 kg N/ha led to a significant increase in seed, oil and dry matter yields up to 85.3, 72.35 and 97.9%, respectively. NUE, NUpE (nitrogen uptake efficiency) and NUtE (nitrogen utilization efficiency) decreased by increasing nitrogen application. Regarding oil content, it was negatively affected by nitrogen fertilization, declining from 40.78% for control to 37.77% for 150 kg N/ha. Likewise, nitrogen use and nitrogen utilization efficiency for oil production (ONUE & ONUtE) were negatively affected by nitrogen application. The genotypic variation was statistically significant for all investigated traits. The variety hybrid ‘Trapper’ was the most interesting for ONUE, NUE, seed yield and dry matter. However, for oil yield it was comparable to ‘Moufida’ and ‘Alia’ which showed the highest values for harvest index, branching, pods number per plant, oil content and ONUE. These varieties grown under 120 kg N/ha treatment can be recommended for Morocco. [ABSTRACT FROM AUTHOR]

The audiological features of hearing loss (HL) in patients with autosomal recessive deafness type 1A (DFNB1A) caused by splice site variants of the GJB2 gene are less studied than those of patients with other variants of this gene. In this study, we present the audiological features of DFNB1A in a large cohort of 134 patients with the homozygous splice site variant c.-23+1G>A and 34 patients with other biallelic GJB2 genotypes (n = 168 patients with DFNB1A). We found that the preservation of hearing thresholds in the speech frequency range (PTA0.5,1.0,2.0,4.0 kHz) in patients with the c.[-23+1G>A];[-23+1G>A] genotype is significantly better than in patients with the "severe" c.[35delG];[35delG] genotype (p = 0.005) and significantly worse than in patients with the "mild" c.[109G>A];[109G>A] genotype (p = 0.041). This finding indicates a "medium" pathological effect of this splice site variant on hearing function. A detailed clinical and audiological analysis showed that in patients with the c.[-23+1G>A];[-23+1G>A] genotype, HL is characterized as congenital or early onset (57.5% onset before 12 months), sensorineural (97.8%), bilateral, symmetrical (82.8%), variable in severity (from mild to profound HL, median hearing threshold in PTA0.5,1.0,2.0,4.0 kHz is 86.73±21.98 dB), with an extremely "flat" audioprofile, and with a tendency toward slow progression (a positive correlation of hearing thresholds with age, r = 0.144, p = 0.041). In addition, we found that the hearing thresholds in PTA0.5,1.0,2.0,4.0 kHz were significantly better preserved in females (82.34 dB) than in males (90.62 dB) (p = 0.001). We can conclude that in patients with DFNB1A caused by the c.-23+1G>A variant, male sex is associated with deteriorating auditory function; in contrast, female sex is a protective factor. [ABSTRACT FROM AUTHOR]

ABSTRACT Dwarfing genes that are considerably reducing plant height are used in many cereals. In triticale, the rye‐derived dominant dwarfing gene Ddw1 was introgressed in commercial varieties. It has already been shown that this gene increases Fusarium head blight (FHB) susceptibility in one segregating population. We aimed for verifying this effect in the genetically unrelated doubled haploid (DH) population Cando (Ddw1) × Tritikon (ddw1), with 182 progenies in an experiment with artificial inoculation across six location–year combinations (environments). Linkage mapping was performed with DArTseq markers. The progenies significantly (p < 0.001) varied for FHB severity, plant height and heading stage with high entry‐mean heritabilities (0.85–0.98). The population showed a bimodal distribution for plant height. A significant QTL on chromosome 5RL was found for all three traits explaining 38%, 62% and 43% of the genotypic variation for FHB severity, plant height and heading stage, respectively, and most likely representing Ddw1. This gene increased FHB severity by 5.6 percentage points, delayed heading by 2.7 EC stages and reduced plant height by 29.6 cm on average. To use this gene in practical triticale breeding, the genetic background must be enriched with FHB resistance QTL to counterbalance the negative effect of Ddw1 either by introgression of major FHB QTL from exotic sources or by genomic selection within the adapted gene pool. [ABSTRACT FROM AUTHOR]

Background: Metabolic reprogramming is one of the hallmarks of cancer, and in breast cancer (BC), several metabolic enzymes are overexpressed and overactivated. One of these, Enolase 1 (ENO1), catalyses glycolysis and is involved in the regulation of multiple signalling pathways. Objectives: This study aimed to evaluate in silico the prognostic and predictive effects of ENO1 expression in BC. Design: This is a bioinformatic in silico analysis. Methods: Using available online platforms (Kaplan–Meier [KM] plotter, receiver operating characteristic curve [ROC] plotter, cBioPortal, Genotype-2-Outcome [G-2-O], MethSurv, and Tumour–Immune System Interaction Database [TISIDB]), we performed a bioinformatic in silico analysis to establish the prognostic and predictive effects related to ENO1 expression in BC. A network analysis was performed using the Oncomine platform, and signalling, epigenetic, and immune regulation pathways were explored. Results: ENO1 was overexpressed in all the analysed Oncomine, epigenetic, and immune pathways in triple-negative, but not in hormone receptor–positive BCs. In human epidermal growth factor receptor 2 (HER2)-positive BCs, ENO1 expression showed a mixed profile. Analysis on disease progression and histological types showed ENO1 overexpression in ductal in situ and invasive carcinoma, in high-grade tumours followed by advanced or metastasis and was linked to worse survival. High ENO1 expression was also associated with relapse-free, distant metastasis-free and overall survival, irrespectively of treatment and was mainly related to basal subtype. Conclusion: ENO1 overexpression recruits a range of signalling pathways during disease progression conferring a worse prognosis and can be potentially used as a biomarker of disease progression and therapeutic target, particularly in triple-negative and in ductal invasive carcinoma. [ABSTRACT FROM AUTHOR]

Background: Development of multidrug resistance in Uropathogenic Escherichia coli (UPEC) makes treatment of Urinary Tract Infections (UTIs) a major challenge. This study was conducted to investigate the effect of trans-resveratrol (t-RSV) at a subinhibitory concentration (sub-MIC-t-RSV) on phenotypic and genotypic expression of virulence factors of clinical isolates of UPEC and develop a nanoformulation of t-RSV. Fifty-five clinical UPEC strains were investigated for the presence of virulence factors by phenotypic methods and PCR detection of virulence genes. The effect of sub-MIC-t-RSV was studied on the phenotypic and genotypic expression of virulence factors. t-RSV-loaded nanoemulgel formulation was prepared and characterized. Results: Out of the 55 tested isolates, 50.9% were biofilm producers, 23.6% showed both mannose-sensitive and mannose-resistant hemagglutination, 21.8% were serum-resistant, 18.2% were hemolysin producers, while 36.4% showed cytotoxic effect on HEp-2 cells. A total of 25.5% of the isolates harbor one or more of hly-A, cnf-1 and papC genes, while 54.5% were positive for one or more of fimH, iss and BssS genes. A concentration of 100 µg/mL of t-RSV effectively downregulates the phenotypic and genotypic expression of the virulence factors in positive isolates. A stable t-RSV-nanaoemulgel with droplet size of 180.3 nm and Zetapotential of -46.9 mV was obtained. Conclusion: The study proves the effective role of t-RSV as an antivirulence agent against clinical UPEC isolates in vitro and develops a stable t-RSV-nanoemulgel formulation to be assessed in vivo. The promising antibacterial and antivirulence properties of t-RSV place this natural compound to be a better alternative in the treatment of persistent UTIs. [ABSTRACT FROM AUTHOR]

Summary Cis‐regulatory element editing can generate quantitative trait variation that mitigates extreme phenotypes and harmful pleiotropy associated with coding sequence mutations. Here, we applied a multiplexed CRISPR/Cas9 approach, informed by bioinformatic datasets, to generate genotypic variation in the promoter of OsSTOMAGEN, a positive regulator of rice stomatal density. Engineered genotypic variation corresponded to broad and continuous variation in stomatal density, ranging from 70% to 120% of wild‐type stomatal density. This panel of stomatal variants was leveraged in physiological assays to establish discrete relationships between stomatal morphological variation and stomatal conductance, carbon assimilation and intrinsic water use efficiency in steady‐state and fluctuating light conditions. Additionally, promoter alleles were subjected to vegetative drought regimes to assay the effects of the edited alleles on developmental response to drought. Notably, the capacity for drought‐responsive stomatal density reprogramming in stomagen and two cis‐regulatory edited alleles was reduced. Collectively our data demonstrate that cis‐regulatory element editing can generate near‐isogenic trait variation that can be leveraged for establishing relationships between anatomy and physiology, providing a basis for optimizing traits across diverse environments. [ABSTRACT FROM AUTHOR]

Summary Leaf economic spectrum (LES) relationships have been studied across many different plant lineages and at different organizational scales. However, the temporal stability of the LES relationships is largely unknown. We used the wild blueberry system with high genotypic diversity to test whether trait–trait relationships across genotypes demonstrate the same LES relationships found in the global database (GLOPNET) and whether they are stable across years. We studied leaf structure, photosynthesis, and leaf nutrients for 16 genotypes of two wild blueberry species semi‐naturally grown in a common farm in Maine, USA, across 4 yr. We found substantial variation in leaf structure, physiology, and nutrient traits within and among genotypes, as well as across years in wild blueberries. The LES trait–trait relationships (covariance structure) across genotypes were not always found in all years. The trait syndrome of wild blueberries was shifted by changing environmental conditions over the years. Additionally, traits in 1 yr cannot be used to predict those of another year. Our findings show that LES generally holds among genotypes but is temporally unstable, stressing the significant influence of trait plasticity in response to fluctuating environmental conditions across years, and the importance of temporal dimensions in shaping functional traits and species coexistence. [ABSTRACT FROM AUTHOR]

ABSTRACT International guidelines suggest cessation of nucleos(t)ide analogues (NA) independent of HBsAg loss in HBeAg‐negative patients after 2–3 years of viral suppression. Detectable HBV‐RNA levels at the time of NA cessation were linked to a better prediction of relapse after NA withdrawal in small cohorts of HBeAg‐negative patients. This study proves the impact of HBV‐RNA levels in the prediction of relapse in a large cohort of HBeAg‐negative patients, mainly infected with genotype B or C. Serum levels of HBV‐RNA, HBsAg, anti‐HBc and HBcrAg were determined before NA withdrawal in 154 HBeAg‐negative patients, participating either in a therapeutic vaccination trial (NCT02249988) or in an observational register trial (NCT03643172). Importantly, vaccination showed no impact on relapse. Endpoints of the study were virological relapse (HBV‐DNA > 2000 IU/mL) or biochemical relapse (attendant ALT levels ≥ 2 × ULN) 24 weeks after NA cessation. Virological relapse occurred in 54.5% of patients (N = 84/154), including eight patients (10%) developing an ALT flare. Baseline HBV‐RNA level did not differ significantly between relapsers and off‐treatment responders (p = 0.92). No significant difference occurred in proportions of detectable HBV‐RNA levels between off‐treatment responders (N = 27/70; 38.6%) and relapsers (N = 31/84; 36.9%) (p = 0.99). Combining predefined HBsAg cut‐offs (100 IU/mL, p = 0.0013), anti‐HBc cut‐offs (325 IU/mL, p = 0.0117) or HBcrAg cut‐offs (2 log U/mL, p = 0.66) with undetectable HBV‐RNA (HBsAg, p = 0.0057; anti‐HBc, p = 0.085; HBcrAg, p = 0.60) did not improve relapse prediction. The value of HBV‐RNA levels at timepoint of NA cessation for the prediction of relapse is limited in HBeAg‐negative patients.Trial Registration: ABX 203‐002: NCT02249988; Terminator 2: NCT03643172 [ABSTRACT FROM AUTHOR]

BackgroundAimSubjects and methodsResultsConclusionAlthough numerous mechanisms are involved in vitiligo pathogenesis, few studies correlate N-acetyltransferase 2 to this disease.To assess the N-acetyltransferase 2 (rs1799929) gene and its serum levels in vitiligo patients.In this case-control study, 65 vitiligo cases were compared to 65 age- and sex-matched healthy controls. Serum NAT2 levels and the NAT2 gene polymorphism (rs1799929) were evaluated using ELISA and real-time PCR, respectively.Serum N-acetyltransferase 2 levels were significantly lower in cases than in controls, 1.24 ± 0.31 vs. 2.01 ± 0.46 (p = 0.001). CC genotype was more dominant in controls (58.5%) than in cases (20%). TT and CT genotypes were more dominant in cases (30.8% and 49.2%) than in controls (13.8% and 27.7%), respectively (p = 0.001). The C allele was more prominent in controls (72.3%) than in cases (44.6%) while the T allele was more dominant in cases (55.4%) than in controls (27.7%) (p = 0.001). N-acetyltransferase 2 slow acetylator phenotype (TT genotype) was higher in cases (30.8%) than in controls (13.8%) and rapid acetylator phenotypes (CC and CT genotypes) were higher in controls (86.2%) than in cases (69.2%) (p = 0.035).Slow acetylator genotype (TT) of NAT2 gene (rs1799929) and low serum levels of NAT2 enzyme might play a role in the susceptibility and pathogenesis of vitiligo. [ABSTRACT FROM AUTHOR]

Simple Summary: Anal human papilloma virus (HPV) is the leading etiology of anal and cervical cancer. While cervical HPV screening for women is well established, anal HPV screening is restrained to a limited population and specific indications. Our group performed concomitant anal and cervical screening in 275 women at a single gynecologic appointment and revealed high-risk anal HPV in 91 women (33%). The present follow-up study intended to analyze the outcomes of these women during a specialized follow-up in a dedicated high-resolution anoscopy (HRA) outpatient clinic. Independent risk factors for anal HPV were anal intercourse and the presence of cervical HR-HPV with a three- and fourfold increased risk, respectively. Background: This study represents a follow-up analysis of the AnusGynecology (ANGY) study. Methods: This prospective, cross-sectional, single-center study recruited women for concomitant cervical and anal screening of HPV genotypes and cytology during a single appointment. All women with findings of either HPV or any type of dysplastic lesions on anal smears were offered follow-up in a specialized high-resolution anoscopy (HRA) outpatient clinic, representing the study cohort for this follow-up study. Results: Overall, 275 patients (mean age 42 ± 12) were included. Among them, 102 (37%) had cervical high-risk (HR) HPV. In total, HPV was (incidentally) revealed in 91 patients (33%) on anal smears, while any degree of anal squamous intraepithelial lesion (SIL) was found in 30 patients (11%), 6 if which were high-grade SIL (H-SIL). Furthermore, 10 out of 19 biopsies were positive (3 H-SIL lesions). Only half (48/91, 53%) of the women agreed to undergo the recommended specialized follow-up evaluation. Of them, 18 (38%) were diagnosed with dysplastic lesions (9 low grade (L-SIL) and 9 H-SIL, respectively) on biopsies, while the remaining visits revealed no abnormalities. Multivariable analysis revealed cervical HR-HPV infection (OR 4, 95% CI 2.2–7.5) and anal intercourse (OR 3.1, 95% CI 1.7–5.9) as independent risk factors for anal HR-HPV infection. Conclusions: Close follow-up of these women is hence strongly recommended. [ABSTRACT FROM AUTHOR]

Simple Summary: Cervical cancer is the fourth most common cancer in women worldwide, with HPV being a prevalent cause. Recent automated signal detection methods in ISH assays have shown promise for detecting HPV DNA in cervical tissue. This study compared an ISH probe (Inform HPV II and III) to PCR assays in cervical tissue samples with varying degrees of cervical intraepithelial neoplasia (CIN) and normal cervix tissue. Findings indicated a significant association between ISH III levels and HPV outcomes; patients with positive outcomes had lower ISH III levels (MD = −7961.82, p = 0.005). However, automatic signal detection for ISH is limited in cervical tissue, making genotyping-based HPV testing more effective, as it allows for larger sample collection. ISH results should be interpreted alongside clinical history and morphology. Background: Cervical cancer is fourth the most common cancer in women worldwide. Due to the prevalence of human papillomavirus (HPV) in the population (80–90%), scientists are likely to discover even more associations of this pathogen with other diseases in the future. In recent years, In Situ Hybridization (ISH) assays that use automated signal-detecting methods in formalin-fixed, paraffin-embedded (FFPE) cervical tissue, such as the enzyme-categorized signal-detecting system, have shown a higher sensitivity. Objectives and Methods: To evaluate automatic signal detection of ISH assay for detecting HPV DNA, we compared the ability of an ISH probe, Inform HPV II and III (Ventana Medical Systems, Tucson, AZ), to that of PCR assays to detect HPV DNA in cervical tissue specimens with cervical intraepithelial neoplasia (CIN; CIN 1, 28 cases; CIN 2, 22 cases; and CIN 3, 20 cases) and normal cervix (2 cases). Results: Our findings showed a significant relation was confirmed between ISH III level and HPV outcome (positive/negative). Patients with positive HPV outcomes had significantly lower ISH III levels, MD = −7961.82 CI95 [−17,230.00; −199.21], p = 0.005. Conclusions: Automatic signal detection of ISH assay is not particularly applicable to cervical tissue material. A more useful method of confirming the presence of HPV in the cervix is the HPV test with genotyping, as it allows for collecting a larger amount of material from the cervical disc and canal. The interpretation of a positive or negative ISH test must be guided in the context of clinical history and morphology. [ABSTRACT FROM AUTHOR]

Background: Clopidogrel is widely used for the secondary prevention of atherothrombotic events in patients with coronary artery disease (CAD), ischemic stroke, and peripheral arterial disease (PAD). CYP2C19 plays a pivotal role in the conversion of clopidogrel to its active metabolite. Clopidogrel-treated carriers of a CYP2C19 loss-of-function allele (LOF) may have a higher risk of new atherothrombotic events. Previous studies on genotype-guided treatment were mainly performed in CAD and showed mixed results. Purpose: To simultaneously investigate the impact of CYP2C19 genotype status on the rate of atherothrombotic events in the most common types of atherosclerotic disease (CAD, stroke, PAD). Methods: A comprehensive search in Pubmed, EMBASE, and MEDLINE from their inception to July 23rd 2023 was performed. Randomized controlled trials (RCTs) comparing genotype-guided and standard antithrombotic treatment, and cohort studies and post hoc analyses of RCTs concerning the association between CYP2C19 genotype status and clinical outcomes in clopidogrel-treated patients were included. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the safety end point major bleeding. Secondary endpoints were myocardial infarction, stent thrombosis, and ischemic stroke. Results: Forty-four studies were identified: 11 studies on CAD, 29 studies on stroke, and 4 studies on PAD. In CAD, genotype-guided therapy significantly reduced the risk of MACE [risk ratio (RR) 0.60, 95% confidence interval (CI) 0.43–0.83], myocardial infarction (RR 0.53, 95% CI 0.42–0.68), and stent thrombosis (RR 0.64, 95% CI 0.43–0.94), compared with standard antithrombotic treatment. The rate of major bleeding did not differ significantly (RR 0.93, 95% CI 0.70–1.23). Most RCTs were performed in patients after percutaneous coronary intervention (9/11). In stroke, LOF carriers had a significantly higher risk of MACE (RR 1.61, 95% CI 1.25–2.08) and recurrent ischemic stroke (RR 1.89, 95% CI 1.48–2.40) compared with non-carriers. No significant differences were found in major bleeding (RR 0.90, 95% CI 0.43–1.89). In the 6955 patients with symptomatic PAD treated with clopidogrel in the EUCLID trial, no differences in MACE or major bleeding were found between LOF carriers and non-carriers. In three smaller studies on patients with PAD treated with clopidogrel after endovascular therapy, CYP2C19 genotype status was significantly associated with atherothrombotic events. Conclusions: Genotype-guided treatment significantly decreased the rate of atherothrombotic events in patients with CAD, especially after PCI. In patients with history of stroke, LOF carriers treated with clopidogrel had a higher risk of MACE and recurrent stroke. The available evidence in PAD with regard to major adverse limb events is too limited to draw meaningful conclusions. Registration: PROSPERO identifier no. CRD42020220284. [ABSTRACT FROM AUTHOR]

Hypertensive disorders of pregnancy (HDP) are a great danger. A previous GWAS found a relationship between rs259983 of the ZNF831 gene and HDP, such as for chronic hypertension (CHTN) and preeclampsia (PE). We conducted the case-control study to determine the association between rs259983 of the ZNF831 gene and HDP in women with Gestational Diabetes Mellitus (GDM). For target genotyping, we developed primers and TaqMan probes. In analyzing the population, we did not manage to find a relationship between PE and rs259983 of the ZNF831 gene. Additional study of women with PE and PE superimposed on CHTN (SIPE) establishes an association between rs259983 of the ZNF831 gene only with SIPE. Carriers of CC genotypes have been discovered to have a 5.05 times higher risk of SIPE development in women with GDM. [ABSTRACT FROM AUTHOR]

Background: The challenges in culturing Treponema pallidum have hindered molecular-biological analysis. This study aims to establish a molecular epidemiological analysis of syphilis among Japanese men who have sex with men (MSM) and to investigate the relationship between bacteremia and associated pathophysiology. Methods: We used whole blood specimens from syphilis-diagnosed individuals in Tokyo, collected between February 2019 and June 2022. All individuals were MSM, and most were people with HIV (97.2%). We used a multi-locus sequence typing (MLST) scheme for epidemiological analysis. Sequences for MLST (TP0136, TP0548, and TP0705) were obtained. Results: Out of 71 whole blood samples, 26 samples (36.6%) were positive for TP0136, and we sequenced three loci for MLST in 22 samples (31.0%). The most frequently detected sequence type (ST) was ST3 (n = 9), followed by ST6 (n = 6). Phylogenetic analysis revealed that 12 samples belonged to the SS14-like group (60%), and 8 samples belonged to the Nichols-like group (40%). Treponema pallidum subsp. endemicum (TEN), the cause of bejel was detected in three samples (12%). There was a significant association between TP0136 detection rate and C- reactive protein (CRP) (77.0% at a cut-off:0.5 mg/dL). Conclusion: Both SS14-like and Nichols-like strains were circulating concurrently, and TEN could have been sexually transmitted among MSM with HIV. Elevated CRP may indicate the presence of the pathogen in the blood. [ABSTRACT FROM AUTHOR]

Recognizing the influence of pathogen diversity on infection dynamics is crucial for mitigating emerging infectious diseases. Characterising such diversity is often complex, for instance when multiple pathogen variants exist that interact differently with the environment and host. Here, we explore genotypic and phenotypic variation of Batrachochytrium salamandrivorans (Bsal), an emerging fungal pathogen that is driving declines among an increasing number of European amphibian species. For thirteen isolates, spanning most of the known temporal and geographical Bsal range in Europe, we mapped phenotypic diversity through numerous measurements that describe varying reproductive rates in vitro across a range of temperatures. Bsal isolates are revealed to have different thermal optima and tolerances, with phenotypic variation correlating with genomic diversity. Using a mechanistic niche model of the fire salamander (Salamandra salamandra) as an example, we illustrate how host steady-state body temperature and Bsal thermal range variation may influence pathogen growth through space and time across Europe. Our combined findings show how the identity of emergent pathogen variants may strongly influence when and which host populations are most at risk. Author summary: In 2013, a new, salamander-killing fungus, Batrachochytrium salamandrivorans (Bsal) was discovered in the Netherlands. Since then, Bsal outbreaks have occurred in a growing number of countries and amphibian species across Europe, causing rapid population collapses. A lot remains unknown about this pathogen, with most studies so far focusing on the type strain from the first outbreak site. Here we show that strains from other outbreaks behave differently and may threaten different amphibian populations at different times. We found that observed phenotypic variation correlated with genotypic variation and identified molecular functions and biological processes under selection across the European Bsal epidemic. As both the fungus and the amphibian hosts are very temperature sensitive, we tested Bsal growth across a range of temperatures. We found strains displayed different thermal ranges and optimal temperatures and combined these thermal growth curves with models of amphibian host body temperatures to predict strain geographical and temporal ranges. Our findings help to explain observed Bsal epidemiology and provide insights into how strain identity strongly influences when and which host populations are most at risk, with important implications for Bsal research and amphibian conservation efforts. [ABSTRACT FROM AUTHOR]

ABSTRACT Phenotypic plasticity is the property of a genotype to produce different phenotypes under different environmental conditions. Understanding genetic and environmental factors behind phenotypic plasticity helps answer some longstanding biology questions and improve phenotype prediction. In this study, we investigated the phenotypic plasticity of flowering time and plant height with a set of diverse sorghum lines evaluated across 14 natural field environments. An environmental index was identified to quantitatively connect the environments. Reaction norms were then obtained with the identified indices for genetic dissection of phenotypic plasticity and performance prediction. Genome‐wide association studies (GWAS) detected different sets of loci for reaction‐norm parameters (intercept and slope), including 10 new genomic regions in addition to known maturity (Ma1) and dwarfing genes (Dw1, Dw2, Dw3, Dw4 and qHT7.1). Cross‐validations under multiple scenarios showed promising results in predicting diverse germplasm in dynamic environments. Additional experiments conducted at four new environments, including one from a site outside of the geographical region of the initial environments, further validated the predictions. Our findings indicate that identifying the environmental index enriches our understanding of gene‐environmental interplay underlying phenotypic plasticity, and that genomic prediction with the environmental dimension facilitates prediction‐guided breeding for future environments. [ABSTRACT FROM AUTHOR]

Developing melon genotypes with resistance to Fusarium oxysporum f. sp. Melonis‐(FOM) race1.2 is a major goal in any breeding program. In this study, we identified the role of 11 gene markers that contribute to polygenic resistance during the FOM1.2–melon interaction. qRT‐PCR analysis elucidated upregulation of candidate marker genes AMT, DXPR, Fom‐2, GLUC, GalS, GRF3, MLO, PRK, RuBlsCo, TLP and WRKY in resistant ‘Shante‐F1’ and ‘Khatouni’, and susceptible ‘Shante‐T' and ‘Shahabadi’ at 7, 14 and 21 days post‐inoculation (dpi). We also studied changes in defence‐related enzyme activity: chitinase (CHI), β‐1,3‐glucanase (GLU) and peroxidase (POX) in melon roots. AMT, GLUC and DXPR transcripts were upregulatied in leaf and root tissues of the resistant ‘Shante‐F1’ and ‘Shahabadi’. Transcript levels for GalS and GRF3 increased 6.77‐ and 6.83‐fold in roots of ‘Shante‐F1’ at 7 dpi, whereas in PRK, TLP and WRKY theye increased by 7.84‐, 5.15‐ and 12.26‐fold at 14 dpi, respectively. However, transcript levels increased by 5.18‐fold for Fom‐2 and 8.46‐fold for MLO at 21 dpi. Also, RBC transcript level peaked at 14 dpi with 4.9‐fold increase in leaves of resistant genotypes, whereas AMT increased 2.94‐fold at 21 dpi, and GLUC and DXPR increased 7.11‐ and 2.91‐fold at 14 dpi in ‘Shante‐F', respectively. Defence‐related‐enzyme activity was also upregulated three‐fold in resistant varieties. The dynamic shifts in the melon transcriptome induced by FOM1.2 emphasize that resistance mechanisms are predominantly regulated through signalling pathways involving CHI, GLU, and POX defence response. Surprisingly, the AMT gene, basically resistant to downy mildew, Pseudoperonospora cubensis; GLUC, MLO and PRK resistant to powdery mildew (Sphaerotheca fusca); TLP and WRKY resistant to Phytophthora blight (Phytophthora capsici); and GRF3 and RBC resistant to root knot nematodes (Meloidogyne spp.) were upregulated in resistant genotypes, indicating a dual role of these genes in resistance to more than one disease at a time. [ABSTRACT FROM AUTHOR]

The tropical maize breeding for low-P tolerance and good performance under low-P stress environments can be achieved through selection based on root morphology traits at seedling stage. Here, we assessed the genotypic variation and genetic diversity of a panel of 151 tropical maize inbred lines for root and shoot seedling traits, investigated the relationship among traits and selected a set of promising inbred lines for low-P tolerance and performance. We evaluated the inbred lines at seedling stage in a greenhouse experiment under two conditions: applied P (AP) and non-applied P (NAP). A mixed model approach was used to estimate variance components and predict the genotypic values of each inbred line. The genetic diversity among inbred lines based on root and shoot traits was assessed, and correlations were estimated between tested traits under AP and NAP. Our panel of inbred lines showed huge genetic variability for all traits and presented large genetic diversity under both P conditions. Variance components due to the inbred line x P condition interaction were also highly significant (P < 0.01) for all traits. Root dry weight (RDW) was positively associated with stalk dimeter (SD), shoot dry weight (SDW) and root length, volume, and area under both P conditions. Also, the SD and SDW were associated with most root traits under AP. Based on low-P tolerance and performance indices, we selected a set of top 20 inbred lines to be used in our maize breeding program. We therefore concluded that there is a significant genetic diversity in the tropical maize inbred lines which have the genetic potential to be use in association mapping studies and also to develop improved low-P tolerant and P-efficient hybrids and maize breeding populations for low-P stress environments. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation is widely recognized as a key factor in the pathogenesis of Alzheimer's disease (AD), alongside ß-amyloid deposition and the formation of neurofibrillary tangles. The NLR family pyrin domain containing 3 (NLRP3) inflammasome, part of the innate immune system, has been implicated in the neuropathology of both preclinical amyloid and tau transgenic models. Activation of the NLRP3 pathway involves an initial priming step, which increases the expression of Nlrp3 and interleukin (IL)-1ß, followed by the assembly of the NLRP3 inflammasome complex, comprising NLRP3, ASC, and caspase-1. This assembly leads to the proteolytic maturation of the pro-inflammatory cytokines IL-1ß and IL-18. Additionally, the NLRP3 inflammasome induces Gasdermin D (GSDMD) cleavage, forming membrane pores through which IL-1ß and IL-18 are secreted. Inhibition of NLRP3 has been shown to enhance plaque clearance by modulating microglial activation. Furthermore, blocking NLRP3 in tau transgenic mice has been found to reduce tau phosphorylation by affecting the activity of certain tau kinases and phosphatases. Methods: In this study, organotypic brain slice cultures from P301S transgenic mice were treated with lipopolysaccharide (LPS) plus nigericin as a positive control or exposed to tau seeds (K18) to evaluate NLRP3 inflammasome activation. The effect of tau seeding on NLRP3 activity was further examined using Meso Scale Discovery (MSD) assays to measure IL1ß secretion levels in the presence and absence of NLRP3 inhibitors. The role of NLRP3 activity was investigated in fullbody Nlrp3 knockout mice crossbred with the tau transgenic P301S model. Additionally, full-body and microglia-selective Gsdmd knockout mice were crossbred with P301S mice, and tau pathology and neurodegeneration were evaluated at early and late stages of the disease using immunohistochemistry and biochemical assays. Results: Activation of the NLRP3 pathway was observed in the mouse organotypic slice culture (OSC) model following stimulation with LPS and nigericin or exposure to tau seeds. However, Nlrp3 deficiency did not mitigate tauopathy or neurodegeneration in P301S mice in vivo, showing only a minor effect on plasma neurofilament (NF-L) levels. Consistently, Gsdmd deficiency did not alter tau pathology in P301S mice. Furthermore, neither full-body nor microglia-selective Gsdmd deletion had an impact on neuronal pathology or the release of pro-inflammatory cytokines. Conclusion: The absence of key components of the NLRP3 inflammasome pathway did not yield a beneficial effect on tau pathology or neurodegeneration in the preclinical Tau-P301S mouse model of AD. Nonetheless, organotypic slice cultures could serve as a valuable ex vivo mechanistic model for evaluating NLRP3 pathway activation and pharmacological inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: Modern histocompatibility algorithms depend on the comparison and analysis of high-resolution HLA protein sequences and structures, especially when considering epitope-based algorithms, which aim to model the interactions involved in antibody or T cell binding. HLA genotype imputation can be performed in the cases where only low/intermediate-resolution HLA genotype is available or if specific loci are missing, and by providing an individuals' race/ethnicity/ancestry information, imputation results can be more accurate. This study assesses the effect of imputing high-resolution genotypes on molecular mismatch scores under a variety of ancestry assumptions. Methods: We compared molecular matching scores from "ground-truth" highresolution genotypes against scores from genotypes which are imputed from low-resolution genotypes. Analysis was focused on a simulated patient-donor dataset and confirmed using two real-world datasets, and deviations were aggregated based on various ancestry assumptions. the correct ancestry assumptions can reduce error introduced during imputation. Discussion: We conclude that for epitope analysis, imputation is a valuable and low-risk strategy, as long as care is taken regarding epitope analysis context, ancestry assumptions, and (multiple) imputation strategy. [ABSTRACT FROM AUTHOR]