High LD Research Articles

Improving groundwater vulnerability assessment in structurally controlled hard rock aquifer: insight from lineament density and land use/land cover pattern.

A comprehensive seasonal assessment of groundwater vulnerability was conducted in the weathered hard rock aquifer of the upper Swarnrekha watershed in Ranchi district, India. Lineament density (Ld) and land use/land cover (LULC) were integrated into the conventional DRASTIC and Pesticide DRASTIC (P-DRASTIC) models and were extensively compared with six modified models, viz. DRASTIC-Ld, DRASTIC-Lu, DRASTIC-LdLu, P-DRASTIC-Ld, P-DRASTIC-Lu, and P-DRASTIC-LdLu, to identify the most optimal model for vulnerability mapping in hard rock terrain of the region. Findings were geochemically validated using NO3- concentrations of 68 wells during pre-monsoon (Pre-M) and post-monsoon (Post-M) 2022. Irrespective of the applied model, groundwater vulnerability shows significant seasonal variation, with > 45% of the region classified as high to very high vulnerability in the pre-M, increasing to ̴67% in post-M season, highlighting the importance of seasonal vulnerability assessments. Agriculture and industries' dominant southern region showed higher vulnerability, followed by regions with high Ld and thin weathered zone. Incorporating Ld and LULC parameters into DRASTIC-LdLu and P-DRASTIC-LdLu models increases the 'Very High' vulnerability zones to 17.4% and 17.6% for pre-M and 29.4% and 27.9% for post-M, respectively. Similarly, 'High' vulnerable zones increase from 32.5% and 25% in pre-M to 33.8% and 35.3% in post-M for respective models. Model output comparisons suggest that modified DRASTIC-LdLu and P-DRASTIC-LdLu perform better, with accurate estimations of 83.8% and 89.7% for pre-M and post-M, respectively. However, results of geochemical validation suggest that among all the applied modified models, DRASTIC-LdLu performs best, with accurate estimations of 34.4% and 20.6% for pre-M and post-M, respectively.

Dy-Al-Ce codoped silica: a promising yellow laser glass with enhanced resistance to X-ray-induced photodarkening

To develop Dy doped silica glass with a higher irradiation resistance, which can be adapted to high power violet or blue LD pumped yellow laser fibers, the designed Dy-Al-Ce codoped silica glasses, 0.05Dy2O3-1.5Al2O3-xCe2O3-(98.45-x)SiO2 (x = 0, 0.05, 0.1, 0.25, 0.5), were prepared by the sol-gel method. Their excitation spectra, emission spectra and emission decay curves associated with the yellow emission from 4F9/2 to 6H13/2 of Dy were determined before and after the X-ray irradiation of 1000 Gy. The relation between these spectra and Ce-codoping concentrations is discussed, including the sensitization from Ce to Dy, the reverse energy transfer from Dy to Ce, and especially the X-ray-induced photodarkening, which is detrimental to the 576 nm yellow emission of Dy. The centers that cause the photodarkening are analyzed by electron paramagnetic resonance and radiation induced absorption spectra. It is found that Ce can effectively suppress the Al-oxygen hole center induced by the X-ray across the entire concentration range of Ce-codoping, but a new photodarkening center is generated at higher concentrations of Ce-codoping. Finally, the optimized Ce-codoping concentration of ∼0.1 mol% is used to achieve a promising yellow laser glass of Dy-Al-Ce codoped silica with enhanced irradiation resistance, resulting in its X-ray-induced photodarkening that is only 6% - 14% of that in the Ce-undoped.

Extremely thin but very robust: Surprising cryptogam trait combinations at the end of the leaf economics spectrum

Leaf economics spectrum (LES) describes the fundamental trade-offs between leaf structural, chemical, and physiological investments. Generally, structurally robust thick leaves with high leaf dry mass per unit area (LMA) exhibit lower photosynthetic capacity per dry mass (Amass). Paradoxically, “soft and thin-leaved” mosses and spikemosses have very low Amass, but due to minute-size foliage elements, their LMA and its components, leaf thickness (LT) and density (LD), have not been systematically estimated. Here, we characterized LES and associated traits in cryptogams in unprecedented details, covering five evolutionarily different lineages. We found that mosses and spikemosses had the lowest LMA and LT values ever measured for terrestrial plants. Across a broad range of species from different lineages, Amass and LD were negatively correlated. In contrast, Amass was only related to LMA when LMA was greater than 14 g cm−2. In fact, low Amass reflected high LD and cell wall thickness in the studied cryptogams. We conclude that evolutionarily old plant lineages attained poorly differentiated, ultrathin mesophyll by increasing LD. Across plant lineages, LD, not LMA, is the trait that represents the trade-off between leaf robustness and physiology in the LES.

Integration of apaQTL and eQTL analysis reveals novel SNPs associated with occupational pulmonary fibrosis risk.

To explore the association between apaQTL/eQTL-SNPs and the susceptibility to silicosis. A silicosis-related GWAS was initially conducted to screen for single nucleotide polymorphisms (SNPs) associated with the risk of silicosis. Candidate SNPs with apaQTL and eQTL functions were then obtained from the 3'aQTL-atlas and GTEx databases. Subsequently, additional case-control studies were performed to validate the relationship between the candidate apaQTL/eQTL-SNPs and the risk of silicosis. Finally, experiments were conducted to illustrate APA events occurring at different alleles of the identified apaQTL/eQTL-SNPs. The combined results of the GWAS and iMLDR validations indicate that the variant T allele of the rs2974341 located on SMIM19 (additive model: OR = 0.66, the 95% CI = 0.53-0.84, P = 0.001) and the variant T allele of the rs2390488 located on TMTC4 (additive model: OR = 0.72, 95% CI = 0.57-0.90, P = 0.005) were significantly associated with decreased risk of developing silicosis susceptibility. Furthermore, 3'RACE experiments verified the presence of two poly (A) sites (proximal and distal) in SMIM19, rs2974341 may remotely regulate the binding between miRNA-3646 and SMIM19 with its high LD locus rs2974353 to affect the expression level of SMIM19. The rs2974341 variant T allele may contribute to the generation of the shorter 3'UTR transcript of SMIM19 and affect the binding of miRNA-3646 to the target gene SMIM19. The apaQTL/eQTL-SNPs may provide new perspectives for evaluating the regulatory function of SNPs in the development of silicosis.

Variant to gene mapping for carpal tunnel syndrome risk loci implicates skeletal muscle regulatory elements

Carpal tunnel syndrome (CTS) is a common disorder caused by compression of the median nerve in the wrist, resulting in pain and numbness throughout the hand and forearm. While multiple behavioural and physiological factors influence CTS risk, a growing body of evidence supports a strong genetic contribution. Recent genome-wide association study (GWAS) efforts have reported 53 independent signals associated with CTS. While GWAS can identify genetic loci conferring risk, it does not determine which cell types drive the genetic aetiology of the trait, which variants are "causal" at a given signal, and which effector genes correspond to these non-coding variants. These obstacles limit interpretation of potential disease mechanisms. We analysed CTS GWAS findings in the context of chromatin conformation between gene promoters and accessible chromatin regions across cellular models of bone, skeletal muscle, adipocytes and neurons. We identified proxy variants in high LD with the lead CTS sentinel SNPs residing in promoter connected open chromatin in the skeletal muscle and bone contexts. We detected significant enrichment for heritability in skeletal muscle myotubes, as well as a weaker correlation in human mesenchymal stem cell-derived osteoblasts. In myotubes, our approach implicated 117 genes contacting 60 proxy variants corresponding to 20 of the 53 GWAS signals. In the osteoblast context we implicated 30 genes contacting 24 proxy variants coinciding with 12 signals, of which 19 genes shared. We subsequently prioritized BZW2 as a candidate effector gene in CTS and implicated it as novel gene that perturbs myocyte differentiation invitro. Taken together our results suggest that the CTS genetic component influences the size, integrity, and organization of multiple tissues surrounding the carpal tunnel, in particular muscle and bone, to predispose the nerve to being compressed in this disease setting. This work was supported by NIH Grant UM1 DK126194 (SFAG and WY), R01AG072705 (SFAG & KDH) and the Center for Spatial and Functional Genomics at CHOP (SFAG & ADW). SFAG is supported by the Daniel B. Burke Endowed Chair for Diabetes Research. WY is supported by the Perelman School of Medicine of the University of Pennsylvania.

Genotyping SNPs in lignin biosynthesis gene (CAD1) and transcription factors (MYB1 and MYB2) exhibits association with wood density in teak (Tectona grandis L.f.).

Teak (Tectona grandis L.f.), an important source of tropical timber with immense economic value, is a highly outcrossing forest tree species. 150 unrelated accessions of teak (Tectona grandis L.f.) plus trees assembled as clones at National Teak Germplasm Bank, Chandrapur, Maharashtra, India was investigated for association mapping of candidate lignin biosynthesis gene (CAD1) and transcription factors (MYB1 and MYB2). The CAD1, MYB1 and MYB2 were amplified using specifically designed primers. The amplified sequences were then sequenced and genotyped for 112 SNPs/11 indels. We evaluated the association between SNPs and wood density in teak accessions using GLM and MLM statistical models, with Bonferroni correction applied. The teak accessions recorded an average wood density of 416.69kg.m-3 (CV 4.97%) and comprised of three loosely structured admixed sub-populations (K = 3), containing 72.05% genetic variation within sub-populations with low intragenic LD (0-21% SNP pairs) at P < 0.05 and high LD decay (33-934bp) at R2 = 0.1. GLM and MLM models discounting systematic biases (Q and K matrices) to avoid false discovery revealed five loci at rare variants (MAF 0.003) and three loci at common variants (MAF 0.05) to be significantly (P < 0.05) associated with the wood density. However, the stringent Bonferroni correction (4.06-7.04 × 10-4) yielded only a single associated locus (B1485C/A) from exon of MYB1 transcription factor, contributing to about 10.35% phenotypic variation in wood density trait. Scored SNP locus (B1485C/A) can be developed as a molecular probe for selection of improved planting stock with proven wood density trait for a large-scale teak plantation.

High efficiency LD end surface pumping quasi continuous 355nm laser

High efficiency LD end surface pumping quasi continuous 355nm laser

Abstract B073: Leveraging genomic diversity identifies additional germline risk loci in SMAD6 for Langerhans cell histiocytosis

Abstract Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by lesions including pathogenic CD207+ dendritic cells among an inflammatory infiltrate with recurrent, mutually exclusive somatic activating mutations in MAPK pathway genes in ~85% of LCH lesions; however, germline risk factors remain largely unknown. A SEER analysis reported that incidence of high-risk LCH was higher in Hispanic populations than non-Hispanic populations, and lowest in non-Hispanic Black populations. Our group reported that Hispanic mothers/couples were more likely to have children with LCH compared to non-Hispanic white mothers/couples. In the first GWAS of LCH, our group identified and validated a risk variant in SMAD6 associated with a 3-fold increase in risk. Our current objective is to leverage the genomic diversity of our patient population to identify additional SMAD6 LCH risk loci. Methods: Cases diagnosed with LCH were recruited at Texas Children’s Hospital (n=466). Targeted sequencing of SMAD6 was conducted among cases with ~200x coverage at the Avera Institute of Human Genetics. We accessed aggregate-level SMAD6 sequence data in SMAD6 from a median of 15,694 non-cancer controls in gnomAD v2.1.1. Fisher’s exact test was applied to 154 SMAD6 variants (Bonferroni critical P-value of 3.2 x 10-4) to assess association between SMAD6 variation and case status. Analyses were conducted with SAS and population genetics were assessed in Ensembl. Results: In this case-control analysis, 49 variants were significantly associated with LCH risk, including our previous risk locus. Leveraging population genetics, we found that the top 4 SNPs have low MAF globally (range 2-9%) but are enriched (MAF range 15-23%) in Hispanic/Latinx populations (MXL, CLM, PEL). The top two hits are in high LD in some of the Hispanic/Latinx and Black (ASW) populations (r2: MXL= 0.71, ASW = 1.0, PEL = 0.92), but not globally. The third SNP is in high LD with the peak SNP in these populations, as well (r2: MXL= 0.28, ASW = 0.83, PEL = 0.51). The fourth hit, which is our previously identified risk locus, has moderate LD with the peak SNP in Hispanic/Latinx populations (r2: MXL= 0.31, CLM = 0.3, PEL = 0.13). Conversely, the LD between the 1st and 5th SNPs was low globally and within different populations. Conclusion: We identified additional support for the role of SMAD6 variation in LCH susceptibility across and within diverse ancestral populations. These findings suggest that the top four SMAD6 variants identified in this study vary in how they function as independent signals across populations, especially in Hispanic/Latinx patients. The 5th hit in SMAD6 appears to be the next independent variant across all populations. These results indicate that there are common risk variants across populations and ancestry-specific variants for LCH, which may contribute to the differences in ancestry-specific LCH risk. Broadly, our work emphasizes the benefits of leveraging in, rather than adjusting out, the genomic richness of diverse patient populations. Citation Format: Priya B. Shetty, Erin Peckham-Gregory, Erik Stricker, Howard Lin, Brooks Scull, Erik Ehli, Christel Davis, Kenneth McClain, Philip Lupo, Carl Allen, Michael Scheurer. Leveraging genomic diversity identifies additional germline risk loci in SMAD6 for Langerhans cell histiocytosis [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B073.

Prospective incidence epidemiology study protocol: conducting active surveillance to assess the burden of Lyme disease (BOLD) in primary care practices in endemic areas of six European countries

IntroductionLyme disease (LD) is the most frequent tick-borne disease in the moderate climates of Europe. This study will inform the phase III efficacy study for Pfizer and Valneva’s investigational Lyme...

Genome‐wide association analysis of coleoptile length and interaction with plant height in durum wheat

AbstractGenotypes with longer coleoptiles can be sown in deep soil layers to reach the underground moisture needed for germination in dry areas. Developing new varieties with longer coleoptiles and shorter plant heights would be novel for wheat breeding and production. In this study, coleoptile lengths of a panel of durum wheat (Triticum turgidum ssp. durum) genotypes were determined, and 14,255 DArTseq (SNP and Silico‐DArT) markers were used to identify coleoptile length‐associated markers by genome‐wide association study (GWAS). A wide genetic variation was accounted for both coleoptile length and plant height. The genetic relationships between coleoptile length and plant height were evaluated using plant height values from five different environments. Two environmentally stable MTAs were identified, one for coleoptile length (QCol.su.4BS) and one for plant height (QPh.su.4BS). These MTAs were located on the short arm of chromosome 4B, with LOD scores up to 12.00 and 17.00, respectively. A relatively high LD (r2 = 0.71) was accounted for between QCol.su.4BS and QPh.su.4BS. The LD block intervals of the MTAs overlapped with some genes with roles in plant growth and development. The functions of plausible candidate genes tell us that QCol.su.4BS may be controlling coleoptile length, whereas QPh.su.4BS may be regulating plant height. The combination of the two loci would be desirable. In conclusion, this study sheds light on the genetic control of coleoptile length and its relationship with plant height in durum wheat.

Integration of risk variants from GWAS with SARS-CoV-2 RNA interactome prioritizes FUBP1 and RAB2A as risk genes for COVID-19

The role of host genetic factors in COVID-19 outcomes remains unclear despite various genome-wide association studies (GWAS). We annotate all significant variants and those variants in high LD (R2 > 0.8) from the COVID-19 host genetics initiative (HGI) and identify risk genes by recognizing genes intolerant nonsynonymous mutations in coding regions and genes associated with cis-expression quantitative trait loci (cis-eQTL) in non-coding regions. These genes are enriched in the immune response pathway and viral life cycle. It has been found that host RNA binding proteins (RBPs) participate in different phases of the SARS-CoV-2 life cycle. We collect 503 RBPs that interact with SARS-CoV-2 RNA concluded from in vitro studies. Combining risk genes from the HGI with RBPs, we identify two COVID-19 risk loci that regulate the expression levels of FUBP1 and RAB2A in the lung. Due to the risk allele, COVID-19 patients show downregulation of FUBP1 and upregulation of RAB2A. Using single-cell RNA sequencing data, we show that FUBP1 and RAB2A are expressed in SARS-CoV-2-infected upper respiratory tract epithelial cells. We further identify NC_000001.11:g.77984833C>A and NC_000008.11:g.60559280T>C as functional variants by surveying allele-specific transcription factor sites and cis-regulatory elements and performing motif analysis. To sum up, our research, which associates human genetics with expression levels of RBPs, identifies FUBP1 and RAB2A as two risk genes for COVID-19 and reveals the anti-viral role of FUBP1 and the pro-viral role of RAB2A in the infection of SARS-CoV-2.

Interaction between gestational plane of nutrition and lactation diet composition on lactation performance of Alpine goats of different parities

A study was conducted with 48 multiparous and 31 primiparous Alpine goats to determine the effects of different nutritional planes during gestation and lactation on feed intake, body weight, body condition score and mass index, blood constituent concentrations, and milk yield and composition. Two gestation supplement treatments (GS; Moderate versus High) were imposed for approximately 5.5 months and two lactation diets (LD; Moderate vs. High) within each GS were fed for 16 wk. The Moderate GS (14.2% crude protein; CP) was given at 1.125% body weight (BW; dry matter basis) and the High GS (16.2% CP) was consumed ad libitum, with alfalfa hay available free-choice to all animals. Moderate and High LD contained 16.0 and 16.9% CP and 34.7 and 30.4% neutral detergent fiber, respectively. Body weight (77.5 vs. 72.0 kg) and body condition score (BCS; 3.22 vs. 3.04) at 11 days before kidding were greater (P < 0.05) for High versus Moderate GS, but BW at kidding (62.6 and 64.9 kg; SEM = 1.32) and 3 days later (60.9 and 63.6 kg for Moderate and High GS, respectively; SEM = 1.32) was similar. Litter size (1.9 and 2.4; SEM = 0.59), kid birth weight (3.72 and 3.59 kg; SEM = 0.097), and litter weight (6.55 and 7.13 kg for Moderate and High GS, respectively; SEM = 0.316) were similar between GS diets. However, kid birth weight (3.44 and 3.87 kg; SEM = 0.096) and litter weight (6.23 and 7.46 kg; SEM = 0.364) were greater (P < 0.05) for multiparous versus primiparous goats. Dry matter intake during lactation was greater for Moderate than for High GS (P ≤ 0.051) in kg/day, % BW, and g/kg BW0.75. However, milk fat (3.81, 4.14, 3.85, and 3.77%; SEM = 0.132) and protein concentrations (2.49, 2.50, 2.47, and 2.49%; SEM = 0.047), and raw (2.22, 2.59, 2.39, and 2.45 kg; SEM = 0.173) and energy yields of milk (6.02, 7.42, 6.51, and 6.63 MJ/day for Moderate GS-Moderate LD, Moderate GS-High LD, High GS-Moderate LD, and High GS-High LD, respectively; SEM = 0.453) were not affected by GS, LD, or their interaction. Dry matter intake, milk and its component yields, and heat energy (MJ/day) were higher (P < 0.05) for does than for doelings, but BCS and milk protein and fat concentrations were lower (P < 0.05) for does. Blood nonesterified fatty acid concentration was not affected by any diets, but there was interaction (P < 0.05) between GS and LD for betahydroxybutyric acid concentration. In conclusion, minor to moderate magnitudes of difference in nutritional planes during gestation and lactation had little effect on reproductive and lactation performance, reflecting the considerable capacity of lactating dairy goats for compensatory changes such as feed intake and tissue mobilization and accretion.

Effects of growth conditions on the physicochemical, mineral, and amino acid profile of polyembryonic maize

AbstractBackground and ObjectiveAmong the methods to improve the quality of maize (Zea mays L.) kernels is crossing with better‐quality genotypes and agronomic management. In this study, the quality (lipids, proteins, crude fiber, carbohydrates, ashes, minerals, and amino acids) of polyembryonic (PEm) and nonpolyembryonic (NPEm) maize was evaluated in individual plants (IND) as polyembryonic (PE). Three different genotypes (AE = high polyembryony hybrid maize, NAP = normal‐height high polyembryony maize, and CAI = NPEm hybrid) were selected; in addition, maize kernels were obtained under different growth conditions of population density (HD = high density and LD = low density) and fertilization rates (LF = low fertilization [120 N, 60 P, 0 K], and HF = high fertilization [40 N, 90 P, 0 K]).FindingsThe results indicate that PEm has higher protein (10.3%) and fat (7.5%) content and lower carbohydrate content (2.0%) than CAI. The highest concentration minerals were P, S, Cl, K, Ca, and Fe in all maize genotypes. In addition, NAP of IND plants had a higher content of serine, tyrosine, phenylalanine, glutamine, and alanine. On the other hand, in the experiments where the effect of population density and fertilization level was evaluated, it was observed that PEm produced with LD showed higher ash, fiber, and carbohydrate content (1.1%, 1.4%, and 2.7%, respectively) and lower fat content (6.0%). In addition, PEm produced in HD showed higher values of fat, protein, fiber, K, P, and S than the control group (CAI). Finally, PEm produced with LF showed higher proportions of fat, protein, fiber, K, and P (5.7%, 8.2%, 1.1%, 5.8 mg/100 g, and 1.6 mg/100 g, respectively) compared to the control group (CAI). In addition, fertilization was observed to influence carbohydrate content, showing an increase of up to 24% in HF and up to 10% in LF.ConclusionThe combined use of corn of polyembryonic genotypes with different agronomic managements such as stocking density (LD and HD) and fertilization rate (LF/HF) during grain production can generate significant changes in grain quality.Significance and NoveltyThe use of polyembryonic maize genotypes is an option to improve grain quality. In addition, the results of this study allowed us to observe the effect of agronomic practices such as planting population density and fertilization rate on different variables of interest for grain quality.

Structural variants and short tandem repeats impact gene expression and splicing in bovine testis tissue.

Structural variants (SVs) and short tandem repeats (STRs) are significant sources of genetic variation. However, the impacts of these variants on gene regulation have not been investigated in cattle. Here, we genotyped and characterized 19,408 SVs and 374,821 STRs in 183 bovine genomes and investigated their impact on molecular phenotypes derived from testis transcriptomes. We found that 71% STRs were multiallelic. The vast majority (95%) of STRs and SVs were in intergenic and intronic regions. Only 37% SVs and 40% STRs were in high LD (R2 > 0.8) with surrounding SNPs/Indels, indicating that SNP-based association testing and genomic prediction are blind to a non-negligible portion of genetic variation. We showed that both SVs and STRs were more than two-fold enriched among expression and splicing QTL (e/sQTL) relative to SNPs/Indels and were often associated with differential expression and splicing of multiple genes. Deletions and duplications had larger impacts on splicing and expression than any other type of structural variant. Exonic duplications predominantly increased gene expression either through alternative splicing or other mechanisms, whereas expression- and splicing-associated STRs primarily resided in intronic regions and exhibited bimodal effects on the molecular phenotypes investigated. Most e/sQTL resided within 100 kb of the affected genes or splicing junctions. We pinpoint candidate causal STRs and SVs associated with the expression of SLC13A4 and TTC7B, and alternative splicing of a lncRNA and CAPP1. We provide a catalogue of STRs and SVs for taurine cattle and show that these variants contribute substantially to gene expression and splicing variation.

High Performance Pd/4H-SiC Epitaxial Schottky Barrier Radiation Detectors for Harsh Environment Applications.

Although many refractory metals have been investigated as the choice of contact metal in 4H-SiC devices, palladium (Pd) as a Schottky barrier contact for 4H-SiC radiation detectors for harsh environment applications has not been investigated adequately. Pd is a refractory metal with high material weight-to-thickness ratio and a work function as high as nickel, one of the conventional metal contacts for high performing 4H-SiC Schottky barrier detectors (SBDs). In this article, Pd/4H-SiC epitaxial SBDs have been demonstrated for the first time as a superior self-biased (0 V applied bias) radiation detector when compared to benchmark Ni/4H-SiC SBDs. The Pd/4H-SiC SBD radiation detectors showed a very high energy resolution of 1.9% and 0.49% under self- and optimized bias, respectively, for 5486 keV alpha particles. The SBDs demonstrated a built-in voltage (Vbi) of 2.03 V and a hole diffusion length (Ld) of 30.8 µm. Such high Vbi and Ld led to an excellent charge collection efficiency of 76% in the self-biased mode. Capacitance mode deep level transient spectroscopy (DLTS) results revealed that the "lifetime-killer" Z1/2 trap centers were present in the 4H-SiC epilayer. Another deep level trap was located at 1.09 eV below the conduction band minimum and resembles the EH5 trap with a concentration of 1.98 × 1011 cm-3 and capture cross-section 1.7 × 10-17 cm-2; however, the detector performance was found to be limited by charge trapping in the Z1/2 center. The results presented in this article revealed the unexplored potential of a wide bandgap semiconductor, SiC, as high-efficiency self-biased radiation detectors. Such high performance self-biased radiation detectors are poised to address the longstanding problem of designing self-powered sensor devices for harsh environment applications e.g., advanced nuclear reactors and deep space missions.

Association of R1939W and P1987R variants of Otoferlin (OTOF) gene with severe to profound nonsyndromic sensorineural hearing loss in Pakistani subjects.

To find possible association of R1939W and P1987R variants of OTOF gene with severe to profound NSSHL in cochlear implant subjects. It was a case control study, conducted from June 2021 to February 2022, comprising 50 cases of severe to profound NSSHL who had received cochlear implant from ENT Department, CMH Rawalpindi and 50 age-matched healthy controls from PEMH Rawalpindi. Blood samples were collected from all the subjects, followed by DNA extraction and allele-specific polymerase chain reaction, performed at Multi-disciplinary Laboratory of Department of Biochemistry and Molecular Biology, Army Medical College Rawalpindi. Statistical analysis was done using 'SPSS' and 'XLSTAT', followed by genetic analysis using 'SNPstat'. Mean age of the cases was 5.96 ± 4.62 years (N=50), comprising 58% males and 42% females. All had bilateral and prelingual HL. Parental consanguinity was 72%, whereas 62% cases had a positive family history of deafness. Alleles of R1939W and P1987R were not associated with NSSHL, as shown by their p values of 0.56 and 0.89 respectively. For R1939W ORs were 0.71 (dominant model) and 0.80 (overdominant model), indicating negative association with NSSHL. Regarding P1987R OR was 0.96 (log-additive model). Genotypes of both variants were not in HW Equilibrium (p <0.0001), whereas their alleles showed high LD (D'=0.92). High percentage of parental consanguinity was observed among cochlear implant candidates. The OTOF variants R1939W and P1987R were found to have protective roles against NSSHL in study population.

Variation along P2RX7 interacts with early traumas on severity of anxiety suggesting a role for neuroinflammation

Emotional stress is a leading risk factor in the development of neuropsychiatric disorders possibly via immune activation. P2X7 receptors promote neuroinflammation, and research suggests a relationship between chromosome region 12q2431, in which the P2X7R gene is located, and development of mood disorders, however, few studies concentrate on its association with anxiety. Our aim was to investigate the effects of P2RX7 variation in interaction with early childhood traumas and recent stressors on anxiety. 1752 participants completed questionnaires assessing childhood adversities and recent negative life events, provided data on anxiety using the Brief Symptom Inventory, and were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into linear regression models followed by a linkage disequilibrium-based clumping procedure to identify clumps of SNPs with a significant main or interaction effect. We identified a significant clump with top SNP rs67881993 and containing a set of 29SNPs that are in high LD, which significantly interacted with early childhood traumas but not with recent stress conveying a protective effect against increased anxiety in those exposed to early adversities. Our study demonstrated that P2RX7 variants interact with distal and more etiological stressors in influencing the severity of anxiety symptoms, supporting previous scarce results and demonstrating its role in moderating the effects of stress.

Integrated approach for studying bioactive compounds from Cladosporium spp. against estrogen receptor alpha as breast cancer drug target

Cladosporium spp. have been reported for their great diversity of secondary metabolites which represent as a prominent base material for verifying the biological activities. Several bioactive compounds which have antimicrobial, cytotoxic, quorum sensing inhibitory and phytotoxic activities have been isolated from Cladosporium species. Most of them are still needed to be explored for their anticancer properties. Therefore, the present study is focused on screening and identifying the bioactive compounds of Cladosporium spp. for their anticancer activity via the integrated approaches of Molecular Docking (MD), Molecular Dynamics Simulation (MDS) and Density Functional Theory (DFT) studies. A total of 123 bioactive compounds of Cladosporium spp. were explored for their binding affinity with the selected breast cancer drug target receptor such as estrogen receptor alpha (PDB:6CBZ). The Molecular Docking studies revealed that amongst the bioactive compounds screened, Altertoxin X and Cladosporol H showed a good binding affinity of − 10.5 kcal/mol and − 10.3 kcal/mol, respectively, with the estrogen receptor alpha when compared to the reference compound (17upbeta-Estradiol: − 10.2 kcal/mol). The MDS study indicated the stable binding patterns and conformation of the estrogen receptor alpha-Altertoxin X complex in a stimulating environment. In addition, in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) study suggested that Altertoxin X has a good oral bioavailability with a high LD_{50} value of 2.375 mol/kg and did not cause any hepatotoxicity and skin sensitization. In summary, the integrated approaches revealed that Altertoxin X possesses a promising anticancer activity and could serve as a new therapeutic drug for breast cancer treatment.

Fine-Mapping of SMAD6 Sequence Data Identifies Additional Putative Risk Loci for Langerhans Cell Histiocytosis

Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by lesions including pathogenic CD207+ dendritic cells among an inflammatory infiltrate. Sequencing studies have identified recurrent, mutually exclusive somatic activating mutations in MAPK pathway genes in ~85% of LCH lesions, including BRAF V600E in 50-65%. Despite advances to elucidate the somatic mutational landscape underlying LCH pathogenesis, germline risk factors remain largely unknown. We previously conducted a genome-wide association study of LCH and identified and validated a risk variant in SMAD6 (rs12438941, G->A) associated with a 3.7-fold increase in LCH risk. SMAD6 inhibits bone morphogenetic protein and transforming growth factor-beta (TGF-β)/activin signaling, which are determinants of physiologic myeloid dendritic cell differentiation, and is in close proximity to MAP2K1. Notably, this risk allele is more common in Hispanics, who are at the highest risk of developing LCH, and absent in those of African ancestry who experience the lowest risk of LCH. Our current objective is to further analyze risk of acquiring LCH associated with SMAD6 variations. Methods: Four-hundred and sixty-seven cases diagnosed with LCH were recruited at Texas Children's Hospital. Targeted sequencing of SMAD6 was conducted among cases with ~200x coverage at the Avera Institute of Human Genetics. We accessed aggregate-level SMAD6 sequence data at 940 overlapping loci in SMAD6 from a median of 15,694 non-cancer controls in gnomAD v2.1.1. Variants were pruned using SNPclip due to high linkage disequilibrium (LD; r2 > 0.8) (n = 216 removed), low minor allele frequency (MAF < 0.01) (n = 326 removed), absence from 1000Genomes (n = 240 removed), non-biallelic (n = 3 removed), and absence from dbSNP155 (GRCh37; n = 1 removed). The Fisher's exact test was applied to 154 SMAD6 variants with a Bonferroni critical P-value of 3.2 x 10-4 to assess any association between SMAD6 variation and case status. Sequence data were analyzed in SAS v9.2. Results: In this case-control analysis, 49 variants within SMAD6 were significantly associated with LCH risk (P-values ranging from 4.54 x 10-28 to 2.9 x 10-4), including our previously identified risk locus (P-value: 8.55 x 10-14). Most (48) of the hits were intronic, and one was in the 5' UTR (p = 2.88 x 10-5). The top 4 SNPs had low MAF globally (range 2-9%) but were enriched in the 1000 Genomes AMR (Admixed American superpopulation) population (range 15-23%). The top two SNPs are in high LD in some populations (r2: MXL (Mexican ancestry from Los Angeles) = 0.71, ASW (Americans of African Ancestry in the Southwest USA) = 1.0, PEL (Peruvian from Lima, Peru) = 0.92), but not globally. The third SNP was also in moderately high LD with the peak SNP in some populations (r2: MXL= 0.28, ASW = 0.83, PEL = 0.51). The fourth SNP, which was the variant that was previously identified in our LCH GWAS, has only moderate LD with the peak SNP in some populations (r2: MXL= 0.31, CLM (Colombian from Medellian, Colombia) = 0.3, PEL = 0.13), suggesting that these may be independent signals, and/or that specific SNPs contribute to LCH risk differentially based on ancestry. Conclusions: We identified additional support for associations of germline SMAD6 variants with LCH susceptibility. Our previous risk locus was again enriched among those who develop LCH, and a cluster of loci surrounding our risk locus was identified using this sequence-based approach. Next steps include functional annotation of top hits, analyses to assess whether top hits are associated with LCH patient or clinical characteristics (e.g., genomic ancestry, BRAF V600E mutation status, risk organ involvement), and burden analysis to investigate highly penetrant variants. Overall, this study suggests potential contributions of germline genomics in LCH pathogenesis that may identify a functional role for SMAD6 and account for different incidence rates according to race/ethnicity.

Population genetic analysis of Plasmodium falciparum cell-traversal protein for ookinetes and sporozoite among malaria patients from southern Nigeria.

Plasmodium falciparum immune escape mechanisms affect antigens being prioritized for vaccine design. As a result of the multiple surface antigens the parasite exhibits at different life cycle stages, designing a vaccine that would efficiently boost the immune system in clearing infections has been challenging. The P. falciparum cell-traversal protein for ookinetes and sporozoite (Pfceltos) is instrumental for ookinete traversal of the mosquito midgut and sporozoites invasion of the human liver cells. Pfceltos elicits both humoral and cellular immune response but has been reported with multiple single nucleotide polymorphisms in global isolates. A cross-sectional survey, conducted in southern Nigeria, between January-March 2021 recruited 283 individuals. Of this, 166 demonstrated P. falciparum infections (86 from Cross River and 80 from Edo), 48 (55.8%) while only 36 (45%) were amplified for Pfceltos gene from both sites respectively. Fifty amplified samples were sequenced and analysed for their diversity, polymorphisms and population structure of the gene. The number of segregating sites in Edo State was higher (34) than that of Cross River State. Though nucleotide diversity was higher for Edo compared to Cross River State (θw=0.02505; π=0.03993 versus θw=0.00930; π=0.01033 respectively), the reverse was the case for haplotype diversity (0.757 versus 0.890 for Edo and Cross River respectively). Of the twelve haplotypes observed from both states, only two (KASLPVEK and NAFLSFEK) were shared, with haplotype prevalence higher in Edo (16% and 36%) than Cross River (8% and 4%). The Tajima's D test was positive for both states, with Fst value showing a strong genetic differentiation (Fst=0.25599), indicating the occurrence of balancing selection favoring haplotype circulation at a low frequency. The shared haplotypes, low Hst and Fst values presents a challenge to predict the extent of gene flow. High LD values present a grim public health consequence should a Pfceltos-conjugated vaccine be considered for prophylaxis in Nigeria.