The Biology and Genomics of Human Hair Follicles: A Focus on Androgenetic Alopecia.

Androgenetic alopecia is a highly prevalent condition mainly affecting men. This complex trait is related to aging and genetics; however, multiple other factors, for example, lifestyle, are also involved. Despite its prevalence, the underlying biology of androgenetic alopecia remains elusive, and thus advances in its treatment have been hindered. Herein, we review the functional anatomy of hair follicles and the cell signaling events that play a role in follicle cycling. We also discuss the pathology of androgenetic alopecia and the known molecular mechanisms underlying this condition. Additionally, we describe studies comparing the transcriptional differences in hair follicles between balding and non-balding scalp regions. Given the genetic contribution, we also discuss the most significant risk variants found to be associated with androgenetic alopecia. A more comprehensive understanding of this pathology may be generated through using multi-omics approaches.

Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns.

BACKGROUND: The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). METHODS: A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. RESULTS: Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. CONCLUSIONS: We find no support for an increased risk of BPD with iron supplementation. TRIAL REGISTRATION NUMBER: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT: Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.

The Implementation and Evaluation of a Stock Epinephrine for Schools Program in Maricopa County, Arizona.

The increasing rate of food allergies in children, combined with the role of food as an integral part of the school day has led to the emergence of anaphylaxis as a daily threat to students, regardless of prior allergy diagnosis. Stock epinephrine-non-patient specific epinephrine auto-injectors that may be used during emergencies-is a means for schools to prepare for anaphylactic events and protect children with allergies. The Maricopa County Department of Public Health initiated the School Surveillance and Medication Program (SSMP), a data capture program, to facilitate the process of stocking epinephrine in schools. Spearheaded by the implementation efforts of the Kyah Rayne Foundation, program enrollment increased 146% between the 2020-2021 and 2021-2022 school years. The increased proportion of schools enrolled in the SSMP and the number of school personnel trained to administer epinephrine demonstrates the feasibility of school-centered stock epinephrine programs and validates strategies for increasing program uptake.

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.

Nested association mapping-based GWAS for grain yield and related traits in wheat grown under diverse Australian environments.

KEY MESSAGE: Utilising a nested association mapping (NAM) population-based GWAS, 98 stable marker-trait associations with 127 alleles unique to the exotic parents were detected for grain yield and related traits in wheat. Grain yield, thousand-grain weight, screenings and hectolitre weight are important wheat yield traits. An understanding of their genetic basis is crucial for improving grain yield in breeding programmes. Nested association mapping (NAM) populations are useful resources for the dissection of the genetic basis of complex traits such as grain yield and related traits in wheat. Coupled with phenotypic data collected from multiple environments, NAM populations have the power to detect quantitative trait loci and their multiple alleles, providing germplasm that can be incorporated into breeding programmes. In this study, we evaluated a large-scale wheat NAM population with two recurrent parents in unbalanced trials in nine diverse Australian field environments over three years. By applying a single-stage factor analytical linear mixed model (FALMM) to the NAM multi-environment trials (MET) data and conducting a genome-wide association study (GWAS), we detected 98 stable marker-trait associations (MTAs) with their multiple alleles. 74 MTAs had 127 alleles that were derived from the exotic parents and were absent in either of the two recurrent parents. The exotic alleles had favourable effects on 46 MTAs of the 74 MTAs, for grain yield, thousand-grain weight, screenings and hectolitre weight. Two NAM RILs with consistently high yield in multiple environments were also identified, highlighting the potential of the NAM population in supporting plant breeding through provision of germplasm that can be readily incorporated into breeding programmes. The identified beneficial exotic alleles introgressed into the NAM population provide potential target alleles for the genetic improvement of wheat and further studies aimed at pinpointing the underlying genes.

Development of an Australian Bread Wheat Nested Association Mapping Population, a New Genetic Diversity Resource for Breeding under Dry and Hot Climates.

Genetic diversity, knowledge of the genetic architecture of the traits of interest and efficient means of transferring the desired genetic diversity into the relevant genetic background are prerequisites for plant breeding. Exotic germplasm is a rich source of genetic diversity; however, they harbor undesirable traits that limit their suitability for modern agriculture. Nested association mapping (NAM) populations are valuable genetic resources that enable incorporation of genetic diversity, dissection of complex traits and providing germplasm to breeding programs. We developed the OzNAM by crossing and backcrossing 73 diverse exotic parents to two Australian elite varieties Gladius and Scout. The NAM parents were genotyped using the iSelect wheat 90K Infinium SNP array, and the progeny were genotyped using a custom targeted genotyping-by-sequencing assay based on molecular inversion probes designed to target 12,179 SNPs chosen from the iSelect wheat 90K Infinium SNP array of the parents. In total, 3535 BC1F4:6 RILs from 125 families with 21 to 76 lines per family were genotyped and we found 4964 polymorphic and multi-allelic haplotype markers that spanned the whole genome. A subset of 530 lines from 28 families were evaluated in multi-environment trials over three years. To demonstrate the utility of the population in QTL mapping, we chose to map QTL for maturity and plant height using the RTM-GWAS approach and we identified novel and known QTL for maturity and plant height.

Wheat ms5 male-sterility is induced by recessive homoeologous A and D genome non-specific lipid transfer proteins.

Nuclear male-sterile mutants with non-conditional, recessive and strictly monogenic inheritance are useful for both hybrid and conventional breeding systems, and have long been a research focus for many crops. In allohexaploid wheat, however, genic redundancy results in rarity of such mutants, with the ethyl methanesulfonate-induced mutant ms5 among the few reported to date. Here, we identify TaMs5 as a glycosylphosphatidylinositol-anchored lipid transfer protein required for normal pollen exine development, and by transgenic complementation demonstrate that TaMs5-A restores fertility to ms5. We show ms5 locates to a centromere-proximal interval and has a sterility inheritance pattern modulated by TaMs5-D but not TaMs5-B. We describe two allelic forms of TaMs5-D, one of which is non-functional and confers mono-factorial inheritance of sterility. The second form is functional but shows incomplete dominance. Consistent with reduced functionality, transcript abundance in developing anthers was found to be lower for TaMs5-D than TaMs5-A. At the 3B homoeolocus, we found only non-functional alleles among 178 diverse hexaploid and tetraploid wheats that include landraces and Triticum dicoccoides. Apparent ubiquity of non-functional TaMs5-B alleles suggests loss-of-function arose early in wheat evolution and, therefore, at most knockout of two homoeoloci is required for sterility. This work provides genetic information, resources and tools required for successful implementation of ms5 sterility in breeding systems for bread and durum wheats.

QTL analysis and fine mapping of a QTL for yield-related traits in wheat grown in dry and hot environments.

Genetic control of grain yield and phenology was examined in the Excalibur/Kukri doubled haploid mapping population grown in 32 field experiments across the climatic zones of southern Australia, India and north-western Mexico where the wheat crop experiences drought and heat stress. A total of 128 QTL were identified for four traits: grain yield, thousand grain weight (TGW), days to heading and grain filling duration. These QTL included 24 QTL for yield and 27 for TGW, showing significant interactions with the environment (Q * E). We also identified 14 QTL with a significant, small main effects on yield across environments. The study focussed on a region of chromosome 1B where two main effect QTL were found for yield and TGW without the confounding effect of phenology. Excalibur was the source of favourable alleles: QYld.aww-1B.2 with a peak at 149.5-150.1 cM and QTgw.aww-1B at 168.5-171.4 cM. We developed near isogenic lines (NIL) for the interval including QYld.aww-1B.2 and QTgw.aww-1B and evaluated them under semi-controlled conditions. Significant differences in four pairs of NIL were observed for grain yield but not for TGW, confirming a positive effect of the Excalibur allele for QYld.aww-1B.2. The interval containing QYld.aww-1B.2 was narrowed down to 2.9 cM which corresponded to a 2.2 Mbp genomic region on the chromosome 1B genomic reference sequence of cv. Chinese Spring and contained 39 predicted genes.

Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

Detection of genetic loci associated with plasma fetuin-A: a meta-analysis of genome-wide association studies from the CHARGE Consortium.

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin-A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ∼ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P < 0.05 × 10-8) SNPs near the AHSG locus, the top SNP was rs4917 (P =1.27 × 10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/l (∼13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

Elevated cerebrospinal fluid Galectin-9 is associated with central nervous system immune activation and poor cognitive performance in older HIV-infected individuals.

We previously reported that galectin-9 (Gal-9), a soluble lectin with immunomodulatory properties, is elevated in plasma during HIV infection and induces HIV transcription. The link between Gal-9 and compromised neuronal function is becoming increasingly evident; however, the association with neuroHIV remains unknown. We measured Gal-9 levels by ELISA in cerebrospinal fluid (CSF) and plasma of 70 HIV-infected (HIV+) adults stratified by age (older > 40 years and younger < 40 years) either ART suppressed or with detectable CSF HIV RNA, including a subgroup with cognitive assessments, and 18 HIV uninfected (HIV-) controls. Gal-9 tissue expression was compared in necropsy brain specimens from HIV- and HIV+ donors using gene datasets and immunohistochemistry. Among older HIV+ adults, CSF Gal-9 was elevated in the ART suppressed and CSF viremic groups compared to controls, whereas in the younger group, Gal-9 levels were elevated only in the CSF viremic group (p < 0.05). CSF Gal-9 positively correlated with age in all groups (p < 0.05). CSF Gal-9 tracked with CSF HIV RNA irrespective of age (ß = 0.33; p < 0.05). Higher CSF Gal-9 in the older viremic HIV+ group correlated with worse neuropsychological test performance scores independently of age and CSF HIV RNA (p < 0.05). Furthermore, CSF Gal-9 directly correlated with myeloid activation (CSF-soluble CD163 and neopterin) in both HIV+ older groups (p < 0.05). Among HIV+ necropsy specimens, Gal-9 expression was increased in select brain regions compared to controls (p < 0.05). Gal-9 may serve as a novel neuroimmuno-modulatory protein that is involved in driving cognitive deficits in those aging with HIV and may be valuable in tracking cognitive abnormalities.

Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease.

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the ß-amyloid cascade.

DAWN: a resource for yielding insights into the diversity among wheat genomes.

BACKGROUND: Democratising the growing body of whole genome sequencing data available for Triticum aestivum (bread wheat) has been impeded by the lack of a genome reference and the large computational requirements for analysing these data sets. RESULTS: DAWN (Diversity Among Wheat geNomes) integrates data from the T. aestivum Chinese Spring (CS) IWGSC RefSeq v1.0 genome with public WGS and exome data from 17 and 62 accessions respectively, enabling researchers and breeders alike to investigate genotypic differences between wheat accessions at the level of whole chromosomes down to individual genes. CONCLUSIONS: Using DAWN we show that it is possible to visualise small and large chromosomal deletions, identify haplotypes at a glance and spot the consequences of selective breeding. DAWN allows us to detect the break points of alien introgression segments brought into an accession when transferring desired genes. Furthermore, we can find possible explanations for reduced recombination in parts of a chromosome, we can predict regions with linkage drag, and also look at diversity in centromeric regions.

Essential ocean variables for global sustained observations of biodiversity and ecosystem changes.

Sustained observations of marine biodiversity and ecosystems focused on specific conservation and management problems are needed around the world to effectively mitigate or manage changes resulting from anthropogenic pressures. These observations, while complex and expensive, are required by the international scientific, governance and policy communities to provide baselines against which the effects of human pressures and climate change may be measured and reported, and resources allocated to implement solutions. To identify biological and ecological essential ocean variables (EOVs) for implementation within a global ocean observing system that is relevant for science, informs society, and technologically feasible, we used a driver-pressure-state-impact-response (DPSIR) model. We (1) examined relevant international agreements to identify societal drivers and pressures on marine resources and ecosystems, (2) evaluated the temporal and spatial scales of variables measured by 100+ observing programs, and (3) analysed the impact and scalability of these variables and how they contribute to address societal and scientific issues. EOVs were related to the status of ecosystem components (phytoplankton and zooplankton biomass and diversity, and abundance and distribution of fish, marine turtles, birds and mammals), and to the extent and health of ecosystems (cover and composition of hard coral, seagrass, mangrove and macroalgal canopy). Benthic invertebrate abundance and distribution and microbe diversity and biomass were identified as emerging EOVs to be developed based on emerging requirements and new technologies. The temporal scale at which any shifts in biological systems will be detected will vary across the EOVs, the properties being monitored and the length of the existing time-series. Global implementation to deliver useful products will require collaboration of the scientific and policy sectors and a significant commitment to improve human and infrastructure capacity across the globe, including the development of new, more automated observing technologies, and encouraging the application of international standards and best practices.

Plasma Derived Exosomal Biomarkers of Exposure to Ionizing Radiation in Nonhuman Primates.

Exposure to ionizing radiation induces a cascade of molecular events that ultimately impact endogenous metabolism. Qualitative and quantitative characterization of metabolomic profiles is a pragmatic approach to studying the risks of radiation exposure since it provides a phenotypic readout. Studies were conducted in irradiated nonhuman primates (NHP) to investigate metabolic changes in plasma and plasma-derived exosomes. Specifically, rhesus macaques (Macaca mulatta) were exposed to cobalt-60 gamma-radiation and plasma samples were collected prior to and after exposure to 5.8 Gy or 6.5 Gy radiation. Exosomes were isolated using ultracentrifugation and analyzed by untargeted profiling via ultra-performance liquid chromatography mass spectrometry (UPLC-MS) based metabolomic and lipidomic analyses, with the goal of identifying a molecular signature of irradiation. The enrichment of an exosomal fraction was confirmed using quantitative ELISA. Plasma profiling showed markers of dyslipidemia, inflammation and oxidative stress post-irradiation. Exosomal profiling, on the other hand, enabled detection and identification of low abundance metabolites that comprise exosomal cargo which would otherwise get obscured with plasma profiling. We discovered enrichment of different classes of metabolites including N-acyl-amino acids, Fatty Acid ester of Hydroxyl Fatty Acids (FAHFA's), glycolipids and triglycerides as compared to the plasma metabolome composition with implications in mediation of systemic response to radiation induced stress signaling.

In Vitro Blood-Brain Barrier Modeling adapted for Peripheral Blood Mononuclear Cell Transmigration from HIV-Positive Patients for Clinical Research on Therapeutic Drug Intervention.

OBJECTIVE: HIV-associated cognitive impairment (HACI) continues to persist for HIV-seropositive individuals who are on antiretroviral therapy (ART). HACI develops in part when HIV-infected monocytes (MOs) transmigrate through the blood-brain barrier (BBB) and secrete pro-inflammatory cytokines and chemokines, which leads to neuronal damage. In vitro BBB models are important tools that can elucidate mechanisms of MO transmigration. Previously described in vitro BBB models relied on pathology specimens, resulting in potentially variable and inconsistent results. This project reports on a reliable and consistent alternative in vitro BBB model that has the potential to be used in clinical research intervention studies analyzing the effects of ART on the BBB and on MO transmigration. METHODS: A bilayer BBB model was established with commercially available astrocytes and endothelial cells on a 3µm PET membrane insert to allow the contact of astrocytic foot processes with endothelial cells. Inserts were cultured in growth medium for 7 days before exposure to HIV- or HIV+ peripheral blood mononuclear cells (PBMCs). PBMCs were allowed to transmigrate across the BBB for 24 hours. RESULTS: Confluency and integrity measurements by trans-endothelial electrical resistance (TEER) (136.7 ± 18.3Ω/cm2) and permeability (5.64 ± 2.20%) verified the integrity of the in vitro BBB model. Transmigrated MOs and non-MOs were collected and counted (6.0x104 MOs; 1.1x105 non-MOs). Markers indicative of glial fibrillary acidic protein (GFAP), von Willebrand factor (vWF), and p-glycoprotein (Pgp) were revealed in immunofluorescence staining (IF), indicating BBB phenotype and functionality. CONCLUSION: Potential applications for this model include assessing the HIV DNA copy numbers of transmigrated cells (pre- and post-targeted ART) and understanding the role of oxidative stress related to HIV DNA and HACI.

Typhus Group Rickettsiosis, Texas, USA, 2003-2013.

We characterized the epidemiology of typhus group rickettsiosis in Texas, USA. During 2003-2013, a total of 1,762 cases were reported to the state health department. The number of diagnosed cases and geographic expansion increased over time. Physician awareness is critical to diagnose and effectively treat rickettsial infections.

Prolonged Detection of Zika Virus in Vaginal Secretions and Whole Blood.

Infection with Zika virus is an emerging public health crisis. We observed prolonged detection of virus RNA in vaginal mucosal swab specimens and whole blood for a US traveler with acute Zika virus infection who had visited Honduras. These findings advance understanding of Zika virus infection and provide data for additional testing strategies.

Likely Autochthonous Transmission of Trypanosoma cruzi to Humans, South Central Texas, USA.

Chagas disease, caused by Trypanosoma cruzi, is a major neglected tropical disease affecting the Americas. The epidemiology of this disease in the United States is incomplete. We report evidence of likely autochthonous vectorborne transmission of T. cruzi and health outcomes in T. cruzi-seropositive blood donors in south central Texas, USA.