Dissecting loci that underpin the genetic correlations between production, fertility, and urea traits in Australian Holstein cattle.

Unfavorable genetic correlations between milk production, fertility, and urea traits have been reported. However, knowledge of the genomic regions associated with these unfavorable correlations is limited. Here, we used the correlation scan method to identify and investigate the regions driving or antagonizing the genetic correlations between production vs. fertility, urea vs. fertility, and urea vs. production traits. Driving regions produce an estimate of correlation that is in the same direction as the global correlation. Antagonizing regions produce an estimate in the opposite direction of the global estimates. Our dataset comprised 6567, 4700, and 12,658 Holstein cattle with records of production traits (milk yield, fat yield, and protein yield), fertility (calving interval) and urea traits (milk urea nitrogen and blood urea nitrogen predicted using milk-mid-infrared spectroscopy), respectively. Several regions across the genome drive the correlations between production, fertility, and urea traits. Antagonizing regions were confined to certain parts of the genome and the genes within these regions were mostly involved in preventing metabolic dysregulation, liver reprogramming, metabolism remodeling, and lipid homeostasis. The driving regions were enriched for QTL related to puberty, milk, and health-related traits. Antagonizing regions were mostly related to muscle development, metabolic body weight, and milk traits. In conclusion, we have identified genomic regions of potential importance for dairy cattle breeding. Future studies could investigate the antagonizing regions as potential genomic regions to break the unfavorable correlations and improve milk production as well as fertility and urea traits.

Genomic regions and biological pathways associated with sex-limited reproductive traits in bovine species.

Many animal species exhibit sex-limited traits, where certain phenotypes are exclusively expressed in one sex. Yet, the genomic regions that contribute to these sex-limited traits in males and females remain a subject of debate. Reproductive traits are ideal phenotypes to study sexual differences since they are mostly expressed in a sex-limited way. Therefore, this study aims to use local correlation analyses to identify genomic regions and biological pathways significantly associated with male and female sex-limited traits in two distinct cattle breeds (Brahman [BB] and Tropical Composite [TC]). We used the Correlation Scan method to perform local correlation analysis on 42 trait pairs consisting of six female and seven male reproductive traits recorded on ~1,000 animals for each sex in each breed. To pinpoint a specific region associated with these sex-limited reproductive traits, we investigated the genomic region(s) consistently identified as significant across the 42 trait pairs in each breed. The genes found in the identified regions were subjected to Quantitative Trait Loci (QTL) colocalization, QTL enrichment analyses, and functional analyses to gain biological insight into sexual differences. We found that the genomic regions associated with the sex-limited reproductive phenotypes are widely distributed across all the chromosomes. However, no single region across the genome was associated with all the 42 reproductive trait pairs in the two breeds. Nevertheless, we found a region on the X-chromosome to be most significant for 80% to 90% (BB: 33 and TC: 38) of the total 42 trait pairs. A considerable number of the genes in this region were regulatory genes. By considering only genomic regions that were significant for at least 50% of the 42 trait pairs, we observed more regions spread across the autosomes and the X-chromosome. All genomic regions identified were highly enriched for trait-specific QTL linked to sex-limited traits (percentage of normal sperm, metabolic weight, average daily gain, carcass weight, age at puberty, etc.). The gene list created from these identified regions was enriched for biological pathways that contribute to the observed differences between sexes. Our results demonstrate that genomic regions associated with male and female sex-limited reproductive traits are distributed across the genome. Yet, chromosome X seems to exert a relatively larger effect on the phenotypic variation observed between the sexes.

Many livestock species show sexual differences between males and females. However, we still do not fully understand the specific area of the genome responsible for these differences. This study used a novel method to investigate this research question in two distinct tropically adapted cattle. The study found that the drivers of sexual differences are widely distributed across the animal's genome, but the sex chromosome seems to play a large role. The genes within these regions are mostly protein-coding and regulatory genes. These genes were involved in biological processes that promote differences between males and females.

The determinants of ecological footprint in the UK: The role of transportation activities, renewable energy, trade openness, and globalization.

The objective of this study is to explore the interaction between transportation energy consumption, GDP, renewable energy, trade, globalization and ecological footprint in the United Kingdom over the period 1990-2020. To achieve this aim, the study uses the autoregressive distributed lag (ARDL) approach and Fourier Toda-Yamamoto causality test. The research findings demonstrate that an increase in transportation energy consumption, renewable energy, and globalization is associated with a reduction in environmental pollution. On the contrary, GDP and trade contribute to worsening the environment. Moreover, there exists a unidirectional causal relationship from transportation energy consumption, GDP, renewable energy, trade, and globalization towards the ecological footprint. The findings of the study recommend that the policymakers should implement strategies and provide incentives to increase the deployment of renewables in the transportation sector, specifically focusing on electric vehicles (EVs) and the necessary charging infrastructure. Overall, the UK government should prioritize sustainable environmental development when planning its economic development strategies.

Utility of multi-omics data to inform genomic prediction of heifer fertility traits.

Biologically informed single nucleotide polymorphisms (SNPs) impact genomic prediction accuracy of the target traits. Our previous genomics, proteomics, and transcriptomics work identified candidate genes related to puberty and fertility in Brahman heifers. We aimed to test this biological information for capturing heritability and predicting heifer fertility traits in another breed i.e., Tropical Composite. The SNP from the identified genes including 10 kilobases (kb) region on either side were selected as biologically informed SNP set. The SNP from the rest of the Bos taurus genes including 10-kb region on either side were selected as biologically uninformed SNP set. Bovine high-density (HD) complete SNP set (628,323 SNP) was used as a control. Two populations-Tropical Composites (N = 1331) and Brahman (N = 2310)-had records for three traits: pregnancy after first mating season (PREG1, binary), first conception score (FCS, score 1 to 3), and rebreeding score (REB, score 1 to 3.5). Using the best linear unbiased prediction method, effectiveness of each SNP set to predict the traits was tested in two scenarios: a 5-fold cross-validation within Tropical Composites using biological information from Brahman studies, and application of prediction equations from one breed to the other. The accuracy of prediction was calculated as the correlation between genomic estimated breeding values and adjusted phenotypes. Results show that biologically informed SNP set estimated heritabilities not significantly better than the control HD complete SNP set in Tropical Composites; however, it captured all the observed genetic variance in PREG1 and FCS when modeled together with the biologically uninformed SNP set. In 5-fold cross-validation within Tropical Composites, the biologically informed SNP set performed marginally better (statistically insignificant) in terms of prediction accuracies (PREG1: 0.20, FCS: 0.13, and REB: 0.12) as compared to HD complete SNP set (PREG1: 0.17, FCS: 0.10, and REB: 0.11), and biologically uninformed SNP set (PREG1: 0.16, FCS: 0.10, and REB: 0.11). Across-breed use of prediction equations still remained a challenge: accuracies by all SNP sets dropped to around zero for all traits. The performance of biologically informed SNP was not significantly better than other sets in Tropical Composites. However, results indicate that biological information obtained from Brahman was successful to predict the fertility traits in Tropical Composite population.

Prior biological information can be helpful in the genomic prediction of the traits. Previous multi-omics studies by our group identified genes relevant to puberty and fertility in Brahman cattle, a beef breed in northern Australia. We used this biological information in the genomic prediction of three heifer fertility traits, measured in another beef cattle breed: Tropical Composites. The three traits were: pregnancy status after the first mating season (PREG1), first conception score (FCS), and rebreeding score (REB). To test if prior biological information could capture genetic variation in the traits and improve genomic predictions, we compared the results obtained using three subsets of genetic information (i.e., subsets of DNA variants). The first subset contained only variants deemed biologically relevant (as per previous multi-omics studies). The second subset contained only variants considered biologically irrelevant. The third subset had all the variants contained in the commercial DNA assay known as the bovine high-density chip, intended as a practical control. The results indicate that multi-omics data was informative across breed scenario and can be useful in informing genomic predictions of traits of interest.

Correlation scan: identifying genomic regions that affect genetic correlations applied to fertility traits.

Although the genetic correlations between complex traits have been estimated for more than a century, only recently we have started to map and understand the precise localization of the genomic region(s) that underpin these correlations. Reproductive traits are often genetically correlated. Yet, we don't fully understand the complexities, synergism, or trade-offs between male and female fertility. In this study, we used reproductive traits in two cattle populations (Brahman; BB, Tropical Composite; TC) to develop a novel framework termed correlation scan (CS). This framework was used to identify local regions associated with the genetic correlations between male and female fertility traits. Animals were genotyped with bovine high-density single nucleotide polymorphisms (SNPs) chip assay. The data used consisted of ~1000 individual records measured through frequent ovarian scanning for age at first corpus luteum (AGECL) and a laboratory assay for serum levels of insulin growth hormone (IGF1 measured in bulls, IGF1b, or cows, IGF1c). The methodology developed herein used correlations of 500-SNP effects in a 100-SNPs sliding window in each chromosome to identify local genomic regions that either drive or antagonize the genetic correlations between traits. We used Fisher's Z-statistics through a permutation method to confirm which regions of the genome harboured significant correlations. About 30% of the total genomic regions were identified as driving and antagonizing genetic correlations between male and female fertility traits in the two populations. These regions confirmed the polygenic nature of the traits being studied and pointed to genes of interest. For BB, the most important chromosome in terms of local regions is often located on bovine chromosome (BTA) 14. However, the important regions are spread across few different BTA's in TC. Quantitative trait loci (QTLs) and functional enrichment analysis revealed many significant windows co-localized with known QTLs related to milk production and fertility traits, especially puberty. In general, the enriched reproductive QTLs driving the genetic correlations between male and female fertility are the same for both cattle populations, while the antagonizing regions were population specific. Moreover, most of the antagonizing regions were mapped to chromosome X. These results suggest regions of chromosome X for further investigation into the trade-offs between male and female fertility. We compared the CS with two other recently proposed methods that map local genomic correlations. Some genomic regions were significant across methods. Yet, many significant regions identified with the CS were overlooked by other methods.

Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate.

The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact protein-altering DNMs that contribute to the risk of nsCL/P, we conducted whole-genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs some of which are based on available evidence, contribute to the risk of nsCL/P. These include novel protein-truncating DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Many of these protein-altering DNMs were predicted to be pathogenic. Analysis using mouse transcriptomics data showed that some of these genes are expressed during the development of primary and secondary palate. Gene-set enrichment analysis of the protein-altering DNMs identified palatal development and neural crest migration among the few processes that were significantly enriched. These processes are directly involved in the etiopathogenesis of clefting. The analysis of the coding sequence in the WGS data provides more evidence of the opportunity for novel findings in the African genome.

Physiological Response, Haematology and Stress Condition of Scavenging Chickens in Cement Production Areas.

This study investigated the physiological and stress indices of scavenging chickens in LAFARGE and Dangote cement factories located at Ewekoro and Ibese, respectively and respective adjourning communities of Ogun State, Nigeria. One hundred adult scavenging chickens comprising of 25 from each location were used. The birds were caught at night on their perch and kept in furnished cages till the next morning. Data were collected on their rectal temperature, pulse rate, and respiratory rate . Also 5 mL blood was collected through the wing vein of each chicken. Highest (p < 0.05) pulse rate (215.64 beat/minute) and respiratory rate (19.90 breath/minute) were recorded among the chickens at LAFARGE area. Highest (p < 0.05) packed cell volume (28.06%), hemoglobin (4.01 g/dL), monocyte (4.28%) and glucose (256.53 g/dL) were recorded among ones at Ibese (Dangote). White blood cell (6488.89 × 103µL) was highest (p < 0.05) in chickens at Ewekoro (LAFARGE). The study concluded that cement factories infringe on health status of scavenging chickens in the domains. Effective environmental mitigation programme should be put in place for enhanced welfare of the birds.

Equal access of COVID-19 vaccine distribution in Africa: Challenges and way forward.

The World Health Organization (WHO) in Africa and Africa Center Disease Control (Africa CDC) urge the international community and different countries in Africa to ensure sustainable and concrete action to ensure equal and easy access to the COVID-19 vaccines, as different countries in Africa are still struggling to develop a safe and effective strategy to ensure equal vaccine distribution, if available. Africa CDC has called on the international community to come together to help Africa with COVID-19 vaccines to make equal the vaccine distribution among African countries as many cannot afford the vaccine costs due to the level of poverty and other negative factors. The African Union has endorsed the need for Africa to develop a framework to actively engage in easy accessibility to COVID-19 vaccines, which will allow different countries in Africa to take easy steps that will strengthen the local vaccine distribution system, building workforce skills and knowledge, and enrich outreach services in Africa. The article discusses the need for equal access in the distribution of COVID-19 vaccines in Africa, the challenges, and the necessary recommendations that can help to mitigate these challenges.

EXPERIENCE OF DOMESTIC VIOLENCE AMONG PREGNANT WOMEN IN RURAL AND URBAN AREAS OF NIGER DELTA REGION OF NIGERIA: RISK FACTORS, HELP-SEEKING RESOURCES AND COPING STRATEGIES.

BACKGROUND: Risk factors and coping strategies employed for domestic violence across rural and urban locales remains a topical public health concern. Geographic locations experiencing other forms of violence may contribute additional risk factors to domestic violence. METHODOS: A cross-sectional study design was used to determine and compare the risk factors, help-resources and coping strategies employed by survivors of domestic violence living in rural and urban areas of the Niger-Delta region of Nigeria. Altogether 461 (225 rural, 236 urban) pregnant women participated. Statistical analysis was carried out with SPSS version 21 with p ≤0.05. RESULTS: Predictors of violence identified were: geographical location, residing in a rural area (OR 2.052 95% C.I. 1.349 - 3.122) and alcohol intake by pregnant women (OR 1.691; 95% C.I. 1.022 - 2.798) increased the risk of domestic violence while intimate partner's occupation, being a professional was a protective factor (OR 0.513 95% C.I. 0.327 - 0.806). Less than half of the respondents in both locations (rural 44.0% versus urban 35.2%) sought for help following incidents of violence. Fewer rural (3.1%) than urban (10.7%) of them sought for formal help from the police. The main coping strategy used was 'keeping silent' by 69.4% rural compared to 46.4% urban survivors and the main reason given, was to avoid family disharmony. CONCLUSION: There is urgent need for relevant stakeholders to institute measures to reduce domestic violence especially in rural areas of developing countries and establish well-linked help resource centres across both rural and urban localities.

Clients' Perception of and Satisfaction with Quality of Directly Observed Treatment Short Course: A Comparative Study of Private and Public Health Facilities in Southwestern Nigeria.

BACKGROUND AND OBJECTIVES: One third of the world population are at risk of developing active tuberculosis (TB), resulting in significant mortality and morbidity. The reported low patronage in many TB clinics may not be unrelated to the quality of services received by clients. The objective of this study was to determine clients' perception of and satisfaction with quality of DOTs treatments in private and public health facilities in Oyo State. MATERIALS AND METHODS: A descriptive cross sectional study among 410 eligible clients selected using the multistage sampling method was conducted in Oyo State. Research instrument used were a structured pre-tested interviewer-administered questionnaire. Data was analyzed using the SPSS software version 17.0. RESULTS: Mean age of respondents was 39.0 + 0.68 years, 211(51.5%) were male while 199 (48.5%) were females. 321(78.3%) worked in public health facilities. Majority of the respondents, 385 (94.0%), had good perception of quality of DOTs treatment received. These include good perception of communication (96.0%); of quality of care (90.4%), and good perception of staff attitude among 93.9% of respondents About 97% of the respondents had good satisfaction with the quality of DOTs treatment received. Good satisfaction was found among 98.3% in terms of adherence counseling received, 98.7% on TB treatment received and 98.7%, on waiting time spent, and these were far higher among private than public health facilities. Statistically significant association was found between the type of facility attended by respondents and having adherence counseling service and waiting period experienced (P-values < 0.05). Having received services in a private health facility is the major predictor of favourable perception and good satisfaction with quality of DOTS treatment among respondents studied. CONCLUSION: Though perception of and satisfaction with service delivery were good, this was better in private than in public; thus stressing the need for better monitoring and evaluation of services rendered by health care workers in order to encourage patronage by clients.

Nitrite-induced testicular toxicity in rats: therapeutic potential of walnut oil.

OBJECTIVE: To determine the impact of walnut oil on nitrite-induced testicular toxicity in Sprague-Dawley (SD) rats. Available evidence suggests that walnut oil contains high levels of important unsaturated fatty acids including alpha-linolenic acid (ALA) and omega-3; nitrite is a reproductive toxicant that causes the loss of germ cells in the seminiferous tubules and generates oxidative stress in the testes, thus reducing sperm counts and affecting sperm morphology. METHODS: This study included 24 male and 24 female adult SD rats. The male rats randomly assigned to Group A (controls) were given normal saline 2 ml/kg. The rats in Groups B, C, and D were given 50mg/kg body weight (bwt) of walnut oil, 0.08 mg/kg bwt of nitrite, and 0.08 mg/kg bwt of nitrite + 50 mg/kg of walnut oil respectively for 28 days via gastric gavage. Tested parameters included: testicular histology, sperm parameters, reproductive hormones, fertility, malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione, and catalase (CAT). RESULTS: A severe decrease in spermatogenic cell series, hypocellularity, tubular atrophy, decreased sperm quality, and increased MDA levels were observed in the rats given nitrite only when compared to controls. Rats given 50 mg/kg of walnut oil had significant growth of seminiferous epithelium compared to controls. The rats given walnut oil and nitrite had significant growth of seminiferous epithelium, improved sperm quality, and had decreased MDA levels. CONCLUSION: Walnut oil attenuated the deleterious effects of nitrite to the testes, reduced oxidative stress, and promoted spermatogenesis.

Genomic analyses in African populations identify novel risk loci for cleft palate.

Orofacial clefts are common developmental disorders that pose significant clinical, economical and psychological problems. We conducted genome-wide association analyses for cleft palate only (CPO) and cleft lip with or without palate (CL/P) with ~17 million markers in sub-Saharan Africans. After replication and combined analyses, we identified novel loci for CPO at or near genome-wide significance on chromosomes 2 (near CTNNA2) and 19 (near SULT2A1). In situ hybridization of Sult2a1 in mice showed expression of SULT2A1 in mesenchymal cells in palate, palatal rugae and palatal epithelium in the fused palate. The previously reported 8q24 was the most significant locus for CL/P in our study, and we replicated several previously reported loci including PAX7 and VAX1.

Identification of paternal uniparental disomy on chromosome 22 and a de novo deletion on chromosome 18 in individuals with orofacial clefts.

BACKGROUND: Orofacial clefts are the most common malformations of the head and neck region. Genetic and environmental factors have been implicated in the etiology of these traits. METHODS: We recently conducted genotyping of individuals from the African population using the multiethnic genotyping array (MEGA) to identify common genetic variation associated with nonsyndromic orofacial clefts. The data cleaning of this dataset allowed for screening of annotated sex versus genetic sex, confirmation of identify by descent and identification of large chromosomal anomalies. RESULTS: We identified the first reported orofacial cleft case associated with paternal uniparental disomy (patUPD) on chromosome 22. We also identified a de novo deletion on chromosome 18. In addition to chromosomal anomalies, we identified cases with molecular karyotypes suggesting Klinefelter syndrome, Turner syndrome and Triple X syndrome. CONCLUSION: Observations from our study support the need for genetic testing when clinically indicated in order to exclude chromosomal anomalies associated with clefting. The identification of these chromosomal anomalies and sex aneuploidies is important in genetic counseling for families that are at risk. Clinicians should share any identified genetic findings and place them in context for the families during routine clinical visits and evaluations.

Novel GREM1 Variations in Sub-Saharan African Patients With Cleft Lip and/or Cleft Palate.

OBJECTIVE: Cleft lip and/or cleft palate (CL/P) are congenital anomalies of the face and have multifactorial etiology, with both environmental and genetic risk factors playing crucial roles. Though at least 40 loci have attained genomewide significant association with nonsyndromic CL/P, these loci largely reside in noncoding regions of the human genome, and subsequent resequencing studies of neighboring candidate genes have revealed only a limited number of etiologic coding variants. The present study was conducted to identify etiologic coding variants in GREM1, a locus that has been shown to be largely associated with cleft of both lip and soft palate. PATIENTS AND METHOD: We resequenced DNA from 397 sub-Saharan Africans with CL/P and 192 controls using Sanger sequencing. Following analyses of the sequence data, we observed 2 novel coding variants in GREM1. These variants were not found in the 192 African controls and have never been previously reported in any public genetic variant database that includes more than 5000 combined African and African American controls or from the CL/P literature. RESULTS: The novel variants include p.Pro164Ser in an individual with soft palate cleft only and p.Gly61Asp in an individual with bilateral cleft lip and palate. The proband with the p.Gly61Asp GREM1 variant is a van der Woude (VWS) case who also has an etiologic variant in IRF6 gene. CONCLUSION: Our study demonstrated that there is low number of etiologic coding variants in GREM1, confirming earlier suggestions that variants in regulatory elements may largely account for the association between this locus and CL/P.

Hematological and plasma chemistry values for the African rock python (Python sebae).

Hematology and plasma biochemistry parameters are useful in the assessment and management of threatened and endangered species. Although reference values are readily available for many mammalian species, reference values for snakes are lacking for most species. We determined hematology and plasma biochemistry values for captive African rock pythons (Python sebae) and studied the effects of age, sex, season and hemoparasites on these values. Blood (5 mL) was collected by venipuncture of ventral coccygeal vein from 19 African rock pythons in rainy season and 14 snakes from the same population in dry season. There was no significant statistical difference (P < .05) between males and females to any of the parameters measured except total calcium in the rainy season. Significantly higher values were obtained (P < .05) for the white blood cells (WBC), heterophils, lymphocytes, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and aspartate aminotransferase (AST) in the dry versus the rainy seasons while there were significantly lower values obtained for red blood cells (RBC), glucose and total protein. Statistically significant differences in lymphocyte and monocyte counts were however found between adult and juvenile snakes. Differences in parameters for hepatozoon positive and hepatozoon negative snakes were not statistically significant although parameters like the total WBC count, heterophils and lymphocytes were markedly higher for hepatozoon positive snakes while packed cell volume (PCV) was slightly lower. This is the first study on blood parameters of the African rock python and serves as first pilot values for clinical assessments and future studies of this species.

A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13.

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.

Homogeneous Photocatalytic H2 Production Using a RuII Bathophenanthroline Metal-to-Ligand Charge-Transfer Photosensitizer.

The prototypical [Ru(bpy)3 ]2+ (bpy=2,2'-bipyridine) photosensitizer has been previously demonstrated to be labile in aqueous photocatalytic solutions, especially in the presence of coordinating electron donors. Here, an alternative RuII molecular sensitizer, [Ru(dpp)3 ]2+ (dpp=4,7-diphenyl-1,10-phenanthroline or bathophenanthroline), is described, which is considerably more stable than its bpy congener, allowing enhanced photocatalysis metrics in conjunction with a cobalt glyoxime ([Co(dmgH)2 pyCl], dmgH=dimethylglyoxime, py=pyridine) water reduction catalyst and N,N-dimethyl-p-toluidine (DMT) as the sacrificial donor in a 1:1 mixture of CH3 CN/H2 O. Photoluminescence studies revealed that DMT reductively quenches the excited state of [Ru(dpp)3 ]2+ with a bimolecular rate constant of kq =4.9×109 m-1 s-1 . The rate constant measured for electron transfer from the reduced sensitizer to the [Co(dmgH)2 pyCl] was found to be near the diffusion limit, kCo =2.4×109 m-1 s-1 . H2 production by photocatalysis was independently monitored by using a high-throughput photochemical reactor equipped with pressure transducers, gas chromatogram, and a mass spectrometer for detection; this illustrated that the composition yields high turnover numbers (TONs), approaching 10 000 (H2 /Ru) with respect to the sensitizer and deuteration studies using D2 O confirmed that H2 is primarily produced from protons derived from water in these systems.

Homogeneous Photocatalytic H2 Production Using a RuII Bathophenanthroline Metal-to-Ligand Charge-Transfer Photosensitizer.

Invited for this month's cover are the research groups of Prof. Rony S. Khnayzer at Lebanese American University and Prof. Felix (Phil) N. Castellano at North Carolina State University. The cover picture illustrates the absorption of visible light by a ruthenium bathophenanthroline MLCT chromophore followed by a sequence of electron transfer steps that ultimately leads to the efficient production of hydrogen gas from water. Read the full text of the article at 10.1002/cplu.201600227.