Molecular Mechanisms Driving Switch Behavior in Xylem Cell Differentiation.

Plant xylem cells conduct water and mineral nutrients. Although most plant cells are totipotent, xylem cells are unusual and undergo terminal differentiation. Many genes regulating this process are well characterized, including the Vascular-related NAC Domain 7 (VND7), MYB46, and MYB83 transcription factors, which are proposed to act in interconnected feedforward loops (FFLs). Less is known regarding the molecular mechanisms underlying the terminal transition to xylem cell differentiation. Here, we generate whole-root and single-cell data, which demonstrate that VND7 initiates sharp switching of root cells to xylem cell identity. Based on these data, we identified 4 candidate VND7 downstream target genes capable of generating this switch. Although MYB46 responds to VND7 induction, it is not among these targets. This system provides an important model to study the emergent properties that may give rise to totipotency relative to terminal differentiation and reveals xylem cell subtypes

Enhancing Nurse and Resident Collaboration (ENCORE)

Primary outcome: Improve nurse and resident communication; strengthen the working relationship between residents and nurses. Secondary outcomes: Improve patient outcomes; improve job satisfaction; increase nurse retention.https://scholarlycommons.henryford.com/nursresconf2021/1003/thumbnail.jp

Arsenic Triglutathione [As(GS) 3 ] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23

ABSTRACT The ATP-binding cassette (ABC) transporter multidrug resistance protein 1 (MRP1/ABCC1) is responsible for the cellular export of a chemically diverse array of xenobiotics and endogenous compounds. Arsenic, a human carcinogen, is a high-affinity MRP1 substrate as arsenic triglutathione [As(GS) 3 ]. In this study, marked differences in As(GS) 3 transport kinetics were observed between MRP1-enriched membrane vesicles prepared from human embryonic kidney 293 (HEK) (K m 3.8 mM and V max 307 pmol/mg per minute) and HeLa (K m 0.32 mM and V max 42 pmol/mg per minute) cells. Mutant MRP1 lacking N-linked glycosylation [Asn19/23/1006Gln; sugar-free (SF)-MRP1] expressed in either HEK293 or HeLa cells had low K m and V max values for As(GS) 3 , similar to HeLa wild-type (WT) MRP1. When prepared in the presence of phosphatase inhibitors, both WT-and SF-MRP1-enriched membrane vesicles had a high K m value for As(GS) 3 (3-6 mM), regardless of the cell line. Kinetic parameters of As(GS) 3 for HEKAsn19/23Gln-MRP1 were similar to those of HeLa/HEK-SF-MRP1 and HeLa-WT-MRP1, whereas those of single glycosylation mutants were like those of HEK-WT-MRP1. Mutation of 19 potential MRP1 phosphorylation sites revealed that HEK-Tyr920Phe/ Ser921Ala-MRP1 transported As(GS) 3 like HeLa-WT-MRP1, whereas individual HEK-Tyr920Phe-and -Ser921Ala-MRP1 mutants were similar to HEK-WT-MRP1. Together, these results suggest that Asn19/Asn23 glycosylation and Tyr920/Ser921 phosphorylation are responsible for altering the kinetics of MRP1-mediated As(GS) 3 transport. The kinetics of As(GS) 3 transport by HEK-Asn19/23Gln/Tyr920Glu/Ser921Glu were similar to HEK-WT-MRP1, indicating that the phosphorylation-mimicking substitutions abrogated the influence of Asn19/23Gln glycosylation. Overall, these data suggest that cross-talk between MRP1 glycosylation and phosphorylation occurs and that phosphorylation of Tyr920 and Ser921 can switch MRP1 to a lower-affinity, higher-capacity As(GS) 3 transporter, allowing arsenic detoxification over a broad concentration range

A distributed geospatial approach to describe community characteristics for multisite studies

Understanding place-based contributors to health requires geographically and culturally diverse study populations, but sharing location data is a significant challenge to multisite studies. Here, we describe a standardized and reproducible method to perform geospatial analyses for multisite studies. Using census tract-level information, we created software for geocoding and geospatial data linkage that was distributed to a consortium of birth cohorts located throughout the USA. Individual sites performed geospatial linkages and returned tract-level information for 8810 children to a central site for analyses. Our generalizable approach demonstrates the feasibility of geospatial analyses across study sites to promote collaborative translational research

Clinical and genetic characterisation of dystrophin-deficient muscular dystrophy in a family of Miniature Poodle dogs

Four full-sibling intact male Miniature Poodles were evaluated at 4–19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog

Strengthening the emergency healthcare system for mothers and children in The Gambia

A system to improve the management of emergencies during pregnancy, childbirth, infancy and childhood in a region of The Gambia (Brikama) with a population of approximately 250,000 has been developed

Prospective Associations of Coronary Heart Disease Loci in African Americans Using the MetaboChip: The PAGE Study

Background: Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans. Methods and Results: Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10−8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium. Conclusions: Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans

Large‐scale modelling of deep‐diving cetacean habitats

Versión del editor5,14

Weight Care Project: Health professionals' attitudes and ability to assess body weight status - Study protocol

<p>Abstract</p> <p>Background</p> <p>Health professionals working in primary care and public health have opportunities to address body weight status issues with their patients through face-to-face contact. The objectives of this all-Ireland project are: 1. to assess the attitudes, current practices/behaviours and knowledge of key health professional groups on body weight status; 2. to assess the health professional groups' ability to identify body weight status in both adults and children. The health professional groups are: (a) community related public health nurses; (b) school public health nurses; (c) GPs and practice nurses (primary care); and (d) occupational health nurses (workplace) from both Northern Ireland and the Republic of Ireland.</p> <p>Methods/Design</p> <p>This all-Ireland multi-disciplinary project follows a mixed methods approach using both quantitative and qualitative methodologies, and consists of four components:</p> <p>1. Literature review - to explore the role of health professionals in managing obesity through spontaneous intervention in a variety of health promotion settings.</p> <p>2. Telephone interviews and focus groups - to gain an in-depth insight into the views of health professionals in assessing body weight status.</p> <p>3. Survey (primarily online but also paper-based) - to determine the attitudes, current practices/behaviours and knowledge of health professionals in assessing body weight status.</p> <p>4. Online evaluation study - an online interactive programme will be developed to assess health professionals' ability to identify the body weight status of adults and children.</p> <p>Discussion</p> <p>This project will assess and report the attitudes, current practices/behaviours and knowledge of key health professional groups within Northern Ireland and the Republic of Ireland on body weight status, and their ability to identify body weight status in both adults and children. The results of this project will generate recommendations for clinical practice in managing obesity, which may inform policy guidelines.</p

The effect of LRRK2 loss-of-function variants in humans

Analysis of large genomic datasets, including gnomAD, reveals that partial LRRK2 loss of function is not strongly associated with diseases, serving as an example of how human genetics can be leveraged for target validation in drug discovery. Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes(1,2). Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease(3,4), suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns(5-8), the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)(9), 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work(10), confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.Peer reviewe