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UFGI publication round-up week 3/12

Mol Reprod Dev. 2018 Mar 15. doi: 10.1002/mrd.22976. [Epub ahead of print]

Role of ROCK Signaling in Formation of the Trophectoderm of the Bovine Preimplantation Embryo.

Author information

1
Department of Animal Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program and Genetics Institute, University of Florida, Gainesville, Florida, USA.
2
Laboratory of Reproductive Physiology, Department of Animal Health, School of Veterinary Medicine, UNESP-Universidade Estadual Paulista, Araçatuba, São Paulo, Brazil and Post-Graduate Program in Veterinary Medicine, School of Agrarian and Veterinary Sciences, Department of Animal Reproduction, UNESP-Universidade Estadual Paulista, Jaboticabal, São Paulo, Brazil.

Abstract

Rho-associated coiled-coil containing protein kinases (ROCK1 and ROCK2) are activated by binding to RHO GTPases and phosphorylate a variety of downstream targets including actinomyosin. In the mouse embryo, ROCK signaling acts to promote formation of trophectoderm (TE) and inhibit formation of the inner cell mass (ICM) by polarizing outer cells of the embryo to inactivate Hippo signaling (Kono et al., 2014; Mihajlović and Bruce, 2016). This article is protected by copyright. All rights reserved.

 

 

Sci Rep. 2018 Mar 14;8(1):4529. doi: 10.1038/s41598-018-22574-5.

Application of a Genetic Risk Score to Racially Diverse Type 1 Diabetes Populations Demonstrates the Need for Diversity in Risk-Modeling.

Author information

1
Departments of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Gainesville, Florida, USA.
2
Institute for Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
3
National Institute for Health Research, Exeter Clinical Research Facility, Exeter, UK.
4
Department of Pediatrics, Emory University, Atlanta, GA, USA.
5
Department of Pediatrics, College of Medicine, Gainesville, Florida, USA.
6
Departments of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Gainesville, Florida, USA. tbrusko@ufl.edu.

Abstract

Prior studies identified HLA class-II and 57 additional loci as contributors to genetic susceptibility for type 1 diabetes (T1D). We hypothesized that race and/or ethnicity would be contextually important for evaluating genetic risk markers previously identified from Caucasian/European cohorts. We determined the capacity for a combined genetic risk score (GRS) to discriminate disease-risk subgroups in a racially and ethnically diverse cohort from the southeastern U.S. including 637 T1D patients, 46 at-risk relatives having two or more T1D-related autoantibodies (≥2AAb+), 790 first-degree relatives (≤1AAb+), 68 second-degree relatives (≤1 AAb+), and 405 controls. GRS was higher among Caucasian T1D and at-risk subjects versus ≤ 1AAb+ relatives or controls (P < 0.001). GRS receiver operating characteristic AUC (AUROC) for T1D versus controls was 0.86 (P < 0.001, specificity = 73.9%, sensitivity = 83.3%) among all Caucasian subjects and 0.90 for Hispanic Caucasians (P < 0.001, specificity = 86.5%, sensitivity = 84.4%). Age-at-diagnosis negatively correlated with GRS (P < 0.001) and associated with HLA-DR3/DR4 diplotype. Conversely, GRS was less robust (AUROC = 0.75) and did not correlate with age-of-diagnosis for African Americans. Our findings confirm GRS should be further used in Caucasian populations to assign T1D risk for clinical trials designed for biomarker identification and development of personalized treatment strategies. We also highlight the need to develop a GRS model that accommodates racial diversity.

 

 

Eur J Clin Pharmacol. 2018 Mar 13. doi: 10.1007/s00228-018-2439-z. [Epub ahead of print]

Conflicting meal recommendations for oral oncology drugs: pose risks to patient care?

Yu G1,2,3Wu DN4Gong Y2Li GF5,6,7Zhou HH3.

Author information

1
Subei People’s Hospital, Yangzhou University, Yangzhou, 225001, China.
2
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA.
3
Institute of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410078, China.
4
Department of Pharmacy, Hainan General Hospital, Haikou, China.
5
Subei People’s Hospital, Yangzhou University, Yangzhou, 225001, China. guofu.g.li@gmail.com.
6
Department of Pharmaceutics, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA. guofu.g.li@gmail.com.
7
Center for Drug Clinical Research, Shanghai University of Chinese Medicine, Shanghai, 201203, China. guofu.g.li@gmail.com.

Abstract

PURPOSE:

The labeling information, authorized by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), is expected to guide the method of drug administration with reference to meal intake, aiming at ensuring favorable safety profile and achieving optimal drug exposure. However, interactions between meals and a specific oral anticancer medication are complicated in that could be strongly affected by inter-individual variability in pharmacokinetics, meal compositions, and the timing of drug administration with respect to meal intake, which could lead to conflicting meal recommendations between regulatory authorities. The primary objective of this article was to systemically identify the conflicting food recommendations for oral antineoplastic drugs and explore the potential risks associated with these conflicting recommendations to patient-centered care.

METHODS:

We revisited, compared, and analyzed systemically the publicly accessible regulatory documents of the orally administered, anticancer drugs from the FDA and the EMA.

RESULTS:

After revisiting the labeling information and other regulatory documents of 43 oral oncology agents authorized by FDA during 2010-2016 and by the EMA at the time of this analysis finalized (December 2017), conflicting or inconsistent meal recommendations between the EMA and FDA were identified in 14% (6 of 43) oral anticancer drugs.

CONCLUSION:

Conflicting food recommendations between regulatory authorities could have a large impact on anticancer treatment and patients’ quality of life, leading to suboptimal clinical outcomes. As the most important source of dosing instructions, the labeling information should be regularly recalibrated to provide consistent and informative instructions for drug intake in relation to meals, minimizing unintended interactions with meals and improving patient compliance and adherence. Further efforts on harmonizing food recommendations between regulatory agencies are highly warranted to assure optimal outcomes for individual patients. Moreover, meal-drug interaction studies should be conducted as early as possible to inform the dosing schedules of the subsequent phase 2 and phase 3 trials, thereby facilitating regulatory decision-making in regard to the method of drug administration.

 

 

J Clin Hypertens (Greenwich). 2018 Mar 13. doi: 10.1111/jch.13247. [Epub ahead of print]

Intensive blood pressure lowering reduces adverse cardiovascular outcomes among patients with high-normal glucose: An analysis from the Systolic Blood Pressure Intervention Trial database.

Author information

1
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
2
Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
3
UF Health Cancer Center, University of Florida, Gainesville, FL, USA.
4
Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, USA.

Abstract

The objective of this analysis is to determine the effect of intensive (<120 mm Hg) versus standard (<140 mm Hg) systolic blood pressure (SBP) targets on cardiovascular (CV) outcomes among SPRINT participants with low-normal or high-normal fasting glucose (FG). We categorized the 5425 SPRINT participants with FG <100 mg/dL into 2 groups: <85 mg/dL (low-normal) and 85 to <100 mg/dL (high-normal). Among participants with low-normal glucose, there was no significant difference in the primary outcome (PO) between the 2 treatment arms (adjusted hazard ratio, HR: 1.27 (95% confidence interval [CI] 0.68-2.37, P = .46). However, the intensive SBP target was associated with 27% lower risk for the PO compared with the standard SBP target in those with high-normal glucose (HR 0.73, 0.57-0.93, P = .01). Our results indicate that hypertensive patients with high-normal FG may benefit from intensive SBP lowering, whereas benefits were inconclusive among those with low-normal FG.

 

 

Plant Cell Environ. 2018 Mar 13. doi: 10.1111/pce.13195. [Epub ahead of print]

UPLC-HRMS based Untargeted Metabolic Profiling Reveals Changes in Chickpea (Cicer arietinum) Metabolome following Long-Term Drought Stress.

Author information

1
Department of Plant Sciences, Quaid-I-Azam University, Islamabad, Pakistan.
2
Department of Biosciences, University of Wah, Wah Cantt, Pakistan.
3
Department of Agronomy, IFAS, University of Florida, Gainesville, USA.
4
Horticulture Science Department, IFAS, University of Florida, Gainesville, USA.

Abstract

Genetic improvement for drought tolerance in chickpea requires a solid understanding of biochemical processes involved with different physiological mechanisms. The objective of this study is to demonstrate genetic variations in altered metabolic levels in chickpea varieties (tolerant and sensitive) grown under contrasting water regimes through UPLC-HRMS based untargeted metabolomic profiling. Chickpea plants were exposed to drought stress at the three-leaf stage for 25 days and the leaves were harvested at 14 days and 25 days after the imposition of drought stress. Stress produced significant reduction in chlorophyll content, Fv/Fm, RWC, and shoots and root dry weight. Twenty known metabolites were identified as most important by two different methods including SAM and PLS-DA. The most pronounced increase in accumulation due to drought stress was demonstrated for allantoin, L-proline, L-arginine, L-histidine, L-isoleucine, and tryptophan. Metabolites which showed decreased level of accumulation under drought condition were choline, phenylalanine, GABA, alanine, phenylalanine, tyrosine, glucosamine, guanine, and aspartic acid. Aminoacyl-tRNA and plant secondary metabolite biosynthesis, and amino acid metabolism or synthesis pathways were involved in producing genetic variation under drought condition. Metabolic changes in light of drought conditions highlighted pools of metabolites that affect the metabolic and physiological adjustment in chickpea that reduced drought impacts.

 

 

Nat Genet. 2018 Mar 12. doi: 10.1038/s41588-018-0058-3. [Epub ahead of print]

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Abstract

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

 

 

Arch Insect Biochem Physiol. 2018 Mar 12. doi: 10.1002/arch.21459. [Epub ahead of print]

Proteases and nucleases involved in the biphasic digestion process of the brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae).

Author information

1
Department of Entomology, Iowa State University, Ames, USA.
2
Department of Entomology and Nematology, University of Florida, Gainesville, USA.

Abstract

Management of the brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), an invasive, agricultural pest in the United States, has presented significant challenges. This polyphagous insect uses both extra-oral and gut-based digestion thwarting protein- or nucleotide-based control strategies. The objective of this study was to biochemically characterize the digestive enzymes (proteases and nucleases) from the saliva, salivary gland and the gut of H. halys. Enzyme profiles for the two tissues and saliva radically differ: The pH optimum for proteases in the gut was six, with cysteine proteases predominant. In contrast, the alkaline pH optima for protease activity in the salivary gland (8-10) and saliva (7) reflected abundant serine protease and cathepsin activities. RNase enzymes were most abundant in saliva, while dsRNase and DNase activities were higher in the salivary gland and saliva compared to those in the gut. These very different enzyme profiles highlight the biphasic digestive system used by this invasive species for efficient processing of plant nutrients. Knowledge of H. halys digestive physiology will allow for counteractive measures targeting digestive enzymes or for appropriate protection of protein- or nucleotide-based management options targeting this pest.

 

 

J Am Chem Soc. 2018 Mar 13. doi: 10.1021/jacs.7b11311. [Epub ahead of print]

Nongenetic Approach for Imaging Protein Dimerization by Aptamer Recognition and Proximity-Induced DNA Assembly.

Liang H1Chen S1Li P1Wang L1Li J2Li J1,3Yang HH1,2Tan W3,4.

Author information

1
MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry , Fuzhou University , Fuzhou 350116 , People’s Republic of China.
2
College of Biological Science and Engineering , Fuzhou University , Fuzhou 350116 , People’s Republic of China.
3
Institute of Molecular Medicine, Renji Hospital , Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University , Shanghai , 200240 , People’s Republic of China.
4
Department of Chemistry and Department of Physiology and Functional Genomics, Center for Research at the Bio/Nano Interface, UF Health Cancer Center , University of Florida , Gainesville , Florida 32611-7200 , United States.

Abstract

Herein, we report a nongenetic and real-time approach for imaging protein dimerization on living cell surfaces by aptamer recognition and proximity-induced DNA assembly. We use the aptamer specific for the receptor monomer as a recognition probe. When receptor dimerization occurs, the dimeric receptors bring two aptamer probes into close proximity, thereby triggering dynamic DNA assembly. The proposed approach was successfully applied to visualize dimerization of Met receptor and transforming growth factor-β type II receptor. This approach allows us to image the two states (monomer/dimer) of a receptor protein on living cell surfaces in real time, opening a universal method for further investigation of protein dimerization and the corresponding activation processes in signal transduction.

 

 

J Virol. 2018 Feb 26;92(6). pii: e01884-17. doi: 10.1128/JVI.01884-17. Print 2018 Mar 15.

The ATM and Rad3-Related (ATR) Protein Kinase Pathway Is Activated by Herpes Simplex Virus 1 and Required for Efficient Viral Replication.

Author information

1
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, USA.
2
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, Florida, USA ctopherfis@ufl.edu.

Abstract

The ATM and Rad3-related (ATR) protein kinase and its downstream effector Chk1 are key sensors and organizers of the DNA damage response (DDR) to a variety of insults. Previous studies of herpes simplex virus 1 (HSV-1) showed no evidence for activation of the ATR pathway. Here we demonstrate that both Chk1 and ATR were phosphorylated by 3 h postinfection (h.p.i.). Activation of ATR and Chk1 was observed using 4 different HSV-1 strains in multiple cell types, while a specific ATR inhibitor blocked activation. Mechanistic studies point to early viral gene expression as a key trigger for ATR activation. Both pATR and pChk1 localized to the nucleus within viral replication centers, or associated with their periphery, by 3 h.p.i. Significant levels of pATR and pChk1 were also detected in the cytoplasm, where they colocalized with ICP4 and ICP0. Proximity ligation assays confirmed that pATR and pChk1 were closely and specifically associated with ICP4 and ICP0 in both the nucleus and cytoplasm by 3 h.p.i., but not with ICP8 or ICP27, presumably in a multiprotein complex. Chemically distinct ATR and Chk1 inhibitors blocked HSV-1 replication and infectious virion production, while inhibitors of ATM, Chk2, and DNA-dependent protein kinase (DNA-PK) did not. Together our data show that HSV-1 activates the ATR pathway at early stages of infection and that ATR and Chk1 kinase activities play important roles in HSV-1 replication fitness. These findings indicate that the ATR pathway may provide insight for therapeutic approaches.IMPORTANCE Viruses have evolved complex associations with cellular DNA damage response (DDR) pathways, which sense troublesome DNA structures formed during infection. The first evidence for activation of the ATR pathway by HSV-1 is presented. ATR is activated, and its downstream target Chk1 is robustly phosphorylated, during early stages of infection. Both activated proteins are found in the nucleus associated with viral replication compartments and in the cytoplasm associated with viral proteins. We also demonstrate that both ATR and Chk1 kinase activities are important for viral replication. The findings suggest that HSV-1 activates ATR and Chk1 during early stages of infection and utilizes the enzymes to promote its own replication. The observation may be exploitable for antiviral approaches.

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