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Analysis of the combined effect of rs699 and rs5051 on angiotensinogen expression and hypertension

Chronic Diseases and translational Medicine 2024年第2期10卷 102-117页

作者： Nicholas R.powell tyler Shugg jacob Leighty Matthew Martin Rolf p.Kreutz Michael t.Eadon Dongbing Lai tao Lu todd C.Skaar Division of Clinical pharmacology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of pharmacology and toxicology School of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Cardiology School of MedicineKrannert Institute of CardiologyIndiana UniversityIndianapolisIndianaUSA Division of Nephrology Department of MedicineSchool of MedicineIndiana UniversityIndianapolisIndianaUSA Department of Medical and Molecular Genetics School of MedicineIndiana UniversityIndianapolisIndianaUSA

Background Hypertension(HtN)involves genetic variability in the renin-angiotensin system and influences antihypertensive *** previously reported that angiotensinogen(AGt)messenger RNA(mRNA)is endogenously bound by miR-122-5p and rs699 A>G decreases reporter mRNA in the microRNA functional-assay *** AGt promoter variant rs5051 C>t is in linkage disequilibrium(LD)with rs699 A>G and increases AGt *** independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased AGt by rs5051 C>t counterbalances AGt decreased by rs699 A>G,and when these variants occur independently,it translates to HtN-related *** We used in silico,in vitro,in vivo,and retrospective models to test this *** In silico,rs699 A>G is predicted to increase miR-122-5p binding affinity by 3%.Mir-eCLIp results show rs699 is 40–45 nucleotides from the strongest microRNA-binding site in the AGt ***,rs699 A>G increases AGt mRNA in an AGt-plasmid-cDNA HepG2 expression ***-tissue Expression(GtEx)and UK Biobank analyses demonstrate liver AGt expression and HtN phenotypes are not different when rs699 A>G occurs independently from rs5051 C>***,GtEx and the in vitro experiments suggest rs699 A>G confers cell-type-specific effects on AGt mRNA abundance,and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A>G associations with *** We found that rs5051 C>t and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank,demonstrating a fourfold larger effect than in White *** studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C>t or rs699 A>*** like this will help clinicians move beyond the use of race as a surrogate for genotype.

关键词： angiotensinogen genetic and genomic medicine hypertension rs699

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Aging impairs the osteocytic regulation of collagen integrity and bone quality

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Bone Research 2024年第1期12卷 78-94页

作者： Charles A.Schurman Serra Kaya Neha Dole Nadja M.Maldonado Luna Natalia Castillo Ryan potter jacob p.Rose Joanna Bons Christina D.King Jordan B.Burton Birgit Schilling Simon Melov Simon tang Eric Schaible tamara Alliston Department of Orthopaedic Surgery University of CaliforniaSan FranciscoCA 94143USA UC Berkeley/UCSF Graduate program in Bioengineering San FranciscoCA 94143USA Buck Institute for Research on Aging NovatoCA 94945USA Washington University in St Louis Department of OrthopedicsSt.LouisMO 63130USA Advanced Light Source Lawrence Berkeley National LaboratoryBerkeleyCA 94720USA

poor bone quality is a major factor in skeletal fragility in elderly *** molecular mechanisms that establish and maintain bone quality,independent of bone mass,are unknown but are thought to be primarily determined by *** hypothesize that the age-related decline in bone quality results from the suppression of osteocyte perilacunar/canalicular remodeling(pLR),which maintains bone material *** examined bones from young and aged mice with osteocyte-intrinsic repression of tGFβsignaling(tβRII^(ocy−/−))that suppresses *** control aged bone displayed decreased tGFβsignaling and pLR,but aging did not worsen the existing pLR suppression in male tβRII^(ocy−/−)*** relationship impacted the behavior of collagen material at the nanoscale and tissue scale in macromechanical *** effects of age on bone mass,density,and mineral material behavior were independent of osteocytic tGFβ.We determined that the decline in bone quality with age arises from the loss of osteocyte function and the loss of tGFβ-dependent maintenance of collagen integrity.

关键词： maintain primarily integrity

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Inbreeding and genetic load in a pair of sibling grouse species:tetrastes sewersowi and ***

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Avian Research 2024年第2期15卷 265-270页

作者： Kai Song tom van der Valk Bin Gao peter Halvarsson Yun Fang Wendong Xie Siegfried Klaus Zhiming Han Yue-Hua Sun jacob Hoglund Key Laboratory of Animal Ecology and Conservation Biology Institute of ZoologyChinese Academy of SciencesBeijing100101China Animal Ecology Department of Ecology and GeneticsUppsala UniversityNorbyvagen 18DUppsala75236Sweden Department of Cell and Molecular Biology Uppsala75273Sweden Unit of parasitology Department of Biomedicine and Veterinary Public HealthSwedish University of Agricultural SciencesPO Box 7036Uppsala75007Sweden Lindenhohe 5 JenaD-07749Germany the State Key Laboratory of Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing100101China

Genetic load and inbreeding are recognized as important factors to be considered in conservation *** levels of both can increase the risk of population extinction by negatively impacting fitness-related characters in many species of plants and animals,including humans(inbreeding depression).Genomic tech-niques are increasingly used in measuring and understanding genetic load and inbreeding and their importance in evolution and *** used whole genome resequencing data from two sibling grouse species in subarctic Eurasia to quantify *** found a large range of inbreeding measured as FROH(fraction of runs of homozygosity)in individuals from different populations of Chinese Grouse(tetrastes sewerzowi)and Hazel Grouse(***).FROH estimated from genome-wide runs of homozygosity(ROH)ranged from 0.02 to 0.24 among Chinese Grouse populations and from 0.01 to 0.44 in Hazel *** from a population of Chinese Grouse residing in the Qilian mountains and from the European populations of Hazel Grouse(including samples from Sweden,Germany and Northeast poland)were the most inbred(FROH ranged from 0.10 to 0.23 and 0.11 to 0.44,respectively).these levels are comparable to other highly inbred populations of *** Grouse from northern China and Chinese Grouse residing in the Qinghai-tibetan plateau showed relatively lower inbreeding *** of the ratio between deleterious missense mutations and synonymous mutations revealed higher levels in Chinese Grouse as compared to Hazel *** results are possibly explained by higher fixation rates,mutational melt down,in the range-restricted Chinese Grouse compared to the wide-ranging Hazel ***,when we compared the relatively more severe class of loss-of-function muta-tions,Hazel Grouse had slightly higher levels than Chinese Grouse,a result which may indicate that purifying selection(purging)has been more efficient in Chinese Grouse on this class of mutations.

关键词： Genetic load Inbreeding purifying selection Qinghai-tibetan plateau ROH tetrastes

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In vivo measurement of NADH fluorescence lifetime in skeletal muscle via -ber-coupled time-correlated single photon counting

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Journal of Innovative Optical Health Sciences 2024年第1期17卷 121-134页

作者： Kathryn M.priest jacob V.Schluns Nathania Nischal Colton L.Gattis Jeffrey C.Wolchok timothy J.Muldoon Department of Biomedical Engineering University of Arkansas FayettevilleARUSA

Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXpHOS).NADH is autofluorescent,and itsfluorescence lifetime can be used to infer metabolic dynamics in living ***-coupled time-correlated single photon counting(tCSpC)equipped with an implantable needle probe can be used to measure NADH lifetime in vivo,enabling investigation of changing metabolic demand during muscle contraction or tissue *** study illustrates a proof of concept for point-based,minimally-invasive NADHfluorescence lifetime measurement in *** muscle loss(VML)injuries were created in the left tibialis anterior(tA)muscle of male Sprague Dawley *** lifetime measurements were collected before,during,and after a 30 s tetanic contraction in the injured and uninjured tA muscles,which was subsequently-t to a biexponential decay model to yield a metric of NADH utilization(cytoplasmic vs protein-bound NADH,the A11/A22 ratio).On average,this ratio was higher during and after contraction in uninjured muscle compared to muscle at rest,suggesting higher levels of free NADH in contracting and recovering muscle,indicating increased rates of *** injured muscle,this ratio was higher than uninjured muscle overall but decreased over time,which is consistent with current knowledge of inflammatory response to injury,suggesting tissue regeneration has *** data suggest that-ber-coupled tCSpC has the potential to measure changes in NADH binding in vivo in a minimally invasive manner that requires further investigation.

关键词： Glycolysis oxidative phosphorylation energy metabolism volumetric muscle loss

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A molecular dynamics study of laser-excited gold

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Matter and Radiation at Extremes 2022年第3期7卷 20-30页

作者： jacob M.Molina t.G.White University of Nevada RenoNevada 89557USA

the structural evolution of laser-excited systems of gold has previously been measured through ultrafast MeV electron ***,there has been a long-standing inability of atomistic simulations to provide a consistent picture of the melting process,leading to large discrepancies between the predicted threshold energy density for complete melting,as well as the transition between heterogeneous and homogeneous *** make use of two-temperature classical molecular dynamics simulations utilizing three highly successful interatomic potentials and reproduce electron diffraction data presented by Mo et al.[Science 360,1451–1455(2018)].We recreate the experimental electron diffraction data,employing both a constant and temperature-dependent electron–ion equilibration *** all cases,we are able to match time-resolved electron diffraction data,and find consistency between atomistic simulations and experiments,only by allowing laser energy to be transported away from the interaction *** additional energy-loss pathway,which scales strongly with laser fluence,we attribute to hot electrons leaving the target on a timescale commensurate with melting。

关键词： diffraction. excited dynamics

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Risk of bias and reporting practices in studies comparing VO2max responses to sprint interval *** training:A systematic review and meta-analysis

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Journal of Sport and Health Science 2022年第5期11卷 552-566页

作者： jacob t.Bonafiglia Hashim Islam Nicholas preobrazenski Brendon J.Gurd School of Kinesiology and Health Studies Queen’s UniversityKingstonOntarioK7L 3N6Canada

Background:It remains unclear whether studies comparing _(max)imal oxygen uptake(VO_(2max))response to sprint interval training(SIt)***-intensity continuous training(MICt)are associated with a high risk of bias and poor reporting *** purpose of this study was to evaluate the risk of bias and quality of reporting in studies comparing changes in VO_(2max) between SIt and ***:We conducted a comprehensive literature search of 4 major databases:AMED,CINAHL,EMBASE,and *** were excluded if participants were not healthy adult humans or if training protocols were unsupervised,lasted less than 2 weeks,or utilized mixed exercise *** used the Cochrane Collaboration tool and the CONSORt checklist for non-pharmacological trials to evaluate the risk of bias and reporting quality,***:twenty-eight studies with 30 comparisons(3 studies included 2 SIt groups)were included in our meta-analysis(n=360 SIt participants:body mass index(BMI)=25.9±3.7 kg/m^(2),baseline VO_(2max)=37.9±8.0 mL/kg/min;n=359 MICt participants:BMI=25.5±3.8 kg/m^(2),baseline VO_(2max)=38.3±8.0 mL/kg/min;all mean±SD).All studies had an unclear risk of bias and poor reporting ***:Although we observed a lack of superiority between SIt and MICt for improving VO_(2max)(weighted Hedge’s g=0.004,95%con-fidence interval(95%CI):-0.08 to 0.07),the overall unclear risk of bias calls the validity of this conclusion into *** studies using robust study designs are needed to interrogate the possibility that SIt and MICt result in similar changes in VO_(2max).

关键词： Bias Cardiorespiratory fitness CONSORt Moderate-intensity continuous training Sprint interval training

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traumatic soft tissue defects:a perspective review on reconstruction and communication priorities from the orthopaedic trauma surgeon as a partner in care

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plastic and Aesthetic Research 2022年第1期9卷 284-294页

作者： Joseph t.patterson Haley Nakata jacob Becerra Andrew Duong Department of Orthopedic Surgery Keck School of Medicine of the University of Southern CaliforniaLos AngelesCA 90033USA

Communication and coordination between orthopedic and plastic surgeons improve outcomes in severe extremity ***“orthoplastics”approach to limb salvage incorporates priorities and skillsets from both *** of infection,coordinated skeletal and soft tissue reconstruction,and communication during recovery and rehabilitation are key *** purpose of this review is to describe the orthopedic trauma surgeon’s perspectives on lower extremity reconstruction,including initial management,techniques and timing for provisional and definitive skeletal reconstruction,and considerations for rehabilitation and orthotic use to optimize functional outcomes.

关键词： Orthopedic trauma limb salvage extremity trauma orthoplastic soft tissue reconstruction orthotics rehabilitation

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the Effects of 5 Weeks of Leg-Drive training on Bench press performance in Recreationally-trained,College-Age Men

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Journal of Science in Sport and Exercise 2022年第3期4卷 231-236页

作者： jacob K.Gardner Justin t.Chia Brent M.peterson Kelsey L.Miller Department of Kinesiology and Health Science Biola University13800 Biola AveLa MiradaCA 90639USA Department of Health and Human Development Western Washington University516 High StreetBellinghamWA 98225USA

Introduction the bench press is commonly used to measure upper-body *** much emphasis has been placed on the upper-body,little is known about how the lower-body can play a role in bench press ***-drive is a technique that includes flexing the knee so the feet line up posterior to the knee joint,while simultaneously contracting the knee extensors isometrically during the *** purpose of this study was to compare strength characteristics of lifters in a standard bench press versus a leg-drive bench press over the course of 5-weeks of *** twenty-three recreationally active males(age:22.4±2.1 years,height:175.0±5.9 cm,mass:78.4±9.5 kg)were randomized into a standard bench or leg-drive bench press *** performed four sets to failure,two times per week for five *** of interests were training volume and 1-repetition maximum(1RM)*** training volume,a 2×5(group×week)repeated measures analysis of variance(RMANOVA)was *** the 1RM’s,a 2×2×2(group×press type×time)RMANOVA was used.A priori alpha levels were set to *** Over time,both groups showed an approximate 6%increase in 1RM *** volume for week 4 was 5.6%less than week 5,but was not different from weeks 1 through *** between-group differences were observed for 1RM strength or training *** this results of this work indicates that 5 weeks of leg-drive training is effective in increasing 1RM strength,but was not more effective than standard bench press ***,lifters should choose either lifting style based on personal preference.

关键词： Chest press Lower-body Weight lifting Isometric contraction

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China＇s Belt and Road Initiative：perspectives from India

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China & World Economy 2017年第5期25卷 78-100页

作者： Jabin t. jacob Fellow Institute of Chinese Studies India

China ＂s Belt and Road Initiative （BRI） is often simplistically understood as beingopposed by lndia and supported by pakistan. the reality on the ground is rather morecomplex. the emerging consensus in lndia appears to be that, far from being exclusivelyan economic and infrastructure development program, the BRI may be understood as along-term strategic initiative that seeks to convert China ＂s current economic might intodiplomatic influence. While attempts have been made by Beijing, the reflexive lndiansuspicion of Chinese international projection, including of China ＂s BRL has not yetbeen met by a coherent discourse designed to specifically address lndian concerns. Incontrast, in pakistan, widespread acceptance of the importance and necessity of theChina-pakistan Economic Corridor is increasingly coupled with concerns within sectorsof pakistani society over the fairness, transparency and eventual economic outcomesof the project. Accordingly, this paper is divided into two parts： the first looks at howlndian analysts have viewed and responded to the Chinese discourse and arguments onthe BR1; the second considers the debate over the China-pakistan Economic Corridorwithin pakistan.

关键词： diplomacy, economic integration, infrastructure development, mutual mistrust, strategic competition

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In-vitro antioxidant and anti-inflammatory activities of ethanol stem-bark extract of Blighia sapida ***

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Journal of pharmaceutical Analysis 2022年第2期12卷 350-354页

作者： Mukaila B.Adekola jacob O.Areola Oladapo F.Fagbohun Funke t.Asaolu Gbenga E.Ogundepo Adeniyi O.Fajobi Olubunmi O.Babalola Department of Environmental Management and toxicology Federal University of AgricultureAbeokuta110001Nigeria Department of Medical Biochemistry Obafemi Awolowo UniversityIle-Ife230001Nigeria Department of Biomedical Engineering First Technical University IbadanOyo StateIbadan200001Nigeria Department of Biochemistry and Molecular Biology Obafemi Awolowo UniversityIle-Ife230001Nigeria

Blighia sapida(***)***(Family Sapindaceae)is a branchless straight bole approximately 15 m in *** study evaluated the antioxidant and anti-inflammatory activities of ethanol extract and fractions of *** stem-bark using in vitro *** extract and its fractions were investigated for 1,1-diphenyl-2-picrylhydrazyl(DppH)radical scavenging activity,ferric reducing antioxidant power(FRAp),total antioxidant capacity(tAC),and quantitative phenolic and flavonoid ***-inflammatory activity was evaluated using albumin denaturation and membrane stabilization *** extract and its fractions exhibited radical scavenging and anti-inflammatory *** ethyl acetate fraction possessed maximum phenolic and flavonoid contents(136.67±1.55 gallic acid equivalent mg/g and 75.76±4.03 quercetin equivalent mg/g,respectively).Antioxidant studies revealed that the ethyl acetate fraction displayed superior activity with an IC_(50)=0.09±0.03 mg/mL DppH,and values of 146.96±3.81 ascorbic acid equivalent(AAE)mg/g and 359.20±4.98 AAE mg/g for FRAp and tAC,***,the anti-inflammatory activity was revealed by inhibition of heatinduced albumin denaturation and red blood cell membrane stabilization at concentrations of 200 -1000 mg/mL and 50-250 mg/mL,*** ethanol extract and fractions exhibited antioxidant and anti-inflammatory activities,with ethyl acetate fraction showing superior activity,which could be attributed to secondary metabolites,mainly phenolic ***,the antioxidant and antiinflammatory activities of *** can be exploited by ethnomedicinal users.

关键词： Blighia sapida Extract Anti-inflammatory Antioxidant Radical scavenging

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