Miracle-dz/UniFAR-FTUs huggingface dataset:
Genome-Wide Association Mapping Combined with Reverse Genetics Identifies New Effectors of Low Water Potential-Induced Proline Accumulation in Arabidopsis1[W][OPEN]

Genome-wide association analysis and spatial patterning of single-nucleotide polymorphism data guide reverse genetics to identify new genes linking stress-induced proline accumulation with cellular redox and energy status. Arabidopsis (Arabidopsis thaliana) exhibits natural genetic variation in drought response, including varying levels of proline (Pro) accumulation under low water potential. As Pro accumulation is potentially important for stress tolerance and cellular redox control, we conducted a genome-wide association (GWAS) study of low water potential-induced Pro accumulation using a panel of natural accessions and publicly available single-nucleotide polymorphism (SNP) data sets. Candidate genomic regions were prioritized for subsequent study using metrics considering both the strength and spatial clustering of the association signal. These analyses found many candidate regions likely containing gene(s) influencing Pro accumulation. Reverse genetic analysis of several candidates identified new Pro effector genes, including thioredoxins and several genes encoding Universal Stress Protein A domain proteins. These new Pro effector genes further link Pro accumulation to cellular redox and energy status. Additional new Pro effector genes found include the mitochondrial protease LON1, ribosomal protein RPL24A, protein phosphatase 2A subunit A3, a MADS box protein, and a nucleoside triphosphate hydrolase. Several of these new Pro effector genes were from regions with multiple SNPs, each having moderate association with Pro accumulation. This pattern supports the use of summary approaches that incorporate clusters of SNP associations in addition to consideration of individual SNP probability values. Further GWAS-guided reverse genetics promises to find additional effectors of Pro accumulation. The combination of GWAS and reverse genetics to efficiently identify new effector genes may be especially applicable for traits difficult to analyze by other genetic screening methods.
Effects of spatial variation of cells and nutrient and product concentrations coupled with product inhibition on cell growth in a polymer scaffold.

The effects of spatial variation of cells and nutrient and product concentration, in combination with product inhibition in cell growth kinetics on chondrocyte generation in a polymer scaffold, are analyzed. Experimental studies reported previously have demonstrated spatial dependence in the cultivation of chondrocytes. In the present study, the cell-polymer system is assumed to consist of two distinct phases. The cells, fluid, polymer matrix, and extracellular matrix comprise one phase, and the other phase consists of a fluid and polymer matrix. The only two species in the fluid considered to affect cell growth are the nutrient and product. The multiphase transport process of these two species in the cell-polymer system is described by the species continuity equations and corresponding boundary conditions for each individual phase. A volume-averaging approach is utilized for this system to derive averaged species continuity equations for the nutrient and product concentrations. The volume-averaging approach allows for a single species in a two-phase system to be represented by a single averaged continuity equation. Competitive product inhibition, saturation kinetics of substrate, and cell population control are assumed to affect the cell growth kinetics. A modified Contois growth kinetic model is used to represent the three factors that affect cell growth. A parameter analysis is performed and the results are compared qualitatively with experimental data found in the literature.
Sympathetic dysregulation in heart failure: Mechanisms and therapy

Heart failure is accompanied by sympathetic overactivity, which contributes to the pathophysiology and to poor prognosis. This paper reviews the mechanisms and potential therapy for sympathetic dysregulation in heart failure (HF). Several points are emphasized: (I) There is increased sympathetic activity to skeletal muscle, kidney, and heart, but not to skin, in HF. This information challenges the concept of generalized sympathetic activation in HF and suggests that the factors responsible for sympathetic activation result in a partitioning of excess sympathetic outflow to some but not all tissues and organs. (2) The sympathetic dysregulation appears to result from impairment in cardiac and arterial baroreceptor restraint on sympathetic activity, but this abnormality in baroreceptor function may result from abnormal humoral and/or ionic influences acting on baroreceptor endings or in the central nervous system and not from intrinsic structural abnormalities in baroreceptors. This distinction has potential therapeutic importance because abnormalities in humoral or ionic mechanisms would more likely lend themselves to therapeutic modulation. (3) Digitalis sensitizes cardiac and arterial baroreceptors and inhibits sympathetic nerve activity in patients with HF. This sympathoinhibitory influence of digitalis is maintained during chronic therapy. These observations support the concept that the therapeutic effects of digitalis include autonomic modulation in addition to positive inotropism. In a broader concept, these observations suggest that sympathetic modulation may represent an important target for drugs for treatment of heart failure.
The Influence of Laboratory Coagulation Tests and Clotting Factor Levels on Rotation Thromboelastometry (ROTEM®) During Major Surgery with Hemorrhage

BACKGROUND: The aim of this study was to determine the association between standard laboratory tests, coagulation factor concentrations, and Rotation Thromboelastometry (ROTEM® delta, TEM® International GmbH, Munich, Germany) in patients undergoing major surgery with hemorrhage. METHODS: In 45 patient’s fibrinogen, factor VIII, factor XIII, International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), thrombin time, hemoglobin, leukocytes, and platelet count were simultaneously measured intraoperatively with ROTEM (EXTEM, INTEM, FIBTEM, APTEM) measurements. ROTEM parameters were: clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and &agr;-angle. Demographic and laboratory data were expressed as mean ± SD and median [range]; nonparametric Spearman rank correlations and multiple linear regressions were performed; P-values ⩽0.003 were considered significant. RESULTS: Significant correlations (P ⩽ 0.003) were found for CFT, &agr;-angle, and MCF, in EXTEM, INTEM, and APTEM with platelets, INR, and fibrinogen. Factor VIII (18 measurements) showed a strong correlation (r ≥ 0.7 or r ⩽ −0.7; all P ⩽ 0.003) with MCF, CFT, and &agr;-angle of EXTEM, INTEM, MCF of FIBTEM excluding CT of EXTEM, INTEM, FIBTEM and strong significant correlation for &agr;-angle of APTEM and moderate for CFT and MCF of APTEM. A significant moderate to strong correlation of factor XIII with MCF of EXTEM, INTEM, FIBTEM, and APTEM was found. Hemoglobin was moderately correlated (r = 0.3–0.7 or r = −0.3 to −0.7) with MCF in APTEM (P = 0.003). A moderate to strong correlation of the standard coagulation tests with all ROTEM parameters was found, in particular the CT. The aPTT correlated significantly moderate to strong with CT, CFT, &agr;-angle, and MCF of INTEM. However, multiple linear regressions were not able to show an influence of INR on ROTEM parameters except for APTEM-MCF. A significant impact of the aPTT on INTEM-CT was found. EXTEM, INTEM, and APTEM are significantly influenced by fibrinogen and platelets. CONCLUSIONS: The results confirm the clinical assumption that EXTEM, INTEM, and APTEM are associated with fibrinogen and platelets levels; INTEM-CT significantly to aPTT; and FIBTEM significantly to fibrinogen. Factor VIII showed a significant correlation with all ROTEM parameters except CT of EXTEM, INTEM, FIBTEM, and CFT and MCF of APTEM.
Hybrid Tamarix widespread in U.S. invasion and undetected in native Asian range

Biological invasions are drastically altering natural habitats and threatening biodiversity on both local and global levels. In one of the United States' worst invasions, Eurasian Tamarix plant species have spread rapidly to dominate over 600,000 riparian and wetland hectares. The largest Tamarix invasion consists of Tamarix chinensis and Tamarix ramosissima, two morphologically similar species. To clarify the identity, origins, and population structuring of this invasion, we analyzed DNA sequence data from an intron of a nuclear gene, phosphoenolpyruvate carboxylase (PepC). This intron proved to be highly variable at the population level, and the 269 native and invasive specimens yielded 58 haplotypes, from which we constructed a gene genealogy. Only four of these haplotypes were common to both the U.S. and Eurasia. Surprisingly, we found that the most common plant in this U.S. invasion is a hybrid combination of two species-specific genotypes that were geographically isolated in their native Eurasian range. Less extensive hybrids exist in the invasion, involving combinations of T. ramosissima and T. chinensis with Tamarix parviflora and Tamarix gallica. The presence of potentially novel hybrids in the U.S. illustrates how importation of exotics can alter population structures of species and contribute to invasions.
Intraocular delivery of BDNF following visual cortex lesion upregulates cytosolic branched chain aminotransferase (BCATc) in the rat dorsal lateral geniculate nucleus

Visual cortex ablation in newborn rats determines the almost complete degeneration of neurons in the dorsal lateral geniculate nucleus (dLGN), as a consequence of the axotomy of the geniculo‐cortical fibres. Death of dLGN neurons is massive and rapid, and occurs by apoptosis. We recently showed that exogenous administration of the neurotrophin brain‐derived neurotrophic factor (BDNF) in the eye prevents the degeneration of dLGN neurons occurring after visual cortex lesion in newborn rats. To elucidate the molecular mechanisms of BDNF‐mediated neuroprotection, we sought to identify novel genes regulated by BDNF in the rat dLGN after visual cortex lesion. By using mRNA fingerprinting, we isolated a cDNA fragment upregulated in the dLGN of lesioned rats treated with BDNF. This cDNA fragment shared 100% homology with the rat cytosolic branched chain aminotransferase (BCATc), a key enzyme of glutamate metabolism. Quantitative reverse transcription‐polymerase chain reaction and in situ hybridization confirmed that BCATc mRNA is markedly overexpressed by exogenous supply of BDNF to axotomized dLGNs. Immunohistochemical analysis showed that upregulation of BCATc in the dLGN of lesioned rats treated with BDNF takes place in astrocytes. These results suggest that modulation of glutamate metabolism by astrocytes might play an important role in BDNF‐mediated survival of axotomized dLGN neurons.
Writing War: Soldiers Record the Japanese Empire

Historians have made widespread use of diaries to tell the story of the Second World War in Europe but have paid little attention to personal accounts from the Asia-Pacific Theater. Writing War seeks to remedy this imbalance by examining over two hundred diaries, and many more letters, postcards, and memoirs, written by Chinese, Japanese, and American servicemen from 1937 to 1945, the period of total war in Asia and the Pacific. As he describes conflicts that have often been overlooked in the history of World War II, Aaron William Moore reflects on diaries as tools in the construction of modern identity, which is important to our understanding of history. Any discussion of war responsibility, Moore contends, requires us first to establish individuals as reasonably responsible for their actions. Diaries, in which men develop and assert their identities, prove immensely useful for this task. Tracing the evolution of diarists' personal identities in conjunction with their battlefield experience, Moore explores how the language of the state, mass media, and military affected attitudes toward war, without determining them entirely. He looks at how propaganda worked to mobilize soldiers, and where it failed. And his comparison of the diaries of Japanese and American servicemen allows him to challenge the assumption that East Asian societies of this era were especially prone to totalitarianism. Moore follows the experience of soldiering into the postwar period as well, and considers how the continuing use of wartime language among veterans made their reintegration into society more difficult.
Caspase recruitment domain 15 mutations and rheumatic diseases

Purpose of reviewThe purpose of this article is to review the foundational work and current developments on a group of rheumatic disorders associated with mutations in the caspase recruitment domain 15/nucleotide oligomerization domain 2 gene. Recent findingsTo date, there are at least 10 arthritic conditions for which specific genetic mutations have been demonstrated. They include familial Mediterranean fever; tumor necrosis factor receptor associated periodic syndrome; hyper immunoglobulin D syndrome; neonatal onset multisystemic inflammatory disease; pyogenic arthritis pyoderma gangrenosum and acne; Muckle-Wells syndrome; familial cold autoinflammatory syndrome; immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; Crohn's disease; and familial and sporadic sarcoid granulomatous arthritis. This review focuses on recent progress in the last two diseases and the caspase recruitment domain 15 genetic defects with which they are associated. Up to 50% of patients with familial granulomatous arthritis (Blau's syndrome), 90% of those with sporadic granulomatous arthritis (early-onset sarcoidosis), and 40% of individuals with Crohn's disease have documented mutations in the caspase recruitment domain 15 gene. SummaryAlthough histologically, Crohn's disease and familial and sporadic sarcoid granulomatous arthritis are distinct from rheumatoid arthritis because of the defining presence (albeit in not all cases) of non-caseating granulomata in the synovial and intestinal tissues, respectively, they still represent a promising model of both chronic synovitis and uveitis. In addition, once the actual mechanism is discovered by which defects of the caspase recruitment domain 15 gene product lead to chronic arthritis, it may uncover unsuspected biologic targets for therapeutics.
MicroRNA 21 regulates the proliferation of human adipose tissue‐derived mesenchymal stem cells and high‐fat diet‐induced obesity alters microRNA 21 expression in white adipose tissues

A better understanding of the molecular mechanisms that govern human adipose tissue‐derived mesenchymal stem cells (hASCs) differentiation could provide new insights into a number of diseases including obesity. Our previous study demonstrated that microRNA‐21 (miR‐21) controls the adipogenic differentiation of hASCs. In this study, we determined the expression of miR‐21 in white adipose tissues in a high‐fat diet (HFD)‐induced obesity mouse model to examine the relationship between miR‐21 and obesity and the effect of miR‐21 on hASCs proliferation. Our study showed biphasic changes of miR‐21 expression and a correlation between miR‐21 level and adipocyte number in the epididymal fat of HFD mice. Over‐expression of miR‐21 decreased cell proliferation, whereas inhibiting miR‐21 with 2′‐O‐methyl‐antisense RNA increased it. Over‐expression of miR‐21 decreased both protein and mRNA levels of STAT3, whereas inhibiting miR‐21 with 2′‐O‐methyl‐antisense RNA increased these levels. The activity of a luciferase construct containing the miR‐21 target site from the STAT3 3′UTR was lower in LV‐miR21‐infected hASCs than in LV‐miLacZ infected cells. RNA interference‐mediated down‐regulation of STAT3 decreased cell proliferation without affecting adipogenic differentiation. These findings provide the evidence of the correlation between miR‐21 level and adipocyte number in the white adipose tissue of HFD‐induced obese mice, which provides new insights into the mechanisms of obesity. J. Cell. Physiol. 227: 183–193, 2012. © 2011 Wiley Periodicals, Inc.
Doxycycline Modulates Nitric Oxide Production in Murine Lung Epithelial Cells1

Many effective therapeutic agents exhibit effects that are different from their intended primary mode of action. Antibiotics such as doxycycline and erythromycin A are no exception. They also display anti-inflammatory activity. Using LA4 murine lung alveolar epithelial cells, effects of doxycycline and erythromycin A on inducible NO synthase (iNOS) NO production as well as iNOS protein and mRNA production were investigated. Induction of iNOS was accomplished by treatment with cytomix (TNF-α, IL-1β, and IFN-γ each at 5 ng/ml). Production of NO or iNOS was not detected in controls with or without erythromycin A. In the presence of cytomix, erythromycin A did not decrease NO, nitrite, iNOS protein, or mRNA production. In contrast, doxycycline caused a dose-dependent decrease in NO, nitrite, iNOS protein, and mRNA production in cytomix-treated cells. Doxycycline at 30 μg/ml produced a 90% decrease in nitrite and NO production and a 52% decrease in iNOS mRNA transcription compared with cytomix treatment alone. Actinomycin D treatment suggests that doxycycline decreases stability of iNOS mRNA in cytomix-treated cells. To determine a mechanism for the decrease in iNOS expression, NF-κB and AP-1 transcription regulatory systems and p38 MAPK were examined. Doxycycline treatment gave no statistically significant change in NF-κB activation but did decrease p38 MAPK protein in cytomix-treated cells by 50%, suggesting that p38 MAPK may be responsible for stabilization of iNOS mRNA. These results demonstrate that doxycycline decreases NO production from iNOS by destabilization of iNOS mRNA via decreased expression of p38 MAPK.
Effect of High‐Dose Oral Ganciclovir on Didanosine Disposition in Human Immunodeficiency Virus (HIV)‐Positive Patients

This study was designed to investigate the interaction between high‐dose oral ganciclovir (6,000 mg/day) and didanosine at steady state in patients who were seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection. The study was conducted as an open‐label, randomized, three‐period crossover study. Patients received (in random order) multiple oral doses of didanosine 200 mg every 12 hours alone, ganciclovir 2,000 mg every 8 hours alone, and ganciclovir 2,000 mg every 8 hours in combination with didanosine 200 mg every 12 hours. Blood and urine samples for determinations of drug concentrations were obtained on day 3 of each dose regimen. When ganciclovir was administered either before or 2 hours after didanosine, the mean increases in maximum concentration (Cmax), area under the concentration—time curve (AUC0–12), and percent excreted in urine of didanosine were 58.6% and 87.3%, 87.3% and 124%, and 100% and 153%, respectively. There were no statistically significant effects of didanosine on the steady‐state pharmacokinetics of ganciclovir in the presence of didanosine, irrespective of sequence of administration. There were no significant changes in renal clearance of didanosine, suggesting that the mechanism for the interaction does not involve competition for active renal tubular secretion. The mechanism responsible for increased didanosine concentrations and percent excreted in urine during concurrent ganciclovir therapy may be a result of increased bioavailability of didanosine. However, the mechanism appears to be saturated at oral ganciclovir doses of 3 g/day.
Phosphorylation‐independent desensitization of GABAB receptor by GRK4

Agonist‐promoted desensitization of the heterodimeric metabotropic GABAB receptor was investigated. Whereas no desensitization was observed in HEK293 cells heterologously expressing the receptor, GABA and the synthetic agonist baclofen induced a robust desensitization in cerebellar granule cells endogenously expressing the receptor. Taking advantage of this cell‐specific desensitization phenotype, we identified GRK4 as the kinase involved in the neuronal desensitization. Transfection of small interference RNA directed against GRK4 significantly reduced GRK4 levels in cerebellar granule cells and strongly inhibited the agonist‐promoted desensitization. Reciprocally, transfection of GRK4 in HEK293 cells restored agonist‐promoted desensitization, confirming that this kinase is sufficient to support desensitization. Surprisingly, this desensitization occurred in the absence of ligand‐induced receptor phosphorylation and could be promoted by GRK4 mutants deleted of their kinase domain. Taken together, these results suggest that GRK4 plays a central role in the agonist‐promoted desensitization of GABAB receptor and that it does so through an atypical mechanism that challenges the generally accepted model linking the kinase activity of GRKs to their role in receptor desensitization.
Epidemiology of Shoulder and Elbow Injuries Among United States High School Baseball Players: School Years 2005-2006 Through 2014-2015

Background: Shoulder and elbow injuries are common in young athletes, especially high school baseball players. Understanding the risk factors associated with baseball injuries is an essential first step in the development of injury prevention strategies. Purpose: To provide a comprehensive understanding of the epidemiology of shoulder and elbow injuries among high school baseball players in the United States. Study Design: Descriptive epidemiological study. Methods: Baseball-related injury data were obtained from the National High School Sports-Related Injury Surveillance Study using High School RIO (Reporting Information Online), an Internet-based sports injury surveillance system. Athletic trainers from high schools across the country uploaded data regarding athlete-exposures (AEs) (defined as practice or game participation) and shoulder and elbow injuries from the school years 2005-2006 through 2014-2015. Results: A total of 241 shoulder injuries and 150 elbow injuries occurred during 1,734,198 AEs during the study period, for an overall shoulder injury rate of 1.39 per 10,000 AEs and an overall elbow injury rate of 0.86 per 10,000 AEs. The overall rates of injury were higher in competitions compared with practices for shoulders (rate ratio, 1.44; 95% CI, 1.11-1.85) and elbows (rate ratio, 2.15; 95% CI, 1.56-2.96). The majority of shoulder (39.6%) and elbow (56.9%) injuries were sustained by pitchers, and most injuries were chronic and caused by overuse. Position players were more likely to sustain injuries by contact with the playing surface or apparatus. For pitchers, muscle strains were the most common shoulder injuries (38.7%), while ligament sprains were the most common elbow injuries (42.7%). The majority of pitchers with shoulder (70.8%) and elbow (64.6%) injuries returned to play within 21 days. Among pitchers, a higher proportion of elbow injuries (11.4%) resulted in medical disqualification compared with shoulder injuries (5.6%). Among pitchers, the majority of shoulder (89.2%) and elbow (96.4%) injuries were managed nonsurgically. Conclusion: Shoulder and elbow injury rates and patterns in high school baseball players differed between field positions (pitchers vs position players) and by type of exposure (practice vs competition). This study suggests several areas of emphasis for targeted injury prevention interventions, most notably limiting fatigue and preventing overuse injuries.