Search

Diffuse large B-cell lymphoma (DLBCL) presents a great clinical challenge and has a poor prognosis, with immune-related genes playing a crucial role. We aimed to develop an immune-related prognostic signature for improving prognosis prediction in DLBCL. Samples from the GSE31312 dataset were randomly allocated to discovery and internal validation cohorts. Univariate Cox, random forest, LASSO regression and multivariate Cox analyses were utilized to develop a prognostic signature, which was verified in the internal validation cohort, entire validation cohort and external validation cohort (GSE10846). The tumor microenvironment was investigated using the CIBERSORT and ESTIMATE tools. Gene set enrichment analysis (GSEA) was further applied to analyze the entire GSE31312 cohort. We identified four immune-related genes (CD48, IL1RL, PSDM3, RXFP3) significantly associated with overall survival. Based on discovery and validation cohort analyses, this four-gene signature could classify patients into high- and low-risk groups, with significantly different prognoses. Activated memory CD4 T cells and activated dendritic cells were significantly decreased in the high-risk group, and these patients had lower immune scores. GSEA revealed enrichment of signaling pathways, such as T cell receptor, antigen receptor-mediated, antigen processing and presentation of peptide antigen via MHC class I, in the low-risk group. In conclusion, a robust signature based on four immune-related genes was successfully constructed for predicting prognosis in DLBCL patients.

Abstract: This study aimed to assess the role of leukocyte telomere length (LTL) in the development of atrial fibrillation (AF) among Chinese patients.This is a cross-sectional study. A total of 350 patients from June 2016 to December 2017 were retrospectively analyzed. These included 219 AF patients and 131 with sinus rhythm in the control group. Quantitative real-time PCR was used to measure relative LTL.The relative LTLs of all subjects (n = 350) ranged from 0.4 to 2.41 (0.98 ± 0.29), showing a significant negative correlation (P < .001) with age. The AF-group had significantly shorter LTLs (0.93 ± 0.26 vs 1.07 ± 0.33, P < .001) and were older (61.50 ± 6.49 vs 59.95 ± 6.17, P = .028) than controls. LTLs among patients with persistent AF (PsAF), paroxysmal AF (PAF), and controls were significantly different (P < .001), with LTLs of PsAF patients being the shortest and controls being the longest. After adjusting for possible confounding factors, the PsAF group still showed significantly shorter LTLs than the PAF and control groups (P = .013 and P = .001, respectively). After an 18-month follow-up, 20 out of 119 PAF patients had progressed into PsAF and a relative LTL of ≤0.73 was an independent predictor for progression of PAF into PsAF.LTL was found to be shorter in patients with AF than in age-matched individuals with sinus rhythm and positively correlated with severity of AF. LTL shortening could be an independent risk factor for progression from paroxysmal AF to persistent AF in the short term., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The heterogeneity of major depressive disorder (MDD) is attributed to the fact that diagnostic criteria (e.g., DSM-5) are only based on clinical symptoms. The discovery of blood biomarkers has the potential to change the diagnosis of MDD. The purpose of this study was to identify blood biomarkers of DNA methylation by strategically subtyping patients with MDD by onset age. We analyzed genome-wide DNA methylation of patients with adult-onset depression (AOD; age ≥ 50 years, age at depression onset < 50 years; N = 10) and late-onset depression (LOD; age ≥ 50 years, age at depression onset ≥ 50 years; N = 25) in comparison to that of 30 healthy subjects. The methylation profile of the AOD group was not only different from that of the LOD group but also more homogenous. Six identified methylation CpG sites were validated by pyrosequencing and amplicon bisulfite sequencing as potential markers for AOD in a second set of independent patients with AOD and healthy control subjects (N = 11). The combination of three specific methylation markers achieved the highest accuracy (sensitivity, 64%; specificity, 91%; accuracy, 77%). Taken together, our findings suggest that DNA methylation markers are more suitable for AOD than for LOD patients.

Background: Identification of genetic diversity in heat tolerance and associated traits is of great importance for improving heat tolerance in cool-season grass species. The objectives of this study were to determine genetic variations in heat tolerance associated with phenotypic and physiological traits and to identify molecular markers associated with heat tolerance in a diverse collection of perennial ryegrass (Lolium perenne L.)., Results: Plants of 98 accessions were subjected to heat stress (35/30 °C, day/night) or optimal growth temperature (25/20 °C) for 24 d in growth chambers. Overall heat tolerance of those accessions was ranked by principal component analysis (PCA) based on eight phenotypic and physiological traits. Among these traits, electrolyte leakage (EL), chlorophyll content (Chl), relative water content (RWC) had high correlation coefficients (- 0.858, 0.769, and 0.764, respectively) with the PCA ranking of heat tolerance. We also found expression levels of four Chl catabolic genes (CCGs), including LpNYC1, LpNOL, LpSGR, and LpPPH, were significant higher in heat sensitive ryegrass accessions then heat tolerant ones under heat stress. Furthermore, 66 pairs of simple sequence repeat (SSR) markers were used to perform association analysis based on the PCA result. The population structure of ryegrass can be grouped into three clusters, and accessions in cluster C were relatively more heat tolerant than those in cluster A and B. SSR markers significantly associated with above-mentioned traits were identified (R 2  > 0.05, p < 0.01)., including two pairs of markers located on chromosome 4 in association with Chl content and another four pairs of markers in association with EL., Conclusion: The result not only identified useful physiological parameters, including EL, Chl content, and RWC, and their associated SSR markers for heat-tolerance breeding of perennial ryegrass, but also highlighted the involvement of Chl catabolism in ryegrass heat tolerance. Such knowledge is of significance for heat-tolerance breeding and heat tolerance mechanisms in perennial ryegrass as well as in other cool-season grass species.

Coronaviruses are single-stranded ribonucleic acid viruses that can cause illnesses in humans ranging from the common cold to severe respiratory disease and even death.In March 2020, the World Health Organization declared the 2019 novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as the first pandemic. Compared to women, most countries with available data report that men with COVID-19 have greater disease severity and higher mortality. Lab and animal data indicate that men respond differently to the SARS-CoV-2 infection, offering possible explanations for the epidemiologic observations. The plausible theories underlying these observations include sex-related differences in angiotensin-converting enzyme 2 receptors, immune function, hormones, habits, and coinfection rates.In this review we examine these factors and explore the rationale as to how each may impact COVID-19. Understanding why men are more likely to experience severe disease can help in developing effective treatments, public health policies, and targeted strategies such as early recognition and aggressive testing in subgroups.

An organism's ability to respond effectively to environmental change is critical to its survival. Yet, life stage and overall condition can dictate tolerance thresholds to heightened environmental stressors, such that stress may not be equally felt across individuals and at all times. Also, the transcriptional responses induced by environmental changes can reflect both generalized responses as well as others that are highly specific to the type of change being experienced. Thus, if transcriptional biomarkers specific to a stressor, even under multi-stressor conditions, can be identified, the biomarkers could then be applied in natural environments to determine when and where an individual experiences such a stressor. Here, we experimentally challenged juvenile Chinook salmon ( Oncorhynchus tshawytscha ) to validate candidate gill gene expression biomarkers. A sophisticated experimental design manipulated salinity (freshwater, brackish water and seawater), temperature (10, 14 and 18°C) and dissolved oxygen (normoxia and hypoxia) in all 18 possible combinations for 6 days using separate trials for three smolt statuses (pre-smolt, smolt and de-smolt). In addition, changes in juvenile behaviour, plasma variables, gill Na + /K + -ATPase activity, body size, body morphology and skin pigmentation supplemented the gene expression responses. We identified biomarkers specific to salinity and temperature that transcended the multiple stressors, smolt status and mortality (live, dead and moribund). Similar biomarkers for dissolved oxygen were not identified. This work demonstrates the unique power of gene expression biomarkers to identify a specific stressor even under multi-stressor conditions, and we discuss our next steps for hypoxia biomarkers using an RNA-seq study., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)

Background: As cytokines, including interleukin-10 (IL-10) and transforming growth factor beta 1(TGF-β1) seem to contribute towards the pathogenesis of chronic heart failure (CHF), this study was performed to assess the associations of certain single nucleotide polymorphisms (SNPs) of these genes in a case control study., Methods: This investigation was carried out to determine the frequency of alleles, genotypes and haplotypes of TGF-β1 and IL-10 single-nucleotide polymorphisms (SNPs) in 57 Iranian patients with CHF compared with 140 healthy subjects using polymerase chain reaction with sequence-specific primers method., Results: Results of the analyzed data divulged a negative association for both TGF-β1 GC genotype at codon 25 (P=0.047) and CT genotype at codon 10 (P=0.018) and CHF proneness. Although, TGF-β1 CC genotype at codon 10 was found to be positively associated with CHF (P=0.011). Moreover, the frequency of IL-10 (-1082, -819, -592) ATA haplotype and TGF-β1 (codon 10, codon 25) TG haplotype were significantly lower in the patients group (P=0.004 and P=0.040, respectively), while TGF-β1 (codon 10, codon 25) CG haplotype was overrepresented in patients with CHF (P=0.007)., Conclusions: Cytokine gene polymorphisms might affect vulnerability to CHF. Particular genotypes and haplotypes in IL-10 and TGF-β1 genes could render individuals more susceptible to CHF.

Protein coding sequences represent only 2% of the human genome. Recent advances have demonstrated that a significant portion of the genome is actively transcribed as non-coding RNA molecules. These non-coding RNAs are emerging as key players in the regulation of biological processes, and act as "fine-tuners" of gene expression. Neurological disorders are caused by a wide range of genetic mutations, epigenetic and environmental factors, and the exact pathophysiology of many of these conditions is still unknown. It is currently recognized that dysregulations in the expression of non-coding RNAs are present in many neurological disorders and may be relevant in the mechanisms leading to disease. In addition, circulating non-coding RNAs are emerging as potential biomarkers with great potential impact in clinical practice. In this review, we discuss mainly the role of microRNAs and long non-coding RNAs in several neurological disorders, such as epilepsy, Huntington disease, fragile X-associated ataxia, spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), and pain. In addition, we give information about the conditions where microRNAs have demonstrated to be potential biomarkers such as in epilepsy, pain, and ALS.

Sclerostin is a glycoprotein involved in the regulation of bone metabolism, exclusively secreted by osteocytes. It affects the activity of bone morphogenetic proteins (BMPs) and is an inhibitor of the Wnt/β-catenin metabolic pathway in bone cells. Osteocytes reduce the release of sclerostin in response to mechanical stimuli acting on bone, and thus promote the activation of osteogenic pathway Wnt/β-catenin in osteoblasts. This signaling pathway plays a key role in osteogenesis and bone turnover. Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease. Additionally, experimental and clinical studies suggest that sclerostin may promote vascular calcification. Antibodies directed against sclerostin stimulate bone formation and represent a new therapeutic option in the treatment of diseases with increased bone resorption, such as osteoporosis and inflammatory diseases where there is generalized bone loss, periarticular osteoporosis, and cartilage damage, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and glucocorticoid-induced osteoporosis (GIO). Antibody use has the potential to offer new therapeutic approaches in the therapy of mineral and bone disorders resulting from chronic kidney disease (CKD-MBD) and vascular calcifications.

MicroRNAs (miRNAs and miRs) are endogenous 19-22 nucleotide, small noncoding RNAs with highly conservative and tissue specific expression. They can negatively modulate target gene expressions through decreasing transcription or posttranscriptional inducing mRNA decay. Increasing evidence suggests that deregulated miRNAs play an important role in the genesis of cardiovascular diseases. Additionally, circulating miRNAs can be biomarkers for cardiovascular diseases. MiR-222 has been reported to play important roles in a variety of physiological and pathological processes in the heart. Here we reviewed the recent studies about the roles of miR-222 in cardiovascular diseases. MiR-222 may be a potential cardiovascular biomarker and a new therapeutic target in cardiovascular diseases., Competing Interests: The authors declare there is no conflict of interests.

Background: Sepsis coincides with altered gene expression in different tissues. Accumulating evidence has suggested that microRNAs, long non-coding RNAs, and circular RNAs are important molecules involved in the crosstalk with various pathways pertinent to innate immunity, mitochondrial functions, and apoptosis., Methods: We searched articles indexed in PubMed (MEDLINE), EMBASE and Europe PubMed Central databases using the Medical Subject Heading (MeSH) or Title/Abstract words ("microRNA", "long non-coding RNA", "circular RNA", "sepsis" and/or "septic shock") from inception to Sep 2016. Studies investigating the role of host-derived microRNA, long non-coding RNA, and circular RNA in the pathogenesis of and as biomarkers or therapeutics in sepsis were included. Data were extracted in terms of the role of non-coding RNAs in pathogenesis, and their applicability for use as biomarkers or therapeutics in sepsis. Two independent researchers assessed the quality of studies using a modified guideline from the Systematic Review Center for Laboratory animal Experimentation (SYRCLE), a tool based on the Cochrane Collaboration Risk of Bias tool., Results: Observational studies revealed dysregulation of non-coding RNAs in septic patients. Experimental studies confirmed their crosstalk with JNK/NF-κB and other cellular pathways pertinent to innate immunity, mitochondrial function, and apoptosis. Of the included studies, the SYRCLE scores ranged from 3 to 7 (average score of 4.55). This suggests a moderate risk of bias. Of the 10 articles investigating non-coding RNAs as biomarkers, none of them included a validation cohort. Selective reporting of sensitivity, specificity, and receiver operating curve was common., Conclusions: Although non-coding RNAs appear to be good candidates as biomarkers and therapeutics for sepsis, their differential expression across tissues complicated the process. Further investigation on organ-specific delivery of these regulatory molecules may be useful.

The clam Macridiscus multifarius with a planktonic larval stage of about 10 days is an ecologically and economically important species in the coastal regions of China. In this study, 3 mt-DNA markers (COI, 12S rRNA, and ND1) were used to investigate the population structure and demography of wild M. multifarius populations in 3 coastal localities of the East China Sea (ZS and ZP populations) and Beibu Gulf in the South China Sea (BH population). Sequences of 685 bp in COI, 350 bp in 12S rRNA, and 496 bp in ND1 were determined. High level and significant FST values were obtained among the different localities on the basis of either COI (FST = 0.100-0.444, p < 0.05) or 12S rRNA (FST = 0.199-0.742, p < 0.05) gene, indicating a high degree of genetic differentiation among the populations. FST values were significant but weak for the ND1 gene because it is highly conservative. The median-joining network suggested an obvious genetic differentiation between ZS and BH populations, and the finding is consistent with the results of our demographic analyses using the unweighted pair group method with arithmetic mean. Our study unraveled the extant population genetic structure of M. multifarius and explained the strong population structure of a species with a short planktonic larval stage species; this information could be useful for fishery management measures, including artificial breeding and conservation.

Objective: The aim of this study was to evaluate serum periostin levels in patients with AS in comparison with healthy controls as well as their association with clinical, inflammatory and radiographic parameters and molecules involved in bone formation., Methods: Serum samples for periostin, total Dickkopf-1 (Dkk-1), sclerostin, VEGF and inflammatory markers were obtained from 65 TNF inhibitor-naive patients with AS. The BASDAI, BASFI, modified Stoke AS Spine Score and BASRI for the spine (BASRI-s) were assessed for each patient. Serum periostin levels were also measured in 36 sex-, age- and BMI-matched controls., Results: Serum periostin levels were significantly lower in AS patients compared with controls [234.4 pg/ml (s.e.m. 7.5) vs 291.4 (s.e.m. 8.3), respectively; P < 0.001]. Periostin levels were higher in AS patients with elevated CRP (P = 0.005), high BASDAI (P = 0.014) and low BASRI-s (P = 0.033) and were correlated with BMI (r = -0.304, P = 0.014), ESR (r = 0.395, P = 0.001), CRP (r = 0.413, P = 0.001), BASRI-s (r = -0.242, P = 0.047) and sclerostin (r = -0.280, P = 0.024). In multiple regression analysis, periostin levels were an independent variable of CRP (β = 0.160, P = 0.009) and sclerostin levels (β = -0.311, P = 0.012)., Conclusion: Our data suggest that periostin levels are low in patients with AS. Among AS patients, periostin levels are higher in those with higher disease activity, higher systemic inflammation and less extensive radiographic damage. Periostin is independently associated with CRP and sclerostin levels., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Accurate and rapid diagnosis of active tuberculosis (TB) disease is still hampered by inadequate tools. Although current assays relying on single-marker readouts mostly display inadequate sensitivity and/or specificity, host-related multimarker signatures are especially poorly developed. As a consequence, research programs have been initiated to search for combinations of markers-so-called biosignatures with superior performance. Many such investigations harness high-throughput platforms to analyze the host response during infection and disease. A major challenge for these activities is the analysis of vast amounts of data produced. Specialized bioinformatic tools are being applied to identify the most robust biosignatures for classification of exposed and diseased individuals and prognosis of risk of disease in endemic areas. Validation of the most promising biosignatures in ongoing multicohort studies will bring us a step closer to the identification of an accurate unified signature., (Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.)

Sclerosteosis and Van Buchem disease are two rare bone sclerosing disorders characterized by increased bone mineral density, tall stature and entrapment of cranial nerves due to overgrowth of a highly dense bone. Recent advances in human genetics have revealed the genetic background of these disorders by cloning the SOST gene, which is localized on chromosome region 17q12-q21 and codes for sclerostin. Sclerostin is a protein produced almost exclusively from osteocytes inhibiting bone formation by both osteoblasts and osteocytes. At the molecular level, sclerostin inhibits the Wnt signaling pathway, which plays a critical role in osteoblast development and function. Induced sclerostin deficiency in mice reproduces the bone sclerosing human diseases, while sclerostin excess leads to bone loss and reduced bone strength. The extracellular nature of sclerostin has rendered it a promising target for the development of novel anti-osteoporotic treatment. Otherwise healthy carriers of the SOST mutation present with increased bone mass and low levels of sclerostin in serum in contrast to patients with sclerosteosis, who exhibit undetectable levels, thus pointing to the possibility of titration of sclerostin levels in the circulation. Based on these unique characteristics, human anti-sclerostin antibodies have been developed and tested in ovariectomized rats and monkeys, demonstrating very promising results in bone formation. Clinical phase II and III trials are currently underway thereby translating human genetics to drug development.

Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), whose incidence has increased sharply in the last 4 decades. The annual conversion rate of BE to cancer is significant, but small. The identification of patients at a higher risk of cancer therefore poses a clinical conundrum. Currently, endoscopic surveillance is recommended in BE patients, with the aim of diagnosing either dysplasia or cancer at early stages, both of which are curable with minimally invasive endoscopic techniques. There is a large variation in clinical practice for endoscopic surveillance, and dysplasia as a marker of increased risk is affected by sampling error and high interobserver variability. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by upper gastrointestinal endoscopy. Screening programs have not yet been formally accepted, mainly due to the economic burden that would be generated by widespread indication to upper gastrointestinal endoscopy. In fact, it is currently difficult to formulate an accurate algorithm to confidently target the population at risk, based on the known clinical risk factors for BE and EAC. This review will focus on the clinical and molecular factors that are involved in the development of BE and its conversion to cancer and on how increased knowledge in these areas can improve the clinical management of the disease.

Background: Bipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients., Discussion: A number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD., Summary: Based upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD.

Background: The nutritional deprivation of adolescent girls with anorexia nervosa (AN) reduces bone mass acquisition. A better understanding of this process would improve the medical treatment of bone alteration and its long-term consequences., Objective: The first aim was to model the bone mass acquisition in young women with AN. The second aim was to identify the clinical and biological factors associated with bone demineralization and investigate the potential role of sclerostin and dickkopf-1 protein (DKK-1)., Population and Methods: Ninety-eight AN patients (mean age 18.2 ± 2.6 years) and 63 age-matched controls were enrolled in this study. Areal bone mineral density (aBMD) was determined by dual-energy x-ray absorptiometry. Calciotropic hormones, bone turnover markers, sclerostin, DKK-1, and growth factors were concomitantly evaluated., Results: The aBMD was significantly reduced at all bone sites in AN patients vs controls (range, -3.3% at the radius to -12.1% for total proximal femur). Bone formation markers IGF-1 and DKK-1 were significantly decreased in AN patients, whereas PTH, sclerostin, and the bone resorption markers were increased. In patients, the AN duration, amenorrhea, weight, body mass index, fat mass, and fat-free soft tissue were negatively correlated with aBMD, whereas the age of AN onset was positively correlated. Multiple regression analysis revealed that the duration of amenorrhea was the independent factor most negatively associated with aBMD at all bone sites except the radius., Conclusion: This case-control study demonstrated a dramatic reduction in aBMD, reinforced for the first time by our models, and indicates the need for early, systematic, and adapted bone mass monitoring. Moreover, appropriate treatment should be started early in patients with AN. Increased secretion of sclerostin suggests that it may be a target for pharmacological action.

The human coronary collateral circulation is prognostically relevant. The understanding of collateral formation and its determinants may guide future therapeutic strategies aiming at promoting collateral growth and functionality, and hence reducing the global burden of coronary artery disease (CAD).

Background: The Chinese salamander (Hynobius chinensis), an endangered amphibian species of salamander endemic to China, has attracted much attention because of its value of studying paleontology evolutionary history and decreasing population size. Despite increasing interest in the Hynobius chinensis genome, genomic resources for the species are still very limited. A comprehensive transcriptome of Hynobius chinensis, which will provide a resource for genome annotation, candidate genes identification and molecular marker development should be generated to supplement it., Principal Findings: We performed a de novo assembly of Hynobius chinensis transcriptome by Illumina sequencing. A total of 148,510 nonredundant unigenes with an average length of approximately 580 bp were obtained. In all, 60,388 (40.66%) unigenes showed homologous matches in at least one database and 33,537 (22.58%) unigenes were annotated by all four databases. In total, 41,553 unigenes were categorized into 62 sub-categories by BLAST2GO search, and 19,468 transcripts were assigned to 140 KEGG pathways. A large number of unigenes involved in immune system, local adaptation, reproduction and sex determination were identified, as well as 31,982 simple sequence repeats (SSRs) and 460,923 putative single nucleotide polymorphisms (SNPs)., Conclusion: This dataset represents the first transcriptome analysis of the Chinese salamander (Hynobius chinensis), an endangered species, to be also the first time of hynobiidae. The transcriptome will provide valuable resource for further research in discovery of new genes, protection of population, adaptive evolution and survey of various pathways, as well as development of molecule markers in Chinese salamander; and reference information for closely related species.

The PROP1 protein, encoded by the prophet of Pit-1 (PROP1) gene, exhibits both DNA-binding and transcriptional activation abilities. Its expression leads to the ontogenesis of growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), and pituitary hormone. The missense mutation H173R in PROP1 may result in deficiencies of GH, PRL, TSH, and Pit-1, thereby affecting growth traits. The objective of this study was to characterize the H173R mutation within the PROP1 gene and examine its associations with growth traits in cattle. Accordingly, the H173R mutation was genotyped in 1207 cows belonging to five Chinese native breeds. Three genotypes were identified among the specimens, with genotype AA being the major one. Consequently, the "G" allele was the minor allele. Association testing revealed that the H173R mutation was significantly associated with body weight, average daily weight gain and physical parameters in the analyzed breeds. Interestingly, the cows with genotype AG and/or AA had superior growth traits compared with those expressing the GG genotype, in all tested breeds. These findings revealed that the "A" allele had positive effects on growth traits, which was consistent with the increasing binding ability and enhanced activation capacity associated with the bovine isoform PROP1-173H, representing the "A" allele. Therefore, the H173R mutation can be considered as a DNA marker for selecting individuals with superior growth traits, thereby contributing to research on breeding and genetics in the beef industry., (© 2013.)

With the aim of understanding relationship between genetic and phenotypic variations in cultivated tomato, single nucleotide polymorphism (SNP) markers covering the whole genome of cultivated tomato were developed and genome-wide association studies (GWAS) were performed. The whole genomes of six tomato lines were sequenced with the ABI-5500xl SOLiD sequencer. Sequence reads covering ~13.7× of the genome for each line were obtained, and mapped onto tomato reference genomes (SL2.40) to detect ~1.5 million SNP candidates. Of the identified SNPs, 1.5% were considered to confer gene functions. In the subsequent Illumina GoldenGate assay for 1536 SNPs, 1293 SNPs were successfully genotyped, and 1248 showed polymorphisms among 663 tomato accessions. The whole-genome linkage disequilibrium (LD) analysis detected highly biased LD decays between euchromatic (58 kb) and heterochromatic regions (13.8 Mb). Subsequent GWAS identified SNPs that were significantly associated with agronomical traits, with SNP loci located near genes that were previously reported as candidates for these traits. This study demonstrates that attractive loci can be identified by performing GWAS with a large number of SNPs obtained from re-sequencing analysis.

The nucleus of epidermal keratinocytes (KCs) is a complex and highly compartmentalized organelle, whose structure is markedly changed during terminal differentiation and transition of the genome from a transcriptionally active state seen in the basal and spinous epidermal cells to a fully inactive state in the keratinized cells of the cornified layer. Here, using multicolor confocal microscopy, followed by computational image analysis and mathematical modeling, we demonstrate that in normal mouse footpad epidermis, transition of KCs from basal epidermal layer to the granular layer is accompanied by marked differences in nuclear architecture and microenvironment including the following: (i) decrease in the nuclear volume; (ii) decrease in expression of the markers of transcriptionally active chromatin; (iii) internalization and decrease in the number of nucleoli; (iv) increase in the number of pericentromeric heterochromatic clusters; and (v) increase in the frequency of associations between the pericentromeric clusters, chromosomal territory 3, and nucleoli. These data suggest a role for nucleoli and pericentromeric heterochromatin clusters as organizers of nuclear microenvironment required for proper execution of gene expression programs in differentiating KCs, and provide important background information for further analyses of alterations in the topological genome organization seen in pathological skin conditions, including disorders of epidermal differentiation and epidermal tumors.

Mapping quantitative trait loci (QTL) using genetic marker information is a time-consuming analysis that has interested the mapping community in recent decades. The increasing amount of genetic marker data allows one to consider ever more precise QTL analyses while increasing the demand for computation. Part of the difficulty of detecting QTLs resides in finding appropriate critical values or threshold values, above which a QTL effect is considered significant. Different approaches exist to determine these thresholds, using either empirical methods or algebraic approximations. In this article, we present a new implementation of existing software, QTLMap, which takes advantage of the data parallel nature of the problem by offsetting heavy computations to a graphics processing unit (GPU). Developments on the GPU were implemented using Cuda technology. This new implementation performs up to 75 times faster than the previous multicore implementation, while maintaining the same results and level of precision (Double Precision) and computing both QTL values and thresholds. This speedup allows one to perform more complex analyses, such as linkage disequilibrium linkage analyses (LDLA) and multiQTL analyses, in a reasonable time frame.

Context: Sclerostin, a Wnt antagonist produced by osteocytes, regulates osteoblast activity and is a well-established key player in bone turnover. Recent data indicate that the Wnt pathway may also be involved in vascular calcification., Objective: The present study tests the hypothesis that serum sclerostin levels are associated with vascular calcification in patients with chronic kidney disease (CKD) not yet receiving dialysis., Design, Setting, Participants, and Measurements: We performed a cross-sectional analysis in 154 patients with CKD. Aortic calcification (AC) was assessed by lumbar X-ray and scored with a maximum score of 24. In addition to traditional and nontraditional cardiovascular (CV) risk factors, serum sclerostin levels were assessed (ELISA). Regression analysis was performed to identify determinants of serum sclerostin and AC., Results: AC was present in 59% of patients. Older age (P < .0001), male sex (P = .006), lower estimated glomerular rate (eGFR) (P = .0008), lower bone-specific alkaline phosphatase (P = .03), and the absence of AC (P = .006) were identified as independent determinants of higher serum sclerostin levels. In univariate logistic regression, higher age, diabetes, CV history, higher body mass index, higher serum C-reactive protein and sclerostin levels and lower estimated glomerular rate were all associated with the presence of AC. In multivariate analysis, lower, not higher, sclerostin levels (P = .04, odds ratio [OR] per ng/mL of 0.24), higher age (P < .0001, OR per year of 1.17) and CV history (P = .02, OR for a positive CV history of 3.83) were identified as independent determinants of AC., Conclusions: In this cohort of patients with CKD, we found that patients with aortic calcifications (ACs) had higher sclerostin levels. However, in multivariate analysis, the association became inverse. Additional clinical and experimental studies are urgently required to clarify whether or not sclerostin protects against progression of vascular calcification.

Meta-analysis was performed for three major foliar diseases with the aim to find out the total number of QTL responsible for these diseases and depict some real QTL for molecular breeding and marker assisted selection (MAS) in maize. Furthermore, we confirmed our results with some major known disease resistance genes and most well-known gene family of nucleotide binding site (NBS) encoding genes. Our analysis revealed that disease resistance QTL were randomly distributed in maize genome, but were clustered at different regions of the chromosomes. Totally 389 QTL were observed for these three major diseases in diverse maize germplasm, out of which 63 QTL were controlling more than one disease revealing the presence of multiple disease resistance (MDR). 44 real-QTLs were observed based on 4 QTL as standard in a specific region of genome. We also confirmed the Ht1 and Ht2 genes within the region of real QTL and 14 NBS-encoding genes. On chromosome 8 two NBS genes in one QTL were observed and on chromosome 3, several cluster and maximum MDR QTL were observed indicating that the apparent clustering could be due to genes exhibiting pleiotropic effect. Significant relationship was observed between the number of disease QTL and total genes per chromosome based on the reference genome B73. Therefore, we concluded that disease resistance genes are abundant in maize genome and these results can unleash the phenomenon of MDR. Furthermore, these results could be very handy to focus on hot spot on different chromosome for fine mapping of disease resistance genes and MAS.

Current advances in plant genotyping lead to major progress in the knowledge of genetic architecture of traits of interest. It is increasingly important to develop decision support tools to help breeders and geneticists to conduct marker-assisted selection methods to assemble favorable alleles that are discovered. Algorithms have been implemented, within an interactive graphical interface, to 1) trace parental alleles throughout generations, 2) propose strategies to select the best plants based on estimated molecular scores, and 3) efficiently intermate them depending on the expected value of their progenies. With the possibility to consider a multi-allelic context, OptiMAS opens new prospects to assemble favorable alleles issued from diverse parents and further accelerate genetic gain.

The glucocorticoid (GC) receptor (GR) mediates the effects of physiological and pharmacological GC ligands and has a major role in cutaneous pathophysiology. To dissect the epithelial versus mesenchymal contribution of GR in developing and adult skin, we generated mice with keratinocyte-restricted GR inactivation (GR epidermal knockout or GR(EKO) mice). Developing and early postnatal GR(EKO) mice exhibited impaired epidermal barrier formation, abnormal keratinocyte differentiation, hyperproliferation, and stratum corneum (SC) fragility. At birth, GR(EKO) epidermis showed altered levels of epidermal differentiation complex genes, proteases and protease inhibitors which participate in SC maintenance, and innate immunity genes. Many upregulated genes, including S100a8/a9 and Tslp, also have increased expression in inflammatory skin diseases. Infiltration of macrophages and degranulating mast cells were observed in newborn GR(EKO) skin, hallmarks of atopic dermatitis. In addition to increased extracellular signal-regulated kinase activation, GR(EKO) newborn and adult epidermis had increased levels of phosphorylated signal transducer and activator of transcription 3, a feature of psoriasis. Although adult GR(EKO) epidermis had a mild phenotype of increased proliferation, perturbation of skin homeostasis with detergent or phorbol ester triggered an exaggerated proliferative and hyperkeratotic response relative to wild type. Together, our results show that epidermal loss of GR provokes skin barrier defects and cutaneous inflammation.

Wingless and int (Wnt) proteins are secreted proteins that are important for regulating hematopoietic stem cell self-renewal and differentiation in the bone marrow microenvironment in mice. The mechanisms by which Wnt signaling regulates these hematopoietic cell fate decisions are not fully understood. Secreted Wnt antagonists, which are expressed in bone and bone marrow stromal cells, either bind to Wnt ligands directly or block Wnt receptors and co-receptors to halt Wnt-mediated signal transduction in both osteolineage and hematopoietic cell types. Secreted frizzled related proteins-1 and -2, Wnt inhibitory factor-1, Dickkopf-1, and Sclerostin are Wnt antagonists that influence hematopoietic cell fate decisions in the bone marrow niche. In this review, we compare and contrast the roles of these Wnt antagonists and their effects on hematopoietic development in mice, and also discuss the clinical significance of targeting Wnt antagonists within the context of hematopoietic disease., (Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Long-term transplant outcome is importantly influenced by the age of the organ donor. The mechanisms how age carries out its pathophysiological impact on graft survival are still not understood. One major contributing factor for the observed poor performance of old donor kidneys seems in particular the age-related loss in renal regenerative capacity. In this review, we will summarize recent findings about the molecular basis of renal aging with specific focus on the potential role of somatic cellular senescence and mitochondrial aging in renal transplant outcome., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The processes of bone growth, modeling, and remodeling determine the structure, mass, and biomechanical properties of the skeleton. Dysregulated bone resorption or bone formation may lead to metabolic bone diseases. The Wnt pathway plays an important role in bone formation and regeneration, and expression of two Wnt pathway inhibitors, sclerostin and Dickkopf-1 (DKK1), appears to be associated with changes in bone mass. Inactivation of sclerostin leads to substantially increased bone mass in humans and in genetically manipulated animals. Studies in various animal models of bone disease have shown that inhibition of sclerostin using a monoclonal antibody (Scl-Ab) increases bone formation, density, and strength. Additional studies show that Scl-Ab improves bone healing in models of bone repair. Inhibition of DKK1 by monoclonal antibody (DKK1-Ab) stimulates bone formation in younger animals and to a lesser extent in adult animals and enhances fracture healing. Thus, sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair. Clinical trials are ongoing to evaluate the effects of Scl-Ab and DKK1-Ab in humans for the treatment of bone loss and for bone repair.

Objective: To confirm that oocyte-specific messenger RNAs are detectable in the polar body (PB) of metaphase II (MII) oocytes and determine the effect of age on oocyte-specific transcript levels., Design: Prospective study., Setting: Hospital-based academic research laboratory., Animal(s): CD1 female mice., Intervention(s): Aged (40-50 weeks) and young (7-9 weeks) mice were administered pregnant mare serum gonadotropin (PMSG) and hCG. Oocytes were fertilized in vitro to assess fertilization and developmental competence. The MII oocytes were obtained and first PBs were removed. Messenger RNAs from each PB and its sibling oocyte were reverse transcribed and analyzed by real-time quantitative polymerase chain reaction (PCR)., Main Outcome Measure(s): Fertilization and developmental rates and expression of six oocyte-specific genes (Bmp15, Gdf9, H1foo, Nlrp5, Tcl1, and Zp3) in PBs and sibling oocytes from young versus aged mice., Result(s): Oocytes from aged mice had lower developmental competence. Four genes (H1foo, Nlrp5, Tcl1, and Zp3) were differentially expressed in aged versus young oocytes. All six transcripts were present in PBs from aged and young mice at lower levels than in the sibling oocytes; transcript levels were lower in aged PBs compared with young PBs., Conclusion(s): There is a significant difference in the transcript levels of oocyte-specific genes in aged versus young PB that correlates with age-related decreases in oocyte competence. Differences in gene expression in PB may be potential biomarkers of MII oocyte competence., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Harvest index is a measure of success in partitioning assimilated photosynthate. An improvement of harvest index means an increase in the economic portion of the plant. Our objective was to identify genetic markers associated with harvest index traits using 203 O. sativa accessions. The phenotyping for 14 traits was conducted in both temperate (Arkansas) and subtropical (Texas) climates and the genotyping used 154 SSRs and an indel marker. Heading, plant height and weight, and panicle length had negative correlations, while seed set and grain weight/panicle had positive correlations with harvest index across both locations. Subsequent genetic diversity and population structure analyses identified five groups in this collection, which corresponded to their geographic origins. Model comparisons revealed that different dimensions of principal components analysis (PCA) affected harvest index traits for mapping accuracy, and kinship did not help. In total, 36 markers in Arkansas and 28 markers in Texas were identified to be significantly associated with harvest index traits. Seven and two markers were consistently associated with two or more harvest index correlated traits in Arkansas and Texas, respectively. Additionally, four markers were constitutively identified at both locations, while 32 and 24 markers were identified specifically in Arkansas and Texas, respectively. Allelic analysis of four constitutive markers demonstrated that allele 253 bp of RM431 had significantly greater effect on decreasing plant height, and 390 bp of RM24011 had the greatest effect on decreasing panicle length across both locations. Many of these identified markers are located either nearby or flanking the regions where the QTLs for harvest index have been reported. Thus, the results from this association mapping study complement and enrich the information from linkage-based QTL studies and will be the basis for improving harvest index directly and indirectly in rice.

DNA barcoding has been a major advancement in the field of taxonomy, seeing much effort put into the barcoding of wide taxa of organisms, macro and microalgae included. The mitochondrial-encoded cox1 and plastid-encoded rbcL has been proposed as potential DNA barcodes for rhodophytes, but are yet to be tested on the commercially important carrageenophytes Kappaphycus and Eucheuma. This study gauges the effectiveness of four markers, namely the mitochondrial cox1, cox2, cox2-3 spacer and the plastid rbcL in DNA barcoding on selected Kappaphycus and Eucheuma from Southeast Asia. Marker assessments were performed using established distance and tree-based identification criteria from earlier studies. Barcoding patterns on a larger scale were simulated by empirically testing on the commonly used cox2-3 spacer. The phylogeny of these rhodophytes was also briefly described. In this study, the cox2 marker which satisfies the prerequisites of DNA barcodes was found to exhibit moderately high interspecific divergences with no intraspecific variations, thus a promising marker for the DNA barcoding of Kappaphycus and Eucheuma. However, the already extensively used cox2-3 spacer was deemed to be in overall more appropriate as a DNA barcode for these two genera. On a wider scale, cox1 and rbcL were still better DNA barcodes across the rhodophyte taxa when practicality and cost-efficiency were taken into account. The phylogeny of Kappaphycus and Eucheuma were generally similar to those earlier reported. Still, the application of DNA barcoding has demonstrated our relatively poor taxonomic comprehension of these seaweeds, thus suggesting more in-depth efforts in taxonomic restructuring as well as establishment.

Background and Purpose: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model., Methods: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma., Results: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force., Interpretation: Scl-Ab increases bone formation and screw fixation to a similar degree in loaded and unloaded bone.

Background: The definition of bone quality is evolving particularly from the perspective of anabolic agents that can enhance not only bone mineral density but also bone microarchitecture, composition, morphology, amount of microdamage, and remodeling dynamics., Questions/purposes: This review summarizes the molecular pathways and physiologic effects of current and potential anabolic drugs., Methods: From a MEDLINE search (1996-2010), articles were identified by the search terms "bone quality" (1851 articles), "anabolic agent" (5044 articles), "PTH or parathyroid hormone" (32,229 articles), "strontium" or "strontium ranelate" (283 articles), "prostaglandin" (77,539 articles), and "statin" or "statins" (14,233 articles). The search strategy included combining each with the phrase "bone quality." Another more limited search aimed at finding more novel potential agents., Results: Parathyroid hormone is the only US Food and Drug Administration-approved bone anabolic agent in the United States and has been the most extensively studied in in vitro animal and human trials. Strontium ranelate is approved in Europe but has not undergone Food and Drug Administration trials in the United States. All the studies on prostaglandin agonists have used in vivo animal models and there are no human trials examining prostaglandin agonist effects. The advantages of statins include the long-established advantages and safety profile, but they are limited by their bioavailability in bone. Other potential pathways include proline-rich tyrosine kinase 2 (PYK2) and sclerostin (SOST) inhibition, among others., Conclusions: The ongoing research to enhance the anabolic potential of current agents, identify new agents, and develop better delivery systems will greatly enhance the management of bone quality-related injuries and diseases in the future.

Background: The epithelial cell adhesion molecule (EpCAM) is overexpressed on carcinomas, and its downregulation inhibits the oncogenic potential of multiple tumour types. Here, we investigated underlying mechanisms of epcam overexpression in ovarian carcinoma., Methods: Expression of EpCAM and DNA methylation (bisulphite sequencing) was determined for ovarian cancer cell lines. The association of histone modifications and 16 transcription factors with the epcam promoter was analysed by chromatin immunoprecipitation. Treatment with 5-Aza-2'-deoxycytidine (5-AZAC) was used to induce EpCAM expression., Results: Expression of EpCAM was correlated with DNA methylation and histone modifications. Treatment with 5-AZAC induced EpCAM expression in negative cells. Ten transcription factors were associated with the epcam gene in EpCAM expressing cells, but not in EpCAM-negative cells. Methylation of an Sp1 probe inhibited the binding of nuclear extract proteins in electromobility shift assays; such DNA methylation sensitivity was not observed for an NF-κB probe., Conclusion: This study provides insights in transcriptional regulation of epcam in ovarian cancer. Epigenetic parameters associated with EpCAM overexpression are potentially reversible, allowing novel strategies for sustained silencing of EpCAM expression.

Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of breast cancer, though findings have been inconsistent. This inconsistency may result from differences in etiology for breast tumors of different subtypes. We examined the association between NSAID use and breast cancer characterized by molecular subtypes in a population-based case-control study in Western New York. Cases (n = 1,170) were women with incident, primary, histologically confirmed breast cancer. Controls (n = 2,115) were randomly selected from NY Department of Motor Vehicles records (<65 years) or Medicare rolls (≥ 65 years). Participants answered questions regarding their use of aspirin and ibuprofen in the year prior to interview and their use of aspirin throughout their adult life. Logistic regression models estimated odds ratios (OR) and 95% confidence intervals (95% CI). Recent and lifetime aspirin use was associated with reduced risk, with no differences by subtype. Recent use of ibuprofen was significantly associated with increased risk of ER+/PR+(OR 1.33, 95% CI: 1.09-1.62), HER2- (OR 1.27, 95% CI: 1.05-1.53), and p53- breast cancers (OR 1.28, 95% CI: 1.04-1.57), as well as luminal A or B breast cancers. These findings support the hypothesis of heterogeneous etiologies of breast cancer subtypes and that aspirin and ibuprofen vary in their effects.

Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A(-) variant deficiency, and β-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA.

MiRNAs regulate cardiac development, hypertrophy, and angiogenesis, but their role in cardiac hypertrophy (CH) induced by aerobic training has not previously been studied. Aerobic training promotes physiological CH preserving cardiac function. This study assessed involvement of miRNAs-29 in CH of trained rats. Female Wistar rats (n=7/group) were randomized into three groups: sedentary (S), training 1 (T1), training 2 (T2). T1: swimming sessions of 60 min/5 days/wk/10 wk. T2: similar to T1 until 8th wk. On the 9th wk rats swam 2×/day, and on the 10th wk 3×/day. MiRNAs analysis was performed by miRNA microarray and confirmed by real-time PCR. We assessed: markers of training, CH by ratio of left ventricle (LV) weight/body wt and cardiomyocytes diameter, pathological markers of CH (ANF, skeletal α-actin, α/β-MHC), collagen I and III (COLIAI and COLIIIAI) by real-time PCR, protein collagen by hydroxyproline (OH-proline) concentration, CF and CH by echocardiography. Training improved aerobic capacity and induced CH. MiRNAs-1, 133a, and 133b were downregulated as observed in pathological CH, however, without pathological markers. MiRNA-29c expression increased in T1 (52%) and T2 (123%), correlated with a decrease in COLIAI and COLIIIAI expression in T1 (27%, 38%) and T2 (33%, 48%), respectively. MiRNA-29c was inversely correlated to OH-proline concentration (r=0.61, P<0.05). The E/A ratio increased in T2, indicating improved LV compliance. Thus, these results show that aerobic training increase miR-29 expression and decreased collagen gene expression and concentration in the heart, which is relevant to the improved LV compliance and beneficial cardiac effects, associated with aerobic high performance training.

Ginseng is one of the most widely used herbal medicines in the world. Wild ginseng is thought to be more effective than cultivated ginseng in chemoprevention; however, little has been reported on the differences between wild and cultivated ginseng. In the present study we used suppressive subtractive hybridization to identify wild ginseng-specific genes. One of the clones isolated in this screen was the NRT2 gene (designated pNRT2), a high-affinity nitrate transporter. Real-time reverse transcription-polymerase chain reaction results showed that pNRT2 expression was significantly upregulated in wild ginseng compared with cultivated ginseng. However, pNRT2 mRNA levels were similar between mountain cultivated ginseng and mountain wild ginseng. Nitrate is an important nitrogen source for plant growth, and its soil levels can vary in wild environments; thus it is conceivable that pNRT2 expression is upregulated in wild ginseng and may be an important marker of wild ginseng., (Copyright © 2011 Korean Pharmacopuncture Institute. Published by .. All rights reserved.)

Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p=0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene-environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p=0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement.

The terminal structures of the Borna disease virus (BDV) genome (vRNA) and antigenome (cRNA) differ from those of other negative strand RNA viruses, as both molecules possess four nucleotides at the 3' terminus without an apparent template at the 5' end of the opposite strand. Consequently, the v- and cRNA molecules are not perfect mirror images, a situation that is not compatible with conventional strategies to maintain genetic information. We show here that recombinant viruses recovered from cDNA lacking the nontemplated nucleotides efficiently reconstitute the 3' overhangs. Analyses of recombinant viruses encoding genetic markers in potential alternative template sequences demonstrated that the BDV v- and cRNA molecules are extended by a realign-and-elongation process on internal template motifs located in close proximity to the 3' ends of v- and cRNA, respectively. The data further suggest that cRNA elongation is restricted to a single template motif of the nascent strand, whereas elongation of vRNA might use multiple template motifs. We propose that the elongation of the 3' termini supports the terminal integrity of the genomic RNA molecules during BDV persistence, and furthermore provides an elegant strategy to eliminate the triphosphate groups from the 5' termini of the BDV v- and cRNA without compromising the genetic information of the virus.

Background and Objectives: The serum proteins sclerostin and Dickkopf-1 (Dkk-1) are soluble inhibitors of canonical wnt signaling and were recently identified as components of parathyroid hormone (PTH) signal transduction. This study investigated the associations between sclerostin and Dkk-1 with histomorphometric parameters of bone turnover, mineralization, and volume in stage 5 chronic kidney disease patients on dialysis (CKD-5D)., Design, Setting, Participants, & Measurements: In a cross-sectional study, 60 CKD-5D patients underwent bone biopsies followed by histomorphometry. Levels of sclerostin, Dkk-1, and intact PTH (iPTH) were determined in blood., Results: Serum levels of sclerostin and iPTH correlated negatively. In unadjusted analyses, sclerostin correlated negatively with histomorphometric parameters of turnover, osteoblastic number, and function. In adjusted analyses, sclerostin remained a strong predictor of parameters of bone turnover and osteoblast number. An observed correlation between sclerostin and cancellous bone volume was lost in regression analyses. Sclerostin was superior to iPTH for the positive prediction of high bone turnover and number of osteoblasts. In contrast, iPTH was superior to sclerostin for the negative prediction for high bone turnover and had similar predictive values than sclerostin for the number of osteoblasts. Serum levels of Dkk-1 did not correlate with iPTH or with any histomorphometric parameter., Conclusions: Our data describe a promising role for serum measurements of sclerostin in addition to iPTH in the diagnosis of high bone turnover in CKD-5D patients, whereas measurements of Dkk-1 do not seem to be useful for this purpose., (© 2011 by the American Society of Nephrology)

Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Because microRNAs have been recently implicated in the regulation of cell proliferation and apoptosis, we hypothesized that these regulatory molecules might be implicated in the etiology of PAH. In this study, we show that miR-204 expression in PASMCs is down-regulated in both human and rodent PAH. miR-204 down-regulation correlates with PAH severity and accounts for the proliferative and antiapoptotic phenotypes of PAH-PASMCs. STAT3 activation suppresses miR-204 expression, and miR-204 directly targets SHP2 expression, thereby SHP2 up-regulation, by miR-204 down-regulation, activates the Src kinase and nuclear factor of activated T cells (NFAT). STAT3 also directly induces NFATc2 expression. NFAT and SHP2 were needed to sustain PAH-PASMC proliferation and resistance to apoptosis. Finally, delivery of synthetic miR-204 to the lungs of animals with PAH significantly reduced disease severity. This study uncovers a new regulatory pathway involving miR-204 that is critical to the etiology of PAH and indicates that reestablishing miR-204 expression should be explored as a potential new therapy for this disease.

The functional outcome after stroke is unpredictable; it is not accurately predicted by clinical pictures upon hospital admission. The presence of apoptotic neurons in the ischemic penumbra and perihematoma area may account for poor prognosis, but whether the highly variable stroke outcome reflects differences in genetic susceptibility to apoptosis is elusive. The p53 tumor suppressor protein, an important transcriptional regulator of apoptosis, naturally occurs in humans in two variants with single nucleotide polymorphisms resulting in Arg or Pro at residue 72. We show that poor functional outcome after either ischemic or hemorrhagic stroke was linked to the Arg/Arg genotype. This genotype was also associated with early neurological deterioration in ischemic stroke and with increased residual cavity volume in intracerebral hemorrhage. In primary cultured neurons, Arg(72)-p53, but not Pro(72)-p53, interacted directly with mitochondrial Bcl-xL and activated the intrinsic apoptotic pathway, increasing vulnerability to ischemia-induced apoptotic cell death. These results suggest that the Tp53 Arg/Arg genotype governs neuronal vulnerability to apoptosis and can be considered as a genetic marker predicting poor functional outcome after stroke.

Two hundred and fifty bread wheat lines, mainly Chinese mini core accessions, were assayed for polymorphism and linkage disequilibrium (LD) based on 512 whole-genome microsatellite loci representing a mean marker density of 5.1 cM. A total of 6,724 alleles ranging from 1 to 49 per locus were identified in all collections. The mean PIC value was 0.650, ranging from 0 to 0.965. Population structure and principal coordinate analysis revealed that landraces and modern varieties were two relatively independent genetic sub-groups. Landraces had a higher allelic diversity than modern varieties with respect to both genomes and chromosomes in terms of total number of alleles and allelic richness. 3,833 (57.0%) and 2,788 (41.5%) rare alleles with frequencies of <5% were found in the landrace and modern variety gene pools, respectively, indicating greater numbers of rare variants, or likely new alleles, in landraces. Analysis of molecular variance (AMOVA) showed that A genome had the largest genetic differentiation and D genome the lowest. In contrast to genetic diversity, modern varieties displayed a wider average LD decay across the whole genome for locus pairs with r(2)>0.05 (P<0.001) than the landraces. Mean LD decay distance for the landraces at the whole genome level was <5 cM, while a higher LD decay distance of 5-10 cM in modern varieties. LD decay distances were also somewhat different for each of the 21 chromosomes, being higher for most of the chromosomes in modern varieties (<5 ∼ 25 cM) compared to landraces (<5 ∼ 15 cM), presumably indicating the influences of domestication and breeding. This study facilitates predicting the marker density required to effectively associate genotypes with traits in Chinese wheat genetic resources.