Biology subjects

Jiang, Q.

Publications and source records attributed to Jiang, Q..

120 records · Page 7Linked to original sources

bioRxiv2019

The Clinical Significance and Biological Function of DPEP1 in B-cell Acute Lymphoblastic Leukemia

Dehydropeptidase-1 (DPEP1) is a zinc-dependent metalloproteinase abnormally expressed in many cancers. However, its potential role in adults with B-cell acute lymphoblastic leukaemia (ALL) is unknown.\n\nWe found that in adults with common-B-cell ALL high DPEP1 transcript levels at diagnosis was independently-associated with an increased CIR and worse RFS compared with subjects with low transcript levels. We show an increased proliferation and pro-survival role of DPEP1 in B-cell ALL cells via regulation of phosphCREB and p53 which may be the biological basis of the clinical correlation we report. Our data implicate DPEP1 expression in the biology of common B-cell ALL in adults. We report clinical correlates and provide a potential biological basis for these correlations. If confirmed, analyzing DPEP1 transcript levels at diagnosis could help predict therapy-outcomes. Moreover, regulation of DPEP1 expression could be a therapy target in B-cell ALL.

molecular biology↗

bioRxiv2019

Low rate of follow-up colonoscopy after positive results of colorectal cancer screening in a Chinese urban core district

Colorectal cancer (CRC) is one of the most common cancers in China. In 2003, a systematic CRC registry that enables the determination of CRC incidence and mortality and a CRC screening project were introduced in the Jingan district of Shanghai by the municipal government. This study assessed the registry data to determine the status of CRC and CRC screening rates in the core district of an urban area of China. Data were retrieved from the Official registry information systems of Jingan district Shanghai Cance. The incidence and mortality of CRC, as well as population-based CRC screening rates, were analysed. Individuals who screened positive for CRC based upon results of a high-risk factor questionnaire (HRFQ) and a faecal immunochemical test (FIT) were selected for follow-up colonoscopy (CSPY). From the registry data collected between 2003 and 2013, the standardized incidence rate was 26.44/105, with a significant gender difference. The CRC standardized mortality rate was 10.08/105. In 2013, 17,866 individuals (21.6%) enrolled for CRC screening among the 82,602 candidate residents. The positive screening rate was 16.28% (2909/17866). Among the 2909 positives, 508 (17.5%) underwent follow-up CSPY. In 41.3% of these individuals (210/508), abnormal lesions were detected. Of these, 8 (1.57%) lesions were diagnosed as CRC, and 142 (28.0%) were identified as precancerous lesions. During the assessment period, both the incidence and mortality of CRC in the Jingan district were determined in the area of high CRC prevalence in Chin. Nevertheless, the rate of participation in CRC screening was low (21.6%), and the rate of participation in follow-up CSPY for individuals who screened positive was only 17.5%. Improved participation in CRC screening and follow-up CSPY is expected to lower the incidence and mortality of CRC significantly in the rural areas of China. (288)

cancer biology↗

bioRxiv2019

Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

Age is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

physiology↗

bioRxiv2019

A 3-hydroxy-3-methylglutaryl-CoA synthase-based probe for the discovery of the acyltransferase-less type I polyketide synthases

Acyltransferase (AT)-less type I polyketide synthases (PKSs) produce complex natural products due to the presence of many unique tailoring enzymes. The 3-hydroxy-3-methylglutaryl coenzyme A synthases (HCSs) are responsible for {beta}-alkylation of the growing polyketide intermediates in AT-less type I PKSs. In this study, we discovered a large group of HCSs, closely associated with the characterized and orphan AT-less type I PKSs through in silico genome mining, sequence and genome neighborhood network analysis. Using HCS-based probes, the survey of 1207 inhouse strains and 18 soil samples from different geological locations revealed the vast diversity of HCS-containing AT-less type I PKSs. The presence of HCSs in many AT-less type I PKSs suggests their co-evolutionary relationship. Our study should inspire future efforts to discover new polyketide natural products from AT-less type I PKSs.

microbiology↗

bioRxiv2018

Generation of Cynomolgus Monkeys (Macaca fascicularis) Embryos with ICSI Based on the MII-Stage Oocytes Acquired by Personalized Superovulation Protocol

The use of cynomolgus monkeys (Macaca fascicularis) has facilitated the establishment of gene-modified animal models, and the appropriate number of high-quality mature oocytes (MII-stage oocytes) are crucial in assisted reproductive technologies (ART) of cynomolgus macaques. In this study we performed 3 different superovulation protocols on 24 female cynomolgus monkeys aimed to improve the proportion of MII-stage oocyte retrieval. The results suggested some differences in the proportion of MII-stage oocytes between the personalized superovulation protocol and the superovulation protocols I and II. Afterwards, we performed Intracytoplasmic sperm injection (ICSI) on 22 MII-stage oocytes derived from one animal with personalized superovulation protocol, obtained 15 embryos of 2-4-cells, 2 cases of successful pregnancy after transferring to 4 surrogate female, and obtained 3 aborted fetuses. These results suggested that personalized superovulation protocol incorporated the menstrual cycle length of each cynomolgus monkey, and the timing of oocytes retrieval based on the equation: menstrual cycle length/2 {+/-} 1, which increased the rate of MII-stage oocytes acquired and generation of cynomolgus monkeys embryos with ICSI based on these oocytes, and finally could successfully develop into fetus under conditions that effectively guarantee the synchronization of the surrogate mothers.\n\nSUMMARY STATEMENTThe personalized superovulation protocol based on the menstrual cycle length of each cynomolgus monkey can increase the rate of MII-stage oocytes acquired, and finally could successfully develop into fetus under conditions that minimize damage to the surrogate mothers and effectively guarantee the synchronization of the surrogate mothers.

developmental biology↗

bioRxiv2018

A familial case of Syndactyly type IV due to a novel duplication of ~222.23 kb covering exons 2-17 of the LMBR1 gene: a case report

Syndactyly is one of the most frequent hereditary limb malformations with clinical and genetical complexity. Autosomal dominant Syndactyly type IV (SD4) is a very rare form of syndactyly, occurring as a result of heterozygous mutation in an SHH regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene on chromosome 7q36.3. The SD4 is characterized by complete cutaneous syndactyly of all fingers, cup-shaped hands due to flexion of the fingers and accompanied by polydactyly. Here, we firstly reported a big Chinese family, manifesting cup-shaped hands consistent with SD4 and intrafamilial heterogeneity in clinical phenotype of tibial and fibulal shortening, triphalangeal thumb-polysyndactyly syndrome (TPTPS). Genetically, we identified a novel duplication of [~]222.23 kb covering exons 2-17 of the LMBR1 gene in this family by next generation sequencing. This case expands our new clinical understanding of SD4 phenotype.

genetics↗

bioRxiv2018

Natural selection on TMPRSS6 associated with the blunted erythropoiesis and improved blood viscosity in Tibetan Pigs

Tibetan pigs, indigenous to Tibetan plateau, are well adapted to hypoxia. So far, there have been not any definitively described genes and functional sites responsible for hypoxia adaptation for the Tibetan pig. Here we conducted resequencing of the nearly entire genomic region (40.1 kb) of the candidate gene TMPRSS6 (Transmembrane protease, serine 6) associated with hemoglobin concentration (HGB) and red blood cell count (RBC) in 40 domestic pigs and 40 wild boars from five altitudes along the Tea-horse ancient road and identified 708 SNPs, in addition to an indel (CGTG/----) in the intron 10. Both the CGTG deletion frequency and the pairwise r2 linkage disequilibrium showed an increase with elevated altitudes in 838 domestic pigs from five altitudes, suggesting that TMPRSS6 has been under Darwinian positive selection. As the conserved core sequence of hypoxia-response elements (HREs), the deletion of CGTG in Tibetan pigs decreased the expression levels of TMPRSS6 mRNA and protein in the liver revealed by real-time quantitative PCR and western blot, respectively. To explore whether reduced TMPRSS6 expression level could improve blood viscosity, the relationship between CGTG indel and hematologic and hemorheologic parameters in 482 domestic pigs from continuous altitudes was detected and dissected a genetic effect on reducing HGB by 13.25g/L in Gongbogyamda Tibetan pigs and decreasing MCV by 4.79 fl in Diqing Tibetan pigs. In conclusion, the CGTG deletion of TMPRSS6 resulted in lower HGB and smaller MCV, thereby blunting erythropoiesis and improving blood viscosity as well as erythrocyte deformability.

physiology↗

bioRxiv2018

Dissecting PCNA function with a systematically designed mutation library in yeast

Proliferating cell nuclear antigen (PCNA), encoded by POL30 in Saccharomyces cerevisiae, is a key component of DNA metabolism. Here a library consisting of 308 PCNA mutants was designed and synthesized to probe the contribution of each residue to its biological function. Five regions were identified with elevated sensitivity to DNA damaging reagents using high-throughput phenotype screening. Using a series of genetic and biochemical analyses, we demonstrated that one particular mutant, K168A, which displayed severe DNA damage sensitivity, abolished the DNA damage tolerance (DDT) pathway by disrupting interactions between PCNA and Rad5p. Subsequent domain analysis showed that the PCNA/Rad5p interaction is prerequisite for the function of Rad5p in DDT. Our study not only provides a resource in the form of a library of versatile mutants to study PCNA functions, but also reveals a key regulatory function of Rad5p, which highlights the importance of the PCNA-Rad5p interaction.\n\nAuthor summaryPCNA is regarded as the maestro of DNA replication fork because of the astonishing ability to interact with lots of partner proteins that participate in various DNA metabolism processes. However, it has remained elusive as to how does PCNA orchestrate these functions in harmony. Here, we constructed a systematic mutation library of PCNA, which covers every amino acid to map the functional sites of it. This carefully designed synthetic mutant pool could be generally useful and serve as a flexible resource, such as dissecting the functional mechanism of PCNA by genetic relationship analysis with key proteins through Synthetic genetic array. We further dissected the intrinsic mechanism for damage sensitivity of PCNAK168A, the most severe DNA damage sensitive mutant in our alanine scanning mutation library, this helps us to get better understanding of how PCNA participates in DNA damage tolerance (DDT) pathways. Our findings indicate that K168 site is vital for the interaction between DDT related partner proteins and PCNA, and also highlight the importance of the PCNA-Rad5p interaction.

genetics↗

bioRxiv2018

Genetically increased serum calcium levels reduce Alzheimer’s disease risk

IMPORTANCE Alzheimers disease (AD) is the leading cause of disability in the elderly. It has been a long time about the calcium hypothesis of AD on the basis of emerging evidence since 1994. However, most studies focused on the association between calcium homeostasis and AD, and concerned the intracellular calcium concentration. Only few studies reported reduced serum calcium levels in AD. Until now, it remains unclear whether serum calcium levels are genetically associated with AD risk.\n\nOBJECTIVE To evaluate the genetic association between increased serum calcium levels and AD risk\n\nDESIGN, SETTING, AND PARTICIPANTS We performed a Mendelian randomization study to investigate the association of increased serum calcium with AD risk using the genetic variants from the large-scale serum calcium genome-wide association study (GWAS) dataset (N=61,079 individuals of European descent) and the large-scale AD GWAS dataset (N=54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Inverse-variance weighted meta-analysis (IVW) was used to provide a combined estimate of the genetic association. Meanwhile, we selected the weighted median regression and MR-Egger regression as the complementary analysis methods to examine the robustness of the IVW estimate.\n\nEXPOSURES Genetic predisposition to increased serum calcium levels\n\nMAIN OUTCOMES AND MEASURES The risk of AD.\n\nRESULTS We selected 6 independent genetic variants influencing serum calcium levels as the instrumental variables. IVW analysis showed that a genetically increased serum calcium level (per 1 standard deviation (SD) increase 0.5-mg/dL) was significantly associated with a reduced AD risk (OR=0.56, 95% CI: 0.34-0.94, P=5.00E-03). Meanwhile, both the weighted median estimate (OR=0.60, 95% CI: 0.34-1.06, P=0.08) and MR-Egger estimate (OR=0.66, 95% CI: 0.26-1.67, P=0.381) were consistent with the IVW estimate in terms of direction and magnitude.\n\nCONCLUSIONS AND RELEVANCE We provided evidence that genetically increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be further conducted to assess the effect of serum calcium levels on AD risk, and further clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.\n\nKey PointsQuestion Is there a genetic relationship between elevated serum calcium levels and the risk of Alzheimers disease?\n\nFindings This Mendelian randomization study showed that the genetically increased serum calcium levels were associated with the reduced risk of Alzheimers disease.\n\nMeaning These findings provide evidence that genetically increased serum calcium levels could reduce the risk of Alzheimers disease.

genetics↗

bioRxiv2017

Effect of vertical slit turbulence on metabolism and swimming behavior of juvenile grass carp (ctenopharyngodon idella)

Baffles were incorporated into the swim chamber of a flume-type swimming respirometer, and the effect of vertical slit turbulence on the swimming behavior and metabolism of juvenile grass carp were investigated. Results showed a significant lower TBF in turbulent flow than in laminar flow (p< 0.05). However, differences in TBF at different inlet velocities were not significant (p> 0.05), whether the fish passed through the baffles or not. In turbulent flow, the residence time ratios of test fish at different flow zone were low water velocity > medium velocity > high velocity. Oxygen consumption rate (MO2) increased with flow velocity and was higher in turbulent flow than in laminar flow. Further, the speed exponent c, in turbulent flow, was significantly higher than in laminar flow, indicated a decrease swimming efficiency. This study of fish swimming in turbulent flow extends knowledge of fish ecology and provides data for guiding the design of hydrokinetic turbulent where needed, so preventing ecological impacts.

animal behavior and cognition↗

bioRxiv2017

Beyond thermodynamic constraints: Evolutionary history shapes protein sequence variation

Biological evolution generates a surprising amount of site-specific variability in protein sequences. Yet attempts at modeling this process have been only moderately successful, and current models based on protein structural metrics explain, at best, 60% of the observed variation. Surprisingly, simple measures of protein structure, such as solvent accessibility, are often better predictors of site-specific variability than more complex models employing all-atom energy functions and detailed structural modeling. We suggest here that these more complex models perform poorly because they lack consideration of the evolutionary process that is in part captured by the simpler metrics. We compare protein sequences that are computationally designed to sequences that are computationally evolved using the same protein-design energy function and to homologous natural sequences. We find that by a wide variety of metrics, evolved sequences are much more similar to natural sequences than are designed sequences. In particular, designed sequences are too conserved on the protein surface relative to natural sequences whereas evolved sequences are not. Our results suggest that evolutionary simulation produces a realistic sampling of sequence space. By contrast, protein design--at least as currently implemented--does not. Existing energy functions seem to be sufficiently accurate to correctly describe the key thermodynamic constraints acting on protein sequences, but they need to be paired with realistic sampling schemes to generate realistic sequence alignments.

evolutionary biology↗

bioRxiv2017

Rice TSV3 Encoding Obg-like GTPase Protein is Essential for Chloroplast Development during the Early Leaf Stage under Cold Stress

The Spo0B-associated GTP-binding (Obg) proteins occupy a wide variety of roles in the viability of nearly all bacteria. Its detailed roles in higher plants have not yet been elucidated. A novel rice thermo-sensitive virescent mutant tsv3 was identified in this study that displayed albino phenotype at 20{degrees}C before the 3-leaf stage while being normal green at 32{degrees}C or even at 20{degrees}C after the 4-leaf stage. The mutant phenotype was aligned with altered chlorophyll (Chl) content and chloroplast development. Map-based cloning and complementation test showed that TSV3 encoded a kind of small GTP binding protein. Subcellular localization revealed that TSV3 was in chloroplast. TSV3 transcripts were highly expressed in leaves and weak or undetectable in other tissues, suggesting the tissue-specific expression. In tsv3 mutant, the transcriptional levels of certain genes associated with biogenesis of chloroplast ribosomes 50S subunit were severely decreased at the 3-leaf-stage under cold stress, but could be recovered to normal levels at a higher temperature (32{degrees}C). The observations from this study indicated that the rice nuclear-encoded TSV3 plays important roles in chloroplast development at early leaf stage under cold stress.

plant biology↗