Glycolytic enzyme Enolase-1 regulates insulin gene expression in pancreatic ß-cell.

Enolase-1 (Eno1) plays a critical role in regulating glucose metabolism; however, its specific impact on pancreatic islet ß-cells remains elusive. This study aimed to provide a preliminary exploration of Eno1 function in pancreatic islet ß-cells. The findings revealed that the expression of ENO1 mRNA in type 2 diabetes donors was significantly increased and positively correlated with HbA1C and negatively correlated with insulin gene expression. A high level of Eno1 in human insulin-secreting rat INS-1832/13 cells with co-localization with intracellular insulin proteins was accordingly observed. Silencing of Eno1 using siRNA or inhibiting Eno1 protein activity with an Eno1 antagonist significantly reduced insulin secretion and insulin content in ß-cells, while the proinsulin/insulin content ratio remained unchanged. This reduction in ß-cells function was accompanied by a notable decrease in intracellular ATP and mitochondrial cytochrome C levels. Overall, our findings confirm that Eno1 regulates the insulin secretion process, particularly glucose metabolism and ATP production in the ß-cells. The mechanism primarily involves its influence on insulin production, suggesting that Eno1 represents a potential target for ß-cell protection and diabetes treatment.

Anciently duplicated genes continuously recruited to heart expression in vertebrate evolution are associated with heart chamber increase.

Although gene/genome duplications in the early stage of vertebrates have been thought to provide major resources of raw genetic materials for evolutionary innovations, it is unclear whether they continuously contribute to the evolution of morphological complexity during the course of vertebrate evolution, such as the evolution from two heart chambers (fishes) to four heart chambers (mammals and birds). We addressed this issue by our heart RNA-Seq experiments combined with published data, using 13 vertebrates and one invertebrate (sea squirt, as an outgroup). Our evolutionary transcriptome analysis showed that number of ancient paralogous genes expressed in heart tends to increase with the increase of heart chamber number along the vertebrate phylogeny, in spite that most of them were duplicated at the time near to the origin of vertebrates or even more ancient. Moreover, those paralogs expressed in heart exert considerably different functions from heart-expressed singletons: the former are functionally enriched in cardiac muscle and muscle contraction-related categories, whereas the latter play more basic functions of energy generation like aerobic respiration. These findings together support the notion that recruiting anciently paralogous genes that are expressed in heart is associated with the increase of chamber number in vertebrate evolution.

Associations of metabolic dysfunction-associated fatty liver disease and hepatic fibrosis with bone mineral density and risk of osteopenia/osteoporosis in T2DM patients.

Background: Existing evidence on the associations of liver steatosis and fibrosis with bone mineral density (BMD) and risk of osteopenia/osteoporosis was limited with conflicting results. We aimed to evaluate the associations of metabolic dysfunction-associated fatty liver disease (MAFLD) and hepatic fibrosis with BMD and risk of osteopenia/osteoporosis in type 2 diabetes mellitus (T2DM) patients. Methods: Baseline information of an ongoing cohort of 249 T2DM patients in Xiamen, China was analyzed. MAFLD was defined as the presence of hepatic steatosis [diagnosed by either hepatic ultrasonography scanning or fatty liver index (FLI) score >60] for T2DM patients. BMD was measured using dual-energy x-ray absorptiometry at total lumbar (L2-4), femur neck (FN), and total hip (TH) and was categorized as normal (T ≥ -1.0), osteopenia (-2.5 < T < -1.0), or osteoporosis (T ≤ -2.5) according to its minimum T-score. Results: Among the 249 T2DM patients, prevalence rates of MAFLD, osteopenia, and osteoporosis were 57.8%, 50.6%, and 17.7%, respectively. Patients with MAFLD had significantly higher BMD T-scores of L2-4, FN, and TH and the minimum as well as lower prevalence of osteoporosis than patients without MAFLD. Hepatic steatosis indices, including FLI score, fatty liver (FLI ≥ 60 or hepatic ultrasonography scanning), and MAFLD, were significantly and positively associated with all T-scores, while hepatic fibrosis index and FIB-4 score, but not NAFLD fibrosis score (NFS), were negatively associated with all T-scores. MAFLD was significantly associated with the decreased risk of osteopenia/osteoporosis and osteoporosis with unadjusted odds ratios (ORs) (95% CI) of 0.565 (0.324-0.987) and 0.434 (0.224-0.843) (both p-values < 0.05), respectively. As for liver fibrosis, FIB-4 score, but not NFS, was significantly associated with elevated risk of osteoporosis with an unadjusted OR (95% CI) per SD increase of FIB-4 score of 1.446 (1.080-1.936, p-value = 0.013). Adjusting for potential confounding variables, especially body mass index, in the multivariable regression analyses, all associations of hepatic steatosis and fibrosis indices with BMD and risk of osteopenia/osteoporosis were not statistically significant. Conclusion: MAFLD and hepatic fibrosis were not significantly associated with BMD and risk of osteopenia/osteoporosis independent of obesity. Nevertheless, screening and management of MAFLD and osteopenia/osteoporosis were still important for the prevention of fracture in T2DM patients.

Correction: Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci.

[This corrects the article DOI: 10.1371/journal.pgen.1009431.].

A pharmacokinetic analysis of amisulpride in adult Chinese patients with schizophrenia: Impact of creatinine clearance.

OBJECTIVE: To develop a stable population pharmacokinetic (PPK) model of amisulpride and to investigate the effects of covariates on the pharmacokinetic parameters in adult Chinese patients with schizophrenia. MATERIALS AND METHODS: This retrospective study was carried out using 168 serum samples from 88 patients collected during routine clinical monitoring. Covariates recorded included demographic parameters (gender, age, weight), clinical parameters (serum creatinine, creatinine clearance), and intake of co-medications. The amisulpride PPK model was established using a nonlinear mixed effects modeling (NONMEM) approach. Goodness-of-fit (GOF) plots, bootstrap validation (1,000 runs), and normalized prediction distribution error (NPDE) were used in the evaluation of the final model. RESULTS: A one-compartment model with first-order absorption and elimination was developed. The population estimates for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 32.6 L/h and 391 L, respectively. Estimated creatinine clearance (eCLcr) was a significant covariate for CL/F. The established model was: CL/F = 32.6 × (eCLcr/114.3)0.485 (L/h). The stability of the model was confirmed using GOF plots, bootstrap, and NPDE. CONCLUSION: Creatinine clearance is a major covariate which is positively correlated with CL/F. Therefore, additional dose adjustments of amisulpride may be required on the basis of eCLcr. An ethnic difference may exist in the pharmacokinetics of amisulpride, but further research is needed in order to confirm this possibility. The PPK model of amisulpride for adult Chinese schizophrenic patients established here using NONMEM, is potentially an important tool for individualizing drug dosage and therapeutic drug monitoring.

Non-obese or lean non-alcoholic fatty liver disease was associated with increased risk of cancer in patients with type 2 diabetes mellitus.

INTRODUCTION: Risk of non-obese or lean non-alcoholic fatty liver disease (NAFLD) for cancer in patients with type 2 diabetes mellitus (T2DM) is less known. We aimed to evaluate independent associations of NAFLD, especially non-obese or lean NAFLD, and body mass index (BMI) on risks of cancer in patients with T2DM. RESEARCH DESIGN AND METHODS: Cross-sectional analyses of baseline information on a cohort of 233 patients with T2DM were conducted in Xiamen, China. NAFLD was identified by hepatic ultrasonography diagnosis of hepatic steatosis without excessive alcohol consumption, viral or autoimmune liver disease. Fibrosis-4 (FIB-4) score was calculated to quantify severity of hepatic fibrosis. RESULTS: All types of cancers were diagnosed on 19 (8.2%) patients. Prevalence of cancer was significantly higher in those with NAFLD than those without (15.5% vs 4.0%, p=0.002), but were not significantly different among BMI categories (6.8%, 13.7% and 6.5% for those with underweight or normal weight (n=74), overweight (n=51) and obesity (n=108), respectively, p=0.258). With adjustment for potential confounding factors in the multivariable logistic regression models, NAFLD was significantly associated with increased risk of cancer with the adjusted OR (95% CI) of 5.969 (1.349 to 26.413, p=0.019). Stratified analyses across BMI categories found similar association of NAFLD with risk of cancer for those non-obese or lean (the adjusted OR (95% CI) 17.446 (1.690 to 180.095, p=0.016)) but not for those with either overweight (OR (95% CI) 11.642 (0.832 to 162.963, p=0.068) or obesity (OR (95% CI) 0.917 (0.170 to 4.954, p=0.920). FIB-4 score was not significantly associated with risk of cancer for all subjects or stratified across BMI categories. BMI was not significantly associated with risk of cancer for all patients or stratified by NAFLD. CONCLUSIONS: NAFLD, even non-obese or lean NAFLD, was independently associated with increased risk of cancer in patients with T2DM. Screening and management of NAFLD, especially for those with underweight or normal weight, should be strengthened from the perspective of improving prevention and management of cancer in patients with T2DM.

Association of Plasma Sex-Related Hormones Levels with Bone Mineral Densities and Risk of Osteoporosis and Osteopenia in Men and Menopausal Women with Type 2 Diabetes Mellitus.

Objective: This study aimed to examine associations between plasma sex-related hormones with bone mineral density (BMD) and risks of osteoporosis or osteopenia in men and postmenopausal women patients with type 2 diabetes mellitus (T2DM). Methods: Baseline information on an ongoing cohort of 149 men and 102 postmenopausal women with T2DM in Xiamen, China were analyzed. Plasma estradiol (E2), total testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PRL) were measured. BMD of lumbar spine (L2-4), femoral neck (FN) and total hip (TH) were determined by dual-energy X-ray absorptiometry (DXA). Osteoporosis or osteopenia was defined as the minimum T-scores of BMD of these three different sites of -1.0 or below. Results: T2DM patients with osteoporosis/osteopenia (66.4% in men and 79.4% in postmenopausal women), compared to those without, showed significantly decreased level of E2 (75.3±28.9 vs. 107.8±25.9pmol/L and 18.4 (18.4-29.5) vs. 22.8 (18.4-40.5) pmol/L for men and postmenopausal women, respectively, both p-values <0.05), but not other sex-related hormones (including T, FSH, LH, or PRL). For all T2DM patients together and men separately, multivariable linear regression and logistic regression analyses showed that higher E2 levels were significantly associated with higher BMD T-scores in L2-4, FN, TH and minimum of these three different sites, lower 10-year probability of major osteoporotic fractures (MOF) and hip fractures (HFs) estimated by Fracture Risk Assessment Tool score, as well as decreased risk of osteoporosis/osteopenia. As for postmenopausal women T2DM patients, E2 level was positively associated with BMD T-scores in L2-4 and minimum of three different sites but was not independently associated with risk of osteoporosis/osteopenia. Conclusion: Higher plasma E2 was significantly associated with increased BMD and lower risk of osteoporosis or osteopenia in T2DM patients, especially for men. Screening of BMD and estradiol levels as well as evaluating risks of osteoporosis/osteopenia are important for T2DM patients.

Plumeriapropionics A-E, Carboxyl-Substituted Phenylpropionic Acid Derivatives with Anti-Inflammatory Activity from Plumeria rubra L.

Five rare carboxyl-substituted phenylpropionic acid derivatives, plumeriapropionics A-E (1-5), together with one known analog, cerberic acid B (6), were isolated from flowers of Plumeria rubra L. Their structures were elucidated using comprehensive spectroscopic methods. To date, only one compound of this structural type has been reported. The inhibitory activities of compounds 1-6 against nitric oxide (NO) production induced by lipopolysaccharide (LPS) were evaluated in vitro using mouse macrophage RAW264.7 cells. Compounds 1-6 showed remarkable inhibitory activities on NO production, with IC50 values in the range of 6.52 ± 0.23 to 35.68 ± 0.17 µM. These results indicate that the discovery of carboxyl-substituted phenylpropionic acid derivatives from the flowers of P. rubra, which show significant anti-inflammatory properties, could be of great importance for the research and development of novel natural anti-inflammatory agents.

Draft Genome of White-blotched River Stingray Provides Novel Clues for Niche Adaptation and Skeleton Formation.

The white-blotched river stingray (Potamotrygon leopoldi) is a cartilaginous fish native to the Xingu River, a tributary of the Amazon River system. As a rare freshwater-dwelling cartilaginous fish in the Potamotrygonidae family in which no member has the genome sequencing information, P. leopoldi provides the evolutionary details in fish phylogeny, niche adaptation, and skeleton formation. In this study, we present its draft genome of 4.11 Gb comprised of 16,227 contigs and 13,238 scaffolds, with contig N50 of 3937 kb and scaffold N50 of 5675 kb in size. Our analysis shows that P. leopoldi is a slow-evolving fish that diverged from elephant sharks about 96 million years ago. Moreover, two gene families related to the immune system, immunoglobulin heavy constant delta genes and T-cell receptor alpha/delta variable genes, exhibit expantion in P. leopoldi only. We also identified the Hox gene clusters in P. leopoldi and discovered that seven Hox genes shared by five representative fish species are missing in P. leopoldi. The RNA sequencing data from P. leopoldi and other three fish species demonstrate that fishes have a more diversified tissue expression spectrum as compared with the corresponding mammalian data. Our functional studies suggest that the lack of the GC gene encoding vitamin D-binding protein in cartilaginous fishes (both P. leopoldi and Callorhinchus milii) could partly explain the absence of hard bone in their endoskeleton. Overall, this genome resource provides new insights into the niche adaptation, body plan, and skeleton formation of P. leopoldi as well as the genome evolution in cartilaginous fishes.

Associations of Obesity Indices with Bone Mineral Densities and Risk of Osteoporosis Stratified Across Diabetic Vascular Disease in T2DM Patients.

Objective: To evaluate associations of obesity indices with bone mineral densities (BMD) and risk of osteoporosis in T2DM patients totally and stratified across presence of any diabetic cardiovascular complications. Methods: Cross-sectional analyses of baseline information on a cohort of 250 T2DM patients were conducted in Xiamen, China. Obesity indices included body weight, height, body mass index (BMI), waist and waist hip ratio (WHR). BMD was measured using dual-energy X-ray absorptiometry at three different sites, and osteoporosis was defined based on the minimum T-scores of BMD. Presence of any diabetic vascular complications was confirmed by checking their medical records histories. Results: Among the 250 T2DM patients, 50 (20.0%) were defined as osteoporosis. Multivariable linear regression and multivariable logistic regression analyses showed that igher obesity indices, including body weight, BMI and waist, but neither body height nor waist hip ratio, were positively associated with the minimum T-scores of BMD and had significantly decreased risk of osteoporosis. Stratified analyses across presence of any of diabetic vascular complications showed similar results for those with any of diabetic vascular complications, while no significant association between obesity indices and minimum T-scores of BMD was found for those without. Postmenopausal women (vs men) and ever drinking were significantly associated with increased risk of osteoporosis, and the adjusted odds ratios (95% CIs) were 5.165 (1.762-15.138, p = 0.003) and 3.789 (1.087-13.214, p = 0.037), respectively. None of metabolic profiles, including systolic and diastolic blood pressure, triglyceride, total cholesterol, high-density lipoprotein cholesterol, HbA1c and blood uric acid, was significantly associated with either minimum T-scores of BMD or risk of osteoporosis. Conclusion: Associations of obesity indices with either BMD or risk of osteoporosis in T2DM patients varied by presence of any diabetic vascular complication and should be not interpreted as causal without considering the often-unmeasured effect modification by health status.

Prevalence and prognosis of hard-to-heal wounds with comorbidities in China.

OBJECTIVE: Regular retrospective analysis is necessary for potential improvement in clinical practice for the treatment of hard-to-heal wounds. Comorbidities and outcomes have demonstrated spatial and temporal diversity, emphasising the importance of updates in epidemiology. The complexity of healing hard-to-heal wounds has long been known, and so we sought evidence-based improvement on the current principles of treatment. METHOD: Demographic and clinical information of patients from the WoundCareLog database was collected. Patients who met the inclusion criteria and completed follow-up after treatment were included. Comorbidities were diagnosed and classified into eight categories based on ICD-10. We compared the demographic and aetiological characteristics between patients with and without comorbidities by t-test and Chi-squared test. The impact of comorbidities on wound healing were evaluated with a multivariate Cox model. RESULTS: A total of 2163 patients met the inclusion criteria and were enrolled, of whom 37.0% were aged 61-80 years, 36.0% were aged 41-60 years and 60.8% were male. The lower extremities and buttocks were the most commonly affected areas with hard-to-heal wounds. Non-traumatic wounds accounted for 66.6% of cases, and infection, pressure and diabetes were the most common causes. Paralysis and diabetes were the most important factors which led to a prolonged healing process and inferior clinical outcomes. CONCLUSION: Comorbidities of hard-to-heal wounds were treated as separate contributors and their weighted effect on outcome was calculated through correlation analysis. Paralysis and diabetes were the most unfavourable comorbidities affecting the treatment of non-traumatic hard-to-heal wounds. Our study highlighted the priority of comorbidity treatment through data-driven approaches. It provides potential value in developing better public health strategies and preventive medicine.

Evolution of a chordate-specific mechanism for myoblast fusion.

Vertebrate myoblast fusion allows for multinucleated muscle fibers to compound the size and strength of mononucleated cells, but the evolution of this important process is unknown. We investigated the evolutionary origins and function of membrane-coalescing agents Myomaker and Myomixer in various groups of chordates. Here, we report that Myomaker likely arose through gene duplication in the last common ancestor of tunicates and vertebrates, while Myomixer appears to have evolved de novo in early vertebrates. Functional tests revealed a complex evolutionary history of myoblast fusion. A prevertebrate phase of muscle multinucleation driven by Myomaker was followed by the later emergence of Myomixer that enables the highly efficient fusion system of vertebrates. Evolutionary comparisons between vertebrate and nonvertebrate Myomaker revealed key structural and mechanistic insights into myoblast fusion. Thus, our findings suggest an evolutionary model of chordate fusogens and illustrate how new genes shape the emergence of novel morphogenetic traits and mechanisms.

Mutagenic Characteristics of Six Heavy Metals in Escherichia coli: The Commonality and Specificity.

The history of long-term environmental exposure to heavy metals can be recorded in the genome as sporadic and specific mutations. Variable environments introduce diverse and adaptive mutations to organisms. To reveal the information hidden in genomes about environmental exposure to heavy metals, we performed long-term mutation accumulation (MA) experiments with Escherichia coli, analyzed genomes from 36 populations across 1650 generations with 6 heavy metal exposure regimes (arsenic, cadmium, chromium, copper, nickel, and lead), and inferred metal-specific evolution modes at the genomic level. All heavy metals induced genetic mutations with a mean rate of 3.459 × 10-9 per nucleotide per generation. The mutational spectrum exhibited distinct signatures; however, heavy metals also shared common mutation signatures prominently associated with all cancer types. The mutated genes showed an average similarity of 54.4% within the same exposure regime, whereas only 38.8% between exposure regimes. In terms of biological insights, mutated genes were enriched to fundamental cellular processes such as metabolism, motility, and transport. Our study elucidates the mutagenic commonality and specificity of environmental heavy metals, which are highly specific at mutational features and locus, but conserved at gene and functional levels, and may play crucial roles in the convergence of adaptation to heavy metals.

Global, Regional, and National Levels and Trends in the Burden of Pressure Ulcer from 1990 to 2019: A Systematic Analysis for the Global Burden of Disease 2019.

Pressure ulcer (PU) is a type of chronic ulcer, placing a high burden not only on patients' families but also on national healthcare systems globally. To determine the level, trends, and burden of PU worldwide and to provide an essential foundation for building targeted public policies on PUs at the national, regional, and global levels, data on PU were obtained from the Global Burden of Disease (GBD) 2019 Study. The incidence, disability-adjusted life years (DALYs), and deaths of PUs in 204 countries and regions from 1990 to 2019 were calculated and stratified by sex, age, geographical location, and sociodemographic index (SDI). The estimated annual percentage change (EAPC) of incidence, DALYs, and deaths was calculated to evaluate the temporal trends. A total of 3,170,796 new cases (95% uncertainty interval (UI), 3,499,729-2,875,433 cases) of PU were identified globally in 2019, more than 55% of which were among male individuals, and most of the new cases were concentrated in those 75-90 years of age. The burden of PU measured in DALYs was 481 423 (95% UI, 583 429-374 334) in 2019, 73% and 27% of which could be attributed to years of life lost (YLLs) and years lived with disability (YLDs), respectively. The burden increased gradually from 1990 to 2019 (from 267 846 [360 562-211 024] to 481 423 [95% UI, 583 429-374 334]). A total of 24 389 deaths were attributed to PU (95% UI, 31 260.82-17 299). The EAPC of incidence, DALYs, and deaths were negative in most regions, the age-standardized rate (ASR) of incidence, DALYs, and deaths were considered to be decreasing in most of the regions, and the EAPCs were negatively correlated with the SDI levels, universal health coverage (UHC), and gross domestic product (GDP), which shows that the ASRs of PU decreased as the economy developed and countries' healthcare system performances improved.

Application of Compound Polymyxin B Ointment in the Treatment of Chronic Refractory Wounds.

The purpose of this study was to investigate the clinical efficacy of compound polymyxin B ointment for treating chronic refractory wounds. A retrospective analysis was performed on 111 patients who underwent chronic refractory wound treatment. Patients were divided into 2 groups, with 45 patients included in the experimental group (compound polymyxin B group) and 66 patients included in the control group (silver sulfadiazine group). After thorough debridement in both groups, either compound polymyxin B ointment or silver sulfadiazine cream was evenly applied to the patient's wound and covered with sterile gauze. In both groups, dressing changes were dependent on the wound's condition and secretions. Using the Bates-Jensen Wound Assessment Tool (BWAT), patients in both groups were scored, after which wound healing, infection, and healing time were compared. There was no significant difference in BWAT scores between the 2 groups on the 7th or 14th day; however, on the 21st day, the BWAT score in the experimental group was significantly lower than that of the control group. The difference was statistically significant (P < .05). There was no significant difference in the BWAT-I scores between the 2 groups on the seventh day. The healing time in the experimental group was significantly shorter than that of the control group, and the difference was statistically significant (P < .05). For the treatment of chronic refractory wounds, thorough debridement followed by compound polymyxin B ointment topical application can reduce and control wound infection effectively and accelerate the process of wound repair.

Oncogenic role of the SOX9-DHCR24-cholesterol biosynthesis axis in IGH-BCL2+ diffuse large B-cell lymphomas.

Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation-sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.

Polysaccharides from Chrysanthemun indicum L. enhance the accumulation of polysaccharide and atractylenolide in Atractylodes macrocephala Koidz.

Atractylodes macrocephala Koidz. (AM), an herb of traditional Chinese medicine, is well-known for anti-oxidant, anti-tumor and immune regulation potential. However, it is low bioactive compound content that restricts the application of this species. Elicitation is considered as an effective method to enhance biomass and bioactive compound in plants. Our precious study found that polysaccharide of Chrysanthemun indicum L. could promote plant growth by triggering plant defense. In the present study, polysaccharide of Chrysanthemun indicum L. is used to stimulate the accumulation of biomass and bioactive compound with different concentration in Atractylodes macrocephala Koidz. during pot, plot and field experiments. The results suggested that polysaccharide of Chrysanthemun indicum L. could significantly enhance the accumulation of biomass, atractylenolides and polysacchrides. Moreover, 2 mg/mL is determined and verified to be the appropriate concentration during field experiments. In addition, RT-qPCR revealed that CIP-induced terpenoid synthesis in AM mainly depended on mevalonate (MVA) pathway. This is the first report on the discovery of polysaccharide of Chrysanthemun indicum L. for the enhanced accumulation of biaomass and bioactive compound and the use of its for agricultural production.

White Blood Cells and Severe COVID-19: A Mendelian Randomization Study.

Increasing evidence shows that white blood cells are associated with the risk of coronavirus disease 2019 (COVID-19), but the direction and causality of this association are not clear. To evaluate the causal associations between various white blood cell traits and the COVID-19 susceptibility and severity, we conducted two-sample bidirectional Mendelian Randomization (MR) analyses with summary statistics from the largest and most recent genome-wide association studies. Our MR results indicated causal protective effects of higher basophil count, basophil percentage of white blood cells, and myeloid white blood cell count on severe COVID-19, with odds ratios (OR) per standard deviation increment of 0.75 (95% CI: 0.60-0.95), 0.70 (95% CI: 0.54-0.92), and 0.85 (95% CI: 0.73-0.98), respectively. Neither COVID-19 severity nor susceptibility was associated with white blood cell traits in our reverse MR results. Genetically predicted high basophil count, basophil percentage of white blood cells, and myeloid white blood cell count are associated with a lower risk of developing severe COVID-19. Individuals with a lower genetic capacity for basophils are likely at risk, while enhancing the production of basophils may be an effective therapeutic strategy.

Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci.

Fish oil supplementation is widely used for reducing serum triglycerides (TAGs) but has mixed effects on other circulating cardiovascular biomarkers. Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs. Here, the gene-diet interaction effects of fish oil supplementation on these lipids were analyzed in a discovery cohort of up to 73,962 UK Biobank participants, using a 1-degree-of-freedom (1df) test for interaction effects and a 2-degrees-of-freedom (2df) test to jointly analyze interaction and main effects. Associations with P < 1×10-6 in either test (26,157; 18,300 unique variants) were advanced to replication in up to 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Replicated associations reaching 1df P < 0.05 (2,175; 1,763 unique variants) were used in meta-analyses. We found 13 replicated and 159 non-replicated (UK Biobank only) loci with significant 2df joint tests that were predominantly driven by main effects and have been previously reported. Four novel interaction loci were identified with 1df P < 5×10-8 in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A>G; minor allele frequency = 0.041), shows exclusively interaction effects. The minor allele is significantly associated with decreased TAGs in individuals with fish oil supplementation, but with increased TAGs in those without supplementation. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Our study identifies novel gene-diet interaction effects for four genetic loci, whose effects on blood lipids are modified by fish oil supplementation. These findings highlight the need and possibility for personalized nutrition.

Altered Blood Cell Traits Underlie a Major Genetic Locus of Severe COVID-19.

BACKGROUND: The genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown. METHODS: To identify intermediate traits associated with the 3p21.31 locus, we first performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310 999 European individuals from the UK Biobank. For genes potentially regulated by the COVID-19 risk variant, we examined associations between their expression and the polygenic score (PGS) of 1263 complex traits in a meta-analysis of 31 684 blood samples. For the prioritized blood cell traits, we tested their associations with age and sex in the same UK Biobank sample. RESULTS: Our PheWAS highlighted multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07 × 10-8, 4.09 × 10-13), eosinophil count and percentage (p = 5.73 × 10-3, 2.20 × 10-3), and neutrophil percentage (p = 3.23 × 10-3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73 × 10-21, 5.08 × 10-19); CCR2 with monocytes (p = 2.40 × 10-10); and CCR1 with monocytes and neutrophil (p = 1.78 × 10-6, 7.17 × 10-5). Additionally, we found that almost all examined white blood cell traits are significantly different across age and sex groups. CONCLUSIONS: Our findings suggest that altered blood cell traits, especially those of monocyte, eosinophil, and neutrophil, may represent the mechanistic links between the genetic locus 3p21.31 and severe COVID-19. They may also underlie the increased risk of severe COVID-19 in older adults and men.