Communication between the stem cell niche and an adjacent differentiation niche through miRNA and EGFR signaling orchestrates exit from the stem cell state in the Drosophila ovary.

The signaling environment, or niche, often governs the initial difference in behavior of an adult stem cell and a derivative that initiates a path towards differentiation. The transition between an instructive stem cell niche and differentiation niche must generally have single-cell resolution, suggesting that multiple mechanisms might be necessary to sharpen the transition. Here, we examined the Drosophila ovary and found that Cap cells, which are key constituents of the germline stem cell (GSC) niche, express a conserved microRNA (miR-124). Surprisingly, loss of miR-124 activity in Cap cells leads to a defect in differentiation of GSC derivatives. We present evidence that the direct functional target of miR-124 in Cap cells is the epidermal growth factor receptor (EGFR) and that failure to limit EGFR expression leads to the ectopic expression of a key anti-differentiation BMP signal in neighboring somatic escort cells (ECs), which constitute a differentiation niche. We further found that Notch signaling connects EFGR activity in Cap cells to BMP expression in ECs. We deduce that the stem cell niche communicates with the differentiation niche through a mechanism that begins with the selective expression of a specific microRNA and culminates in the suppression of the major anti-differentiation signal in neighboring cells, with the functionally important overall role of sharpening the spatial distinction between self-renewal and differentiation environments.

Kidney Function Measures and Mortality: A Mendelian Randomization Study.

RATIONALE & OBJECTIVE: Individuals with a low estimated glomerular filtration rate (eGFR) are at a high risk of death. However, the causes underpinning this association are largely uncertain. This study aimed to assess the causal relationship of low eGFR with all-cause and cause-specific mortality. STUDY DESIGN: Retrospective cohort study incorporating Mendelian randomization (MR). SETTING & PARTICIPANTS: Individual-level data from 436,214 White participants (54.3% female; aged 56.8±8.0 years) included in the UK Biobank. EXPOSURES: eGFR estimated using cystatin C (eGFRcyst). OUTCOMES: The outcomes of interest included all-cause mortality, cardiovascular mortality, cancer mortality, infection mortality, and other-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards analysis for the conventional observational analyses; linear and nonlinear MR analyses implemented using genetic allele scores as instrumental variables representing kidney function to estimate the effect of kidney function on the survival outcomes. RESULTS: During a median follow-up of 12.1 years, there were 30,489 deaths, 6,098 of which were attributed to cardiovascular events, 15,538 to cancer, 1,516 to infection, and 7,227 to other events. In the conventional observational analysis, eGFRcyst exhibited a nonlinear association with all the outcomes. MR analysis suggested that a genetically predicted lower eGFRcyst was linearly associated with a higher rate of cardiovascular mortality (HR, 1.43; 95% CI, 1.18-1.75) across the entire measurement range (every 10-mL/min/1.73m2 decrement). Nonetheless, no causal associations between eGFRcyst and all-cause mortality (HR, 1.07; 95% CI, 0.98-1.17) or any types of noncardiovascular mortality were detected. LIMITATIONS: Potential misclassification of the actual cause of death, a nonrepresentative sample, and potential error in the interpretation of the magnitude of associations generated in MR analyses. CONCLUSIONS: These findings suggest a potential causal association between low eGFR and cardiovascular mortality in the general population, but no causal relationship with all-cause mortality or noncardiovascular mortality was observed. Further studies in other populations are warranted to confirm these findings. PLAIN-LANGUAGE SUMMARY: This study investigated the existence of a causal relationship between lower kidney function and death of different causes. Using data from 436,214 people in the United Kingdom, we applied conventional statistical analyses and those incorporating genetic data to implement Mendelian randomization, an approach that estimates causal associations. The observational analysis showed a nonlinear association between kidney function and various types of mortality outcomes. However, Mendelian randomization analysis suggested a linear increase in the risk of cardiovascular mortality with lower kidney function, but no causal link between the level of kidney function and all-cause or noncardiovascular mortality was identified. Managing kidney health may help reduce cardiovascular mortality, but caution is needed in interpreting the magnitudes of these results. Further validation in other populations and in those with advanced kidney failure is needed.

Unraveling the complex evolutionary history of lepidopteran chromosomes through ancestral chromosome reconstruction and novel chromosome nomenclature.

BACKGROUND: Lepidoptera is one of the most species-rich animal groups, with substantial karyotype variations among species due to chromosomal rearrangements. Knowledge of the evolutionary patterns of lepidopteran chromosomes still needs to be improved. RESULTS: Here, we used chromosome-level genome assemblies of 185 lepidopteran insects to reconstruct an ancestral reference genome and proposed a new chromosome nomenclature. Thus, we renamed over 5000 extant chromosomes with this system, revealing the historical events of chromosomal rearrangements and their features. Additionally, our findings indicate that, compared with autosomes, the Z chromosome in Lepidoptera underwent a fast loss of conserved genes, rapid acquisition of lineage-specific genes, and a low rate of gene duplication. Moreover, we presented evidence that all available 67 W chromosomes originated from a common ancestor chromosome, with four neo-W chromosomes identified, including one generated by fusion with an autosome and three derived through horizontal gene transfer. We also detected nearly 4000 inter-chromosomal gene movement events. Notably, Geminin is transferred from the autosome to the Z chromosome. When located on the autosome, Geminin shows female-biased expression, but on the Z chromosome, it exhibits male-biased expression. This contributes to the sexual dimorphism of body size in silkworms. CONCLUSIONS: Our study sheds light on the complex evolutionary history of lepidopteran chromosomes based on ancestral chromosome reconstruction and novel chromosome nomenclature.

Association Between Thromboelastography and Coronary Heart Disease.

BACKGROUND Thromboelastography (TEG) is a novel blood viscoelasticity detection method revealing blood coagulation status and has been reported to be helpful in predicting clinical outcomes in patients with cardiovascular diseases (CVD). In this study, we aimed to investigate the association between TEG and CVD. MATERIAL AND METHODS A single-center case-control study was performed. Individuals who took TEG tests at Tongji Hospital in Wuhan, China from 2015 to 2019 were included. The nearest-neighbor Mahalanobis matching with replacement, within propensity score calipers of 0.25 was used to control the covariate imbalance between CVD patients and controls. Logistic regression analyses were conducted to assess the relationship between TEG and CVD. Subgroup and sensitivity analyses were performed to evaluate the robustness of the association between TEG and CVD. RESULTS After matching, a total of 151 participants were included in this study, with 83 patients having CVD (49 patients having coronary heart disease [CHD] and 34 patients having an ischemic stroke). By comparison, CHD patients had a significantly higher maximum amplitude (MA) (P=0.02) than controls. After multivariable adjustment, MA (OR 1.11, 95% CI 1.01-1.24, P=0.04) was independently associated with CHD. The association between MA and CHD remained robust across subgroups and in sensitivity analyses. CONCLUSIONS The current study suggests that MA is significantly associated with CHD. Enhanced platelet reactivity as described by high MA might be associated with risk of CHD. The exact role of MA in the measurement of CHD risk needs to be further examined in large-scale prospective cohort studies.

Coordinated molecular and ecological adaptations underlie a highly successful parasitoid.

The success of an organism depends on the molecular and ecological adaptations that promote its beneficial fitness. Parasitoids are valuable biocontrol agents for successfully managing agricultural pests, and they have evolved diversified strategies to adapt to both the physiological condition of hosts and the competition of other parasitoids. Here, we deconstructed the parasitic strategies in a highly successful parasitoid, Trichopria drosophilae, which parasitizes a broad range of Drosophila hosts, including the globally invasive species D. suzukii. We found that T. drosophilae had developed specialized venom proteins that arrest host development to obtain more nutrients via secreting tissue inhibitors of metalloproteinases (TIMPs), as well as a unique type of cell-teratocytes-that digest host tissues for feeding by releasing trypsin proteins. In addition to the molecular adaptations that optimize nutritional uptake, this pupal parasitoid has evolved ecologically adaptive strategies including the conditional tolerance of intraspecific competition to enhance parasitic success in older hosts and the obligate avoidance of interspecific competition with larval parasitoids. Our study not only demystifies how parasitoids weaponize themselves to colonize formidable hosts but also provided empirical evidence of the intricate coordination between the molecular and ecological adaptations that drive evolutionary success.

Cohort profile for the Tongji Cardiovascular Health Study: a prospective multiomics cohort study.

PURPOSE: The Tongji Cardiovascular Health Study aimed to further explore the onset and progression mechanisms of cardiovascular disease (CVD) through a combination of traditional cohort studies and multiomics analysis, including genomics, metabolomics and metagenomics. STUDY DESIGN AND PARTICIPANTS: This study included participants aged 20-70 years old from the Geriatric Health Management Centre of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. After enrollment, each participant underwent a comprehensive series of traditional and novel cardiovascular risk factor assessments at baseline, including questionnaires, physical examinations, laboratory tests, cardiovascular health assessments and biological sample collection for subsequent multiomics analysis (whole genome sequencing, metabolomics study from blood samples and metagenomics study from stool samples). A biennial follow-up will be performed for 10 years to collect the information above and the outcome data. FINDINGS TO DATE: A total of 2601 participants were recruited in this study (73.4% men), with a mean age of 51.5±11.5 years. The most common risk factor is overweight or obesity (54.8%), followed by hypertension (39.7%), hyperlipidaemia (32.4%), current smoking (23.9%) and diabetes (12.3%). Overall, 13.1% and 48.7% of men and women, respectively, did not have any of the CVD risk factors (hypertension, hyperlipidaemia, diabetes, cigarette smoking and overweight or obesity). Additionally, multiomics analyses of a subsample of the participants (n=938) are currently ongoing. FUTURE PLANS: With the progress of the cohort follow-up work, it is expected to provide unique multidimensional and longitudinal data on cardiovascular health in China.

Investigation on repairing diabetic foot ulcer based on 3D bio-printing Gel/dECM/Qcs composite scaffolds.

Diabetic foot ulcers are one of the most serious of the numerous complications of diabetes mellitus, causing great physical trauma and financial stress to patients, and accelerating wound healing in diabetic patients remains one of the major clinical challenges. Exosomes from adipose-derived stem cells can directly and indirectly promote wound healing. However, due to the low retention rate of exosomes in the wound, exosome treatment is difficult to achieve the expected effect. Therefore, it is of great significance to synthesize a composite scaffold that can stably load exosomes and has antibacterial properties. In this study, fresh pig skin was decellularized to obtain decellularized matrix (dECM). Secondly, quaternized chitosan (Qcs) was modified with quaternary ammonium salt to make it soluble in water after quaternization. Finally, Gel-dECM-Qcs (GDQ) bioink was prepared by adding acellular matrix and quaternized chitosan with temperature sensitive gelatin (Gel) as carrier. Tissue engineered composite scaffolds were then prepared by extrusion 3D printing technology. Subsequently, the physicochemical properties, biocompatibility and antimicrobial capacity of the composite scaffolds were determined, and the data showed that the composite scaffolds had good mechanical properties, biocompatibility and antimicrobial capacity, and the maximum stress of the composite scaffolds was 1.16 ± 0.05 MPa, the composite scaffolds were able to proliferate and adhered to the L929 cells, and the kill rates of composite scaffolds against E. coli and S. aureus after incubation for 24 h were 93.24 ± 1.22 % and 97.34 ± 0.23 %, respectively. Overall, the GDQ composite scaffolds have good mechanical properties adapted to skin bending, its good biocompatibility can promote the growth and migration of fibroblasts, reshape injured tissues, accelerate the wound healing, and excellent antimicrobial ability can inhibit the growth of E. coli and S. aureus, reducing the impact of bacterial infections on wounds. Moreover, the composite scaffolds have the potential to be used as exosom-loaded hydrogel dressings, which provides a basis for the subsequent research on the repair of diabetic foot ulcers.

The odorant receptor co-receptor gene contributes to mating and host-searching behaviors in parasitoid wasps.

BACKGROUND: Biological control of pest insects by parasitoid wasps is an effective and environmentally friendly strategy compared with the use of synthetic pesticides. Successful courtship and host-search behaviors of parasitoid wasps are important for biological control efficiency and are often mediated by chemical odorant cues. The odorant receptor co-receptor (Orco) gene has an essential role in the perception of odors in insects. However, the function of Orco in the mating and host-searching behaviors of parasitoid wasps remains underexplored. RESULTS: We identified the full-length Orco genes of four Drosophila parasitoid species in the genus Leptopilina, namely L. heterotoma, L. boulardi, L. syphax and L. drosophilae. Sequence alignment and membrane-topology analysis showed that Leptopilina Orcos had similar amino acid sequences and topology structures. Phylogenetic analysis revealed that Leptopilina Orcos were highly conserved. Furthermore, the results of quantitative real-time polymerase chain reactions showed that all four Orco genes had a typical antennae-biased tissue expression pattern. After knockdown of Orco in these different parasitoid species, we found that Orco-deficient male parasitoid wasps, but not females, lost their courtship ability. Moreover, Orco-deficient female parasitoid wasps presented impaired host-searching performance and decreased oviposition rates. CONCLUSION: Our study demonstrates that Orcos are essential in the mating and host-searching behaviors of parasitoid wasps. To our knowledge, this is the first time that the functions of Orco genes have been characterized in parasitoid wasps, which broadens our understanding of the chemoreception basis of parasitoid wasps and contributes to developing advanced pest management strategies. © 2022 Society of Chemical Industry.

Metabolomics Provides New Insights into Host Manipulation Strategies by Asobara japonica (Hymenoptera: Braconidae), a Fruit Fly Parasitoid.

Asobara japonica (Hymenoptera: Braconidae) is an endoparasitoid wasp that can successfully parasitize a wide range of host species across the Drosophila genus, including the invasive crop pest Drosophila suzukii. Parasitoids are capable of regulating the host metabolism to produce the nutritional metabolites for the survival of their offspring. Here, we intend to investigate the metabolic changes in D. melanogaster hosts after parasitization by A. japonica, using the non-targeted LC-MS (liquid chromatography-mass spectrometry) metabolomics analysis. In total, 3043 metabolites were identified, most of which were not affected by A. japonica parasitization. About 205 metabolites were significantly affected in parasitized hosts in comparison to non-parasitized hosts. The changed metabolites were divided into 10 distinct biochemical groups. Among them, most of the lipid metabolic substances were significantly decreased in parasitized hosts. On the contrary, most of metabolites associated with the metabolism of amino acids and sugars showed a higher abundance of parasitized hosts, and were enriched for a wide range of pathways. In addition, eight neuromodulatory-related substances were upregulated in hosts post A. japonica parasitization. Our results reveal that the metabolites are greatly changed in parasitized hosts, which might help uncover the underlying mechanisms of host manipulation that will advance our understanding of host-parasitoid coevolution.

The vitellogenin receptor gene contributes to mating and host-searching behaviors in parasitoid wasps.

Vitellogenin receptor (VgR) is essential to vitellogenin uptaking and dominates ovary maturation in insects. However, the function of VgR in parasitoid wasps is largely unknown. Here, we applied the Drosophila parasitoid Leptopilina boulardi as a study model to investigate the function of VgR in parasitoids. Despite the conserved sequence characteristics with other insect VgRs, we found L. boulardi VgR (LbVgR) gene was highly expressed in head but lower in ovary. In addition, we found that LbVgR had no effects on ovary development, but participated in host-searching behavior of female L. boulardi and mating behavior of male L. boulardi. Comparative transcriptome analysis further revealed LbVgR might play crucial roles in regulating the expression of some important chemoreception genes to adjust the parasitoid behaviors. These results will broaden our knowledge of the function of VgR in insects, and contribute to develop advanced pest management strategies using parasitoids as biocontrol agents.

Estimated 24-h urinary sodium excretion and risk of end-stage kidney disease.

The association between sodium intake and long-term kidney disease endpoints is debated and yet to be proven. We aimed to investigate the associations of estimated 24-h urinary sodium excretion, reflecting daily sodium intake, with the incidence of end-stage kidney disease (ESKD). In this prospective cohort study including 444,375 UK Biobank participant, 865 (0.2%) ESKD events occurred after median follow-up of 12.7 years. For every 1 g increment in estimated 24-h urinary sodium excretion, multivariable-adjusted hazard ratio for incident ESKD was 1.09 (95% confidence interval 0.94-1.26). Nonlinear associations were not detected with restricted cubic splines. The null findings were confirmed by a series of sensitivity analyses, which attenuated potential bias from measurement errors of the exposure, regression dilution, reverse causality, and competing risks. In conclusion, there is insufficient evidence that estimated 24-h urinary sodium excretion is associated with the incidence of ESKD.

Defining reference values for body composition indices by magnetic resonance imaging in UK Biobank.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for evaluating body composition. However, the reference ranges have not been established. METHODS: Three lean tissue and seven adipose tissue parameters based on MRI data from the UK Biobank were used in this study. Participants with European ancestry and data on at least one parameter were screened. Age- and sex-specific percentile curves were generated using the lambda-mu-sigma method. Three levels of reference ranges were provided, which were equivalent to the mean ± 1 standard deviation (SD), 2 SDs and 2.5 SDs. RESULTS: The final analysis set for each parameter ranged from 4842 to 14 148 participants (53.4%-56.6% women) with a median age of 61. For lean tissue parameters, compared with those at age 45, the median total lean tissue volume and total thigh fat-free muscle volume at age 70 were 2.83 and 1.73 L, and 3.02 and 1.51 L lower in men and women, respectively. The median weight-to-muscle ratios at age 45 were 0.51 and 0.83 kg/L lower compared with those at age 70 in men and women, respectively. Adipose tissue parameters showed inconsistent differences. In men, the median muscle fat infiltration, visceral adipose tissue (VAT) volume, total abdominal adipose tissue index and abdominal fat ratio were 1.48%, 0.32 L, 0.08 L/m2 and 0.4 higher, and the median abdominal subcutaneous adipose tissue (ASAT) volume and total adipose tissue volume were 0.47 and 0.41 L lower, respectively, at age 70 than at age 45. The median total trunk fat volume was approximately 9.53 L at all ages. In women, the median muscle fat infiltration and VAT volume were 1.68% and 0.76 L higher, respectively, at age 70 than at age 45. The median ASAT volume, total adipose tissue volume, total trunk fat volume, total abdominal adipose tissue index and abdominal fat ratio were 0.35 L, 0.78 L, 1.12 L, 0.49 L/m2 and 0.06 higher, respectively, at age 60 than at age 45. The medians of the former three parameters were 0.33 L, 0.14 L and 0.20 L lower, at age 70 than at age 60. The medians of the latter two parameters were approximately 3.64 L/m2 and 0.55 at ages between 60 and 70. CONCLUSIONS: We have established reference ranges for MRI-measured body composition parameters in a large community-dwelling population. These findings provide a more accurate assessment of abnormal adipose and muscle conditions.

Sex-specific equations to estimate body composition: Derivation and validation of diagnostic prediction models using UK Biobank.

BACKGROUND & AIMS: Body mass index and waist circumference are simple measures of obesity. However, they do not distinguish between visceral and subcutaneous fat, or muscle, potentially leading to biased relationships between individual body composition parameters and adverse health outcomes. The purpose of this study was to develop and validate prediction models for volumetric adipose and muscle. METHODS: Based on cross-sectional data of 18,457, 18,260, and 17,052 White adults from the UK Biobank, we developed sex-specific equations to estimate visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and total thigh fat-free muscle (FFM) volumes, respectively. Volumetric magnetic resonance imaging served as the reference. We used the least absolute shrinkage and selection operator and the extreme gradient boosting methods separately to fit three sequential models, the inputs of which included demographics and anthropometrics and, in some, bioelectrical impedance analysis parameters. We applied comprehensive metrics to assess model performance in the temporal validation set. RESULTS: The equations that included more predictors generally performed better. Accuracy of the equations was moderate for VAT (percentage of estimates that differed <30% from the measured values, 70 to 78 in males, 64 to 69 in females) and good for ASAT (85 to 91 in males, 90 to 95 in females) and FFM (99 to 100 in both sexes). All the equations appeared precise (interquartile range of the difference, 0.89 to 1.76 L for VAT, 1.16 to 1.61 L for ASAT, 0.81 to 1.39 L for FFM). Bias of all the equations was negligible (-0.17 to 0.05 L for VAT, -0.10 to 0.12 L for ASAT, -0.07 to 0.09 L for FFM). The equations achieved superior cardiometabolic correlations compared with body mass index and waist circumference. CONCLUSIONS: The developed equations to estimate VAT, ASAT, and FFM volumes achieved moderate to good performance. They may be cost-effective tools to revisit the implications of diverse body components.

Cystatin C-based estimated glomerular filtration rate and risk of stroke in the general population: a prospective cohort study.

Background: Previous results on the association between the estimated glomerular filtration rate (eGFR) and stroke are mixed. Most studies derived the eGFR from serum creatinine, which is affected by non-kidney determinants and thus has possibly biased the association with stroke risk. Methods: In this cohort study, we included 429 566 UK Biobank participants (94.5% white, 54% women, age 56 ± 8 years) free of stroke at enrollment. The eGFRcys and eGFRcr were calculated with serum cystatin C and creatinine, respectively. Outcomes of interest were risk of total stroke and subtypes. We investigated the linear and nonlinear associations using Cox proportional hazards models and restricted cubic splines, corrected for regression dilution bias. Results: During an average follow-up of 10.11 years, 4427 incident strokes occurred, among which 3447 were ischemic and 1163 were hemorrhagic. After adjustment for confounders, the regression dilution-corrected hazard ratios (95% confidence intervals) for every 10 mL/min/1.73 m2 decrement in eGFRcys were 1.10 (1.05-1.14) for total stroke and 1.11 (1.08-1.15) for ischemic stroke. A similar pattern was observed with eGFRcr, although the association was weaker. When either type of eGFR was below 75 mL/min/1.73 m2, the risks of total and ischemic stroke increased exponentially as eGFR decreased. A U-shaped relationship was witnessed if eGFRcr was used instead. There was a null association between eGFR and hemorrhagic stroke. Conclusions: The risks of total stroke and ischemic stroke increased exponentially when the eGFRcys fell below 75 mL/min/1.73 m2.

Helicobacter pylori infection affects the human gastric microbiome, as revealed by metagenomic sequencing.

Helicobacter pylori infection is a prevalent infectious disease, associated with many gastric diseases, including gastritis, gastric ulcer, and gastric cancer. To reveal the characteristics of the gastric microbiome in patients infected with H. pylori, we performed metagenomic shotgun sequencing of stomach swab samples from 96 patients and then conducted metagenomic association analyses between alterations in the gastric microbiome and H. pylori infection status. The overall composition of the gastric microbiota in H. pylori-infected individuals was distinctly different from the negative controls; H. pylori became the dominant species after colonizing the human stomach and significantly decreased the α-diversity of the gastric community (P < 0.05, Wilcoxon rank-sum test). We also identified 6 HPI-associated microbial species (FDR < 0.05, Wilcoxon rank-sum test): Stenotrophomonas maltophilia, Stenotrophomonas unclassified, Chryseobacterium unclassified, Pedobacter unclassified, Variovorax unclassified, and Pseudomonas stutzeri. Furthermore, 55 gastric microbial pathways were enriched in the H. pylori-positive group, whereas only 2 pathways were more abundant in the H. pylori-negative group: dTDP-L-rhamnose biosynthesis and tetrapyrrole biosynthesis (FDR < 0.05, Wilcoxon rank-sum test). Gastritis was not associated with non-H. pylori species in the stomach (P > 0.05, Wilcoxon rank-sum test). This study revealed alterations in gastric microbial taxa and function associated with HPI in the Chinese population, which provides an insight into gastric microbial interactions and their potential role in the pathological process of gastric diseases.

Parasite reliance on its host gut microbiota for nutrition and survival.

Studying the microbial symbionts of eukaryotic hosts has revealed a range of interactions that benefit host biology. Most eukaryotes are also infected by parasites that adversely affect host biology for their own benefit. However, it is largely unclear whether the ability of parasites to develop in hosts also depends on host-associated symbionts, e.g., the gut microbiota. Here, we studied the parasitic wasp Leptopilina boulardi (Lb) and its host Drosophila melanogaster. Results showed that Lb successfully develops in conventional hosts (CN) with a gut microbiota but fails to develop in axenic hosts (AX) without a gut microbiota. We determined that developing Lb larvae consume fat body cells that store lipids. We also determined that much larger amounts of lipid accumulate in fat body cells of parasitized CN hosts than parasitized AX hosts. CN hosts parasitized by Lb exhibited large increases in the abundance of the bacterium Acetobacter pomorum in the gut, but did not affect the abundance of Lactobacillus fructivorans which is another common member of the host gut microbiota. However, AX hosts inoculated with A. pomorum and/or L. fructivorans did not rescue development of Lb. In contrast, AX larvae inoculated with A. pomorum plus other identified gut community members including a Bacillus sp. substantially rescued Lb development. Rescue was further associated with increased lipid accumulation in host fat body cells. Insulin-like peptides increased in brain neurosecretory cells of parasitized CN larvae. Lipid accumulation in the fat body of CN hosts was further associated with reduced Bmm lipase activity mediated by insulin/insulin-like growth factor signaling (IIS). Altogether, our results identify a previously unknown role for the gut microbiota in defining host permissiveness for a parasite. Our findings also identify a new paradigm for parasite manipulation of host metabolism that depends on insulin signaling and the gut microbiota.

Search performance and octopamine neuronal signaling mediate parasitoid induced changes in Drosophila oviposition behavior.

Making the appropriate responses to predation risk is essential for the survival of an organism; however, the underlying mechanisms are still largely unknown. Here, we find that Drosophila has evolved an adaptive strategy to manage the threat from its parasitoid wasp by manipulating the oviposition behavior. Through perception of the differences in host search performance of wasps, Drosophila is able to recognize younger wasps as a higher level of threat and consequently depress the oviposition. We further show that this antiparasitoid behavior is mediated by the regulation of the expression of Tdc2 and Tßh in the ventral nerve cord via LC4 visual projection neurons, which in turn leads to the dramatic reduction in octopamine and the resulting dysfunction of mature follicle trimming and rupture. Our study uncovers a detailed mechanism underlying the defensive behavior in insects that may advance our understanding of predator avoidance in animals.

Machine learning improves risk stratification of coronary heart disease and stroke.

Background: Coronary heart disease (CHD) and cerebral ischemic stroke (CIS) are two major types of cardiovascular disease (CVD) that are increasingly exerting pressure on the healthcare system worldwide. Machine learning holds great promise for improving the accuracy of disease prediction and risk stratification in CVD. However, there is currently no clinically applicable risk stratification model for the Asian population. This study developed a machine learning-based CHD and CIS model to address this issue. Methods: A case-control study was conducted based on 8,624 electronic medical records from 2008 to 2019 at the Tongji Hospital in Wuhan, China. Two machine learning methods (the random down-sampling method and the random forest method) were integrated into 2 ensemble models (the CHD model and the CIS model). The trained models were then interpreted using Shapley Additive exPlanations (SHAP). Results: The CHD and CIS models achieved good performance with the areas under the receiver operating characteristic curve (AUC) of 0.895 and 0.884 in random testing, and 0.905 and 0.889 in sequential testing, respectively. We identified 4 common factors between CHD and CIS: age, brachial-ankle pulse wave velocity, hypertension, and low-density lipoprotein cholesterol (LDL-C). Moreover, carcinoembryonic antigen (CEA) was identified as an independent indicator for CHD. Conclusions: Our ensemble models can provide risk stratification for CHD and CIS with clinically applicable performance. By interpreting the trained models, we provided insights into the common and unique indicators in CHD and CIS. These findings may contribute to a better understanding and management of risk factors associated with CVD.

Development and validation of a cardiovascular diseases risk prediction model for Chinese males (CVDMCM).

Background: Death due to cardiovascular diseases (CVD) increased significantly in China. One possible way to reduce CVD is to identify people at risk and provide targeted intervention. We aim to develop and validate a CVD risk prediction model for Chinese males (CVDMCM) to help clinicians identify those males at risk of CVD and provide targeted intervention. Methods: We conducted a retrospective cohort study of 2,331 Chinese males without CVD at baseline to develop and internally validate the CVDMCM. These participants had a baseline physical examination record (2008-2016) and at least one revisit record by September 2019. With the full cohort, we conducted three models: A model with Framingham CVD risk model predictors; a model with predictors selected by univariate cox proportional hazard model adjusted for age; and a model with predictors selected by LASSO algorithm. Among them, the optimal model, CVDMCM, was obtained based on the Akaike information criterion, the Brier's score, and Harrell's C statistic. Then, CVDMCM, the Framingham CVD risk model, and the Wu's simplified model were all validated and compared. All the validation was carried out by bootstrap resampling strategy (TRIPOD statement type 1b) with the full cohort with 1,000 repetitions. Results: CVDMCM's Harrell's C statistic was 0.769 (95% CI: 0.738-0.799), and D statistic was 4.738 (95% CI: 3.270-6.864). The results of Harrell's C statistic, D statistic and calibration plot demonstrated that CVDMCM outperformed the Framingham CVD model and Wu's simplified model for 4-year CVD risk prediction. Conclusions: We developed and internally validated CVDMCM, which predicted 4-year CVD risk for Chinese males with a better performance than Framingham CVD model and Wu's simplified model. In addition, we developed a web calculator-calCVDrisk for physicians to conveniently generate CVD risk scores and identify those males with a higher risk of CVD.

Glycosaminoglycan biosynthesis pathway in host genome is associated with Helicobacter pylori infection.

Helicobacter pylori is a causative pathogen of many gastric and extra-gastric diseases. It has infected about half of the global population. There were no genome-wide association studies (GWAS) for H. pylori infection conducted in Chinese population, who carried different and relatively homogenous strain of H. pylori. In this work, we performed SNP (single nucleotide polymorphism)-based, gene-based and pathway-based genome-wide association analyses to investigate the genetic basis of host susceptibility to H. pylori infection in 480 Chinese individuals. We also profiled the composition and function of the gut microbiota between H. pylori infection cases and controls. We found several genes and pathways associated with H. pylori infection (P < 0.05), replicated one previously reported SNP rs10004195 in TLR1 gene region (P = 0.02). We also found that glycosaminoglycan biosynthesis related pathway was associated with both onset and progression of H. pylori infection. In the gut microbiome association study, we identified 2 species, 3 genera and several pathways had differential abundance between H. pylori infected cases and controls. This paper is the first GWAS for H. pylori infection in Chinese population, and we combined the genetic and microbial data to comprehensively discuss the basis of host susceptibility to H. pylori infection.