Serum proteome profiling reveals heparanase as a candidate biomarker for chronic thromboembolic pulmonary hypertension.

Determining novel biomarkers for early identification of chronic thromboembolic pulmonary hypertension (CTEPH) could improve patient outcomes. We used the isobaric tag for relative and absolute quantitation approach to compare the serum protein profiles between CTEPH patients and the controls. Bioinformatics analyses and ELISA were also performed. We identified three proteins including heparanase (HPSE), gelsolin (GSN), and secreted protein acidic and rich in cysteine (SPARC) had significant changes in CTEPH. The receiver operating characteristic curve analysis showed that the areas under the curve of HPSE in CTEPH diagnosis were 0.988. Furthermore, HPSE was correlated with multiple parameters of right ventricular function. HPSE concentrations were significantly higher in patients with a low TAPSE/sPAP ratio (≤0.31 mm/mmHg) (65.4 [60.5,68.0] vs. 59.9 [35.9,63.2] ng/mL, p < 0.05). The CTEPH patients treated by balloon pulmonary angioplasty had significantly lower HPSE levels. The study demonstrates that HPSE may be a promising biomarker for noninvasive detection of CTEPH.

Efficacy and safety of anticoagulant for treatment and prophylaxis of VTE patients with renal insufficiency: a systemic review and meta-analysis.

Patients with venous thromboembolism (VTE) comorbid renal insufficiency (RI) are at higher risk of bleeding and thrombosis. Recommendations in guidelines on anticoagulation therapy for those patients remain ambiguous. The goal of this study is to compare the efficacy and safety between different anticoagulant regimens in VTE patients comorbid RI at different stages of treatment and prophylaxis. We performed English-language searches of Pubmed, EMBASE, and Web of Science (inception to Nov 2022). RCTs evaluated anticoagulants for VTE treatment at the acute phase, extension phase, and prophylaxis in patients with RI and reported efficacy and safety outcomes were selected. The methodological quality of the studies was assessed at the outcome level using the risk-of-bias assessment tool developed by the Cochrane Bias Methods Group. A meta-analysis of twenty-five RCTs was conducted, comprising data from twenty-three articles, encompassing a total of 9,680 participants with RI. In the acute phase, the risk of bleeding was increased with novel oral anticoagulants (NOACs) compared to LMWH (RR 1.29, 95% CI 1.04-1.60). For the prophylaxis of VTE, NOACs were associated with an elevated risk of bleeding compared with placebo (RR 1.31, 95%CI 1.02-1.68). In comparison to non-RI patients, both NOACs and vitamin K antagonists (VKA) could increase the risk of bleeding among RI patients (RR 1.45, 95%CI 1.14-1.84 and RR 1.53, 95%CI 1.25-1.88, respectively) during acute phase, while NOACs may increase the incidence of VTE in RI population (RR 1.74, 95%CI 1.29-2.34). RI patients who are under routine anticoagulation have a significantly higher risk of adverse outcomes. LMWH is the most effective and safe option for VTE treatment or prophylaxis in patients with RI.

Potential of novel iron 1,3,5-benzene tricarboxylate loaded on biochar to reduce ammonia and nitrous oxide emissions and its associated biological mechanism during composting.

In this study, a novel iron 1,3,5-benzene tricarboxylate loaded on biochar (BC-FeBTC) was developed and applied to kitchen waste composting. The results demonstrated that the emissions of NH3 and N2O were significantly reduced by 57.2% and 37.8%, respectively, compared with those in control group (CK). Microbiological analysis indicated that BC-FeBTC addition altered the diversity and abundance of community structure as well as key functional genes. The nitrification genes of ammonia-oxidizing bacteria were enhanced, thereby promoting nitrification and reducing the emission of NH3. The typical denitrifying bacterium, Pseudomonas, and critical functional genes (nirS, nirK, and nosZ) were significantly inhibited, contributing to reduced N2O emissions. Network analysis further revealed the important influence of BC-FeBTC in nitrogen transformation driven by functional microbes. These findings offer crucial scientific foundation and guidance for the application of novel materials aimed at mitigating nitrogen loss and environmental pollution during composting.

Circadian rhythms of melatonin and its relationship with anhedonia in patients with mood disorders: a cross-sectional study.

BACKGROUND: Mood disorders are strongly associated with melatonin disturbances. However, it is unclear whether there is a difference in melatonin concentrations and melatonin circadian rhythm profiles between depression and bipolar disorder. In addition, the relationship between anhedonia, a common symptom of affective disorders, and its melatonin circadian rhythm remains under-investigated. METHODS: Thirty-four patients with depression disorder, 20 patients diagnosed with bipolar disorder and 21 healthy controls participated in this study. The Revised Physical Anhedonia Scale (RPAS) was performed to assess anhedonia. Saliva samples were collected from all subjects at fixed time points (a total of 14 points) in two consecutive days for measuring the melatonin concentrations to fit circadian rhythms of subjects. Melatonin circadian rhythms were compared between the three groups using ANOVA. Partial correlation analysis and linear regression analysis were used to explore the correlation between melatonin rhythm variables and anhedonia. RESULTS: We found that the peak phase of melatonin in the depression group was significantly advanced compared to the control group (P < 0.001) and the bipolar disorder group (P = 0.004). The peak phase of melatonin and RPAS showed a negative correlation (P = 0.003) in depression patients, which was also demonstrated in the multiple linear regression model (B=-2.47, P = 0.006). CONCLUSIONS: These results suggest that circadian rhythms of melatonin are differentiated in depression and bipolar disorder and correlate with anhedonia in depression. Future research needs to explore the neurobiological mechanisms linking anhedonia and melatonin circadian rhythms in depressed patients.

Association between exposure to outdoor artificial light at night during pregnancy and glucose homeostasis: A prospective cohort study.

BACKGROUND: Outdoor artificial light at night (ALAN) has been linked to an elevated risk of diabetes, but the available literature on the relationships between ALAN and glucose homeostasis in pregnancy is limited. METHODS: A prospective cohort study of 6730 pregnant women was conducted in Hefei, China. Outdoor ALAN exposure was estimated using satellite data with individual addresses at a spatial resolution of approximately 1 km, and the average ALAN intensity was calculated. Gestational diabetes mellitus (GDM) was diagnosed based on a standard 75-g oral glucose tolerance test. Multivariable linear regression and logistic regression were used to estimate the relationships between ALAN and glucose homeostasis. RESULTS: Outdoor ALAN was associated with elevated glucose homeostasis markers in the first trimester, but not GDM risk. An increase in the interquartile range of outdoor ALAN values was related to a 0.02 (95% confidence interval [CI]: 0.00, 0.03) mmol/L higher fasting plasma glucose, a 0.42 (95% CI: 0.30, 0.54) µU/mL increase in insulin and a 0.09 (95% CI: 0.07, 0.12) increase in homeostatic model assessment of insulin resistance (HOMA-IR) during the first trimester. Subgroup analyses showed that the associations between outdoor ALAN exposure and fasting plasma glucose, insulin, and HOMA-IR were more pronounced among pregnant women who conceived in summer and autumn. CONCLUSIONS: The results provided evidence that brighter outdoor ALAN in the first trimester was related to elevated glucose intolerance in pregnancy, especially in pregnant women conceived in summer and autumn, and effective strategies are needed to prevent and manage light pollution.

Responses of greenhouse gas emissions to aeration coupled with functional membrane during industrial-scale composting of dairy manure: Insights into bacterial community composition and function.

Greenhouse gas (GHG) emissions from manure management processes deserve more attention. Using three industrial-scale experiments, this study comprehensively evaluated the effects of different aeration coupled with semi-permeable membrane-covered strategies on the structure and function of bacterial communities and their impact on GHG emissions during dairy manure aerobic composting. The succession of the bacterial communities tended to be consistent for similar aeration strategies. Ruminiclostridium and norank_f__MBA03 were significantly positively correlated with the methane emission rate, and forced aeration coupled with semi-permeable membrane-covered decreased GHG emissions by inhibiting these taxa. Metabolism was the most active function of the bacterial communities, and its relative abundance accounted for 75.69%-80.23%. The combined process also enhanced carbohydrate metabolism and amino acid metabolism. Therefore, forced aeration coupled with semi-permeable membrane-covered represented a novel strategy for reducing global warming potential by regulating the structure and function of the bacterial communities during aerobic composting of dairy manure.

Association between ambient particulate matters and anhedonia among patients with depression.

Recent studies have linked ambient air pollution to depression. Anhedonia is a core symptom of depression which severely impacts on prognosis. The present study aims to investigate the association of PM2.5 and PM10 exposure with anhedonia in depressed patients. A total of 538 patients with depression who were hospitalized at the Fourth People's Hospital of Hefei between June 2017 and December 2021 were included. We estimated ambient particulate matters exposure, including PM2.5 and PM10, using a satellite-based spatiotemporal model at a resolution of 1 km2. The revised Physical Anhedonia Scale (RPAS) and the revised Social Anhedonia Scale (RSAS) were evaluated. The association of ambient particulate matters and anhedonia was examined using multiple linear regression models, adjusted for potential confounders. We observed that exposure to PM2.5 were significantly associated with increased RSAS score and RPAS score, with the major effect in the 12-month exposure window (ß = 1.238; 95%CI, 0.353, 2.123) and 18-month exposure window (ß = 1.888; 95%CI, 0.699, 3.078), respectively. Meanwhile, PM10 levels were also significantly associated with increased RSAS score and RPAS score, with the major effect in the 18-month exposure window (ß = 1.220; 95%CI, 0.439, 2) and 3-month exposure window (ß = 1.602; 95%CI, 0.062, 3.143), respectively. Subgroup analysis showed that both PM2.5 and PM10 were significantly associated with anhedonia in females, patients < 40 years old, low family income group, and those who had a higher educational level. Our study suggests that long-term PM2.5 and PM10 exposure are associated with more severe anhedonia in patients with depression. These associations were different in subgroup by age, gender, family income, and educational level.

Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist1, has revolutionized the treatment of depression because of its potent, rapid and sustained antidepressant effects2-4. Although the elimination half-life of ketamine is only 13 min in mice5, its antidepressant activities can last for at least 24 h6-9. This large discrepancy poses an interesting basic biological question and has strong clinical implications. Here we demonstrate that after a single systemic injection, ketamine continues to suppress burst firing and block NMDARs in the lateral habenula (LHb) for up to 24 h. This long inhibition of NMDARs is not due to endocytosis but depends on the use-dependent trapping of ketamine in NMDARs. The rate of untrapping is regulated by neural activity. Harnessing the dynamic equilibrium of ketamine-NMDAR interactions by activating the LHb and opening local NMDARs at different plasma ketamine concentrations, we were able to either shorten or prolong the antidepressant effects of ketamine in vivo. These results provide new insights into the causal mechanisms of the sustained antidepressant effects of ketamine. The ability to modulate the duration of ketamine action based on the biophysical properties of ketamine-NMDAR interactions opens up new opportunities for the therapeutic use of ketamine.

Lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization.

IMPORTANCE: The important enteropathogen Salmonella can cause lethal systemic infection via survival and replication in host macrophages. Lactate represents an abundant intracellular metabolite during bacterial infection, which can also induce macrophage M2 polarization. In this study, we found that macrophage-derived lactate promotes the intracellular replication and systemic infection of Salmonella. During Salmonella infection, lactate via the Salmonella type III secretion system effector SteE promotes macrophage M2 polarization, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. This study highlights the complex interactions between Salmonella and macrophages and provides an additional perspective on host-pathogen crosstalk at the metabolic interface.

Antenatal depression moderated the association between gestational diabetes mellitus and fetal hyperinsulinism.

BACKGROUND: Gestational diabetes mellitus and antenatal depression are common comorbidities. However, the combined effects of antenatal depression and diabetes mellitus during pregnancy on fetal ß-cell function are unknown. OBJECTIVE: This study aimed to test whether the association of maternal gestational diabetes mellitus and glucose metabolism with cord blood C-peptide levels varies with antenatal depression. STUDY DESIGN: Data on mother-child pairs (N=5734) from the Maternal and Infant Health Cohort Study in Hefei were analyzed. Gestational diabetes mellitus was diagnosed using the 75-g oral glucose tolerance test at 24 to 28 weeks of gestation. Antenatal depression was measured using the Edinburgh Postnatal Depression Scale during midpregnancy and late pregnancy. Cord blood samples were collected at delivery and tested for C-peptide levels. RESULTS: A total of 1054 mothers (18.38%) were diagnosed with gestational diabetes mellitus. Gestational diabetes mellitus was associated with a 5.57 (95% confidence interval, 3.65-7.50) percentile higher cord blood C-peptide level. This association varied with depression severity: the differences in cord blood C-peptide percentile for gestational diabetes mellitus vs no gestational diabetes mellitus were 5.12 (95% confidence interval, 2.81-9.75) for nonantenatal depression, 7.36 (95% confidence interval, 2.85-13.38) for moderate antenatal depression, and 10.06 (95% confidence interval, 4.69-14.8) for severe antenatal depression in midpregnancy. Similar associations stratified by antenatal depression in late pregnancy were observed. Antenatal depression was significantly positively correlated with fetal hyperinsulinism in participants with gestational diabetes mellitus but not in participants without gestational diabetes mellitus. CONCLUSION: Antenatal depression, which is related to maternal hyperglycemia, can aggravate the risk of fetal hyperinsulinism in early life.

Prenatal environmental adversity and child neurodevelopmental delay: the role of maternal low-grade systemic inflammation and maternal anti-inflammatory diet.

Maternal inflammation has been proposed as a possible pathway connecting prenatal environmental adversity (PEA), which includes maternal overweightness or obesity, diabetes, hypertensive disorders, and mood or anxiety disorders, to child neurodevelopmental delay. However, effective preventive measures have not yet been reported. Herein, we aimed to investigate whether a maternal anti-inflammatory diet reduced the risk of PEA-induced neurodevelopmental delay, by inhibiting inflammation. This prospective study included 7438 mother-child pairs. Maternal overweightness or obesity, diabetes, and hypertensive disorders were diagnosed before 28 week gestation. Maternal depression disorders were identified using the Edinburgh postnatal depression survey (EPDS) during mid-pregnancy. During mid- and late pregnancy, maternal high-sensitivity C-reactive protein (hs-CRP) levels were measured to evaluate systemic inflammation. The inflammatory potential of the diet was evaluated using the food-based empirical dietary inflammatory pattern (EDIP) score during mid-pregnancy. Pregnant women were classified into high- or low-score groups based on the median EDIP score. The outcomes of neurodevelopmental delay at 6-36 month postpartum were extracted from the Register of Child Healthcare. Among the 7438 mother-child pairs, 2937 (39.5%) were exposed to PEA, and neurodevelopmental delay occurred in 540 (7.3%). Children exposed to PEA had a higher risk of neurodevelopmental delay than those not exposed. PEA exposure was associated with increased hs-CRP during pregnancy in a PEA monotonic manner, an interquartile range increase in hs-CRP in mid- and late pregnancy was associated with an increased risk of child neurodevelopmental delay. Higher maternal persistent inflammation partially mediated the effect of PEA exposure on child neurodevelopmental delay by 17.19%. An increased risk of PEA-related neurodevelopmental delay was observed only in the children of mothers with high-EDIP rather than low-EDIP. These results suggest that increased systemic inflammation through mid- and late pregnancy mediates the association between PEA and child neurodevelopmental delay. A maternal anti-inflammatory diet may improve PEA-induced neurodevelopmental delay, by inhibiting inflammation.

[Alda-1 alleviates brain injury after cardiopulmonary resuscitation by regulating acyl-CoA synthetase long-chain family member 4/glutathione peroxidase 4 pathway-mediated ferroptosis in swine].

OBJECTIVE: To investigate whether the acetaldehyde dehydrogenase 2 specific activator, Alda-1, can alleviate brain injury after cardiopulmonary resuscitation (CPR) by inhibiting cell ferroptosis mediated by acyl-CoA synthetase long-chain family member 4/glutathione peroxidase 4 (ACSL4/GPx4) pathway in swine. METHODS: Twenty-two conventional healthy male white swine were divided into Sham group (n = 6), CPR model group (n = 8), and Alda-1 intervention group (CPR+Alda-1 group, n = 8) using a random number table. The swine model of CPR was reproduced by 8 minutes of cardiac arrest induced by ventricular fibrillation through electrical stimulation in the right ventricle followed by 8 minutes of CPR. The Sham group only experienced general preparation. A dose of 0.88 mg/kg of Alda-1 was intravenously injected at 5 minutes after resuscitation in the CPR+Alda-1 group. The same volume of saline was infused in the Sham and CPR model groups. Blood samples were collected from the femoral vein before modeling and 1, 2, 4, 24 hours after resuscitation, and the serum levels of neuron specific enolase (NSE) and S100 ß protein were determined by enzyme-linked immunosorbent assay (ELISA). At 24 hours after resuscitation, the status of neurologic function was evaluated by neurological deficit score (NDS). Thereafter, the animals were sacrificed, and brain cortex was harvested to measure iron deposition by Prussian blue staining, malondialdehyde (MDA) and glutathione (GSH) contents by colorimetry, and ACSL4 and GPx4 protein expressions by Western blotting. RESULTS: Compared with the Sham group, the serum levels of NSE and S100ß after resuscitation were gradually increased over time, and the NDS score was significantly increased, brain cortical iron deposition and MDA content were significantly increased, GSH content and GPx4 protein expression in brain cortical were significantly decreased, and ACSL4 protein expression was significantly increased at 24 hours after resuscitation in the CPR model and CPR+Alda-1 groups, which indicated that cell ferroptosis occurred in the brain cortex, and the ACSL4/GPx4 pathway participated in this process of cell ferroptosis. Compared with the CPR model group, the serum levels of NSE and S100 ß starting 2 hours after resuscitation were significantly decreased in the CPR+Alda-1 group [NSE (µg/L): 24.1±2.4 vs. 28.2±2.1, S100 ß (ng/L): 2 279±169 vs. 2 620±241, both P < 0.05]; at 24 hours after resuscitation, the NDS score and brain cortical iron deposition and MDA content were significantly decreased [NDS score: 120±44 vs. 207±68, iron deposition: (2.61±0.36)% vs. (6.31±1.66)%, MDA (µmol/g): 2.93±0.30 vs. 3.68±0.29, all P < 0.05], brain cortical GSH content and GPx4 expression in brain cortical was significantly increased [GSH (mg/g): 4.59±0.63 vs. 3.51±0.56, GPx4 protein (GPx4/GAPDH): 0.54±0.14 vs. 0.21±0.08, both P < 0.05], and ACSL4 protein expression was significantly decreased (ACSL4/GAPDH: 0.46±0.08 vs. 0.85±0.13, P < 0.05), which indicated that Alda-1 might alleviate brain cortical cell ferroptosis through regulating ACSL4/GPx4 pathway. CONCLUSIONS: Alda-1 can reduce brain injury after CPR in swine, which may be related to the inhibition of ACSL4/GPx4 pathway mediated ferroptosis.

The mediating role of inflammation in the association between pregnancy loss history and gestational diabetes mellitus.

BACKGROUND: To assess the association of pregnancy loss history with an elevated risk of Gestational diabetes mellitus (GDM) and to investigate whether this association was mediated by high-sensitivity C-reactive protein (hs-CRP). METHODS: We prospectively collected venous blood and pregnancy loss history information from 4873 pregnant women at 16-23 weeks of gestation from March 2018 to April 2022. Hs-CRP concentrations were measured from collected blood samples. A 75 g fasting glucose test was performed at 24 to 28 weeks of gestation for the diagnosis of GDM, with data obtained from medical records. Multivariate linear or logistic regression models and mediation analysis were used to examine the relationships between pregnancy loss history, hs-CRP, and GDM. RESULTS: A multivariable-adjusted logistic regression analysis revealed that compared with pregnant women with no induced abortion history, subjects with 1 and ≥ 2 induced abortions had a higher risk for GDM (RR = 1.47, 95% CI = 1.19-1.81; RR = 1.63, 95% CI = 1.28-2.09). Additionally, the mediation analysis indicated this association was mediated by an increased hs-CRP level with a 20.4% of indirect effect ratio. However, no significant association between a history of miscarriage and the prevalence of GDM was observed. CONCLUSIONS: A history of induced abortion was significantly associated with an increased risk of GDM, and this association occurred in a dose-response effect. Hs-CRP may be accounted for a mediation effect in the pathways linking induced abortion history with GDM.

Previous pregnancy loss and gestational cardiovascular health: A prospective cohort of nulliparous women.

Objectives: To estimate the association of previous pregnancy loss with subsequent cardiovascular health during gestation and to examine the role of high-sensitivity C reactive protein (hs-CRP) in the association. Methods: A total of 2,778 nulliparous pregnant women were recruited between March 2015 and November 2020 in Hefei city, China. Their cardiovascular health (CVH) including prepregnancy body mass index (BMI), blood pressure, total cholesterol, fasting plasma glucose, and smoke status were recorded at 24-28 weeks' gestation, as well as their reproductive history. Multivariate linear and logistic regression were performed to examine the association of pregnancy loss with cardiovascular health. And the role of hs-CRP between pregnancy loss and CVH was assessed by the mediation analysis. Results: Compared with women who have no pregnancy loss, women with a history of spontaneous or induced abortions had higher BMI (ß, 0.72, 95% CI, 0.50 to 0.94) and fasting plasma glucose (ß, 0.04, 95% CI, 0.01 to 0.07), and had lower total CVH scores after adjusting for confounders (ß, -0.09, 95% CI, -0.18 to -0.01). CVH scores were most significantly decreased among women with 3 or more induced abortions (ß, -0.26, 95% CI, -0.49, -0.02). The contribution of pregnancy loss to poorer gestational CVH mediated by increased hs-CRP levels was 23.17%. Conclusion: Previous pregnancy loss was associated with poorer cardiovascular health during gestation, which may be mediated by their gestational inflammatory status. Exposure to miscarriage alone was not a significant predictor of poorer CVH.

Effect of vitamin D supplementation on glucose control in mid-late gestation: A randomized controlled trial.

BACKGROUND & AIMS: It is unclear whether vitamin D supplementation contributes to gestational glucose control and whether the specific effects vary in individuals with diverse genetic and metabolic contexts. The study aimed to assess the effect of vitamin D supplementation during pregnancy on subsequent glucose levels and to identify factors modulating the response to vitamin D3 intake. METHODS: We conducted a multicenter randomized controlled trial, 1720 pregnant women recruited from the three antenatal clinics of Hefei city, China, who were allocated to receive either 1600 IU/d vitamin D3 (n = 858) or 400 IU/d vitamin D3 (n = 862) for 2 months at 24-28 weeks' gestation. Outcomes were changes in serum 25-hydroxyvitamin D (25(OH)D) and fasting plasma glucose (FPG) levels from baseline, 32-36 weeks' gestation to delivery (37-41 weeks) quantified using a linear mixed model. RESULTS: After 2 months, FPG levels of the control group significantly increased by 0.22 mmol/L (from 4.6 [0.4] mmol/L to 4.8 [1.2] mmol/L, P < 0.001) at delivery, but that of the intervention group had no significant variation (from 4.6 [0.4] mmol/L to 4.7 [1.1] mmol/L; between-group difference in changes, -0.2 mmol/L, 95% CI, -0.3 to -0.08, P = 0.015). And differences in FPG variation were found in participants with the ApaI SNP CC genotype, or BsmI-CC, TaqI-AA, FokI-AA, respectively. Pregnant women with basal 25(OH)D concentrations higher than 50 nmol/L subgroup showed the greatest decline in FPG levels (between-group difference, -0.3 mmol/L; 95% CI, -0.5 to -0.1, P < 0.001). Moreover, pregnant women with GDM, multiple pregnancies or who were overweight were more likely to have FPG decline from vitamin D treatment. CONCLUSIONS: Vitamin D supplementation significantly protected glucose homeostasis in mid-late gestation, and glycemic response to vitamin D may be dependent on basal 25(OH)D status, VDR gene polymorphism or their metabolic profiles. TRIAL REGISTRATION NUMBER: ChiCTR2100051914. URL OF REGISTRATION: http://www.chictr.org.cn/showproj.aspx?proj=134700.

Deep learning-based polygenic risk analysis for Alzheimer's disease prediction.

BACKGROUND: The polygenic nature of Alzheimer's disease (AD) suggests that multiple variants jointly contribute to disease susceptibility. As an individual's genetic variants are constant throughout life, evaluating the combined effects of multiple disease-associated genetic risks enables reliable AD risk prediction. Because of the complexity of genomic data, current statistical analyses cannot comprehensively capture the polygenic risk of AD, resulting in unsatisfactory disease risk prediction. However, deep learning methods, which capture nonlinearity within high-dimensional genomic data, may enable more accurate disease risk prediction and improve our understanding of AD etiology. Accordingly, we developed deep learning neural network models for modeling AD polygenic risk. METHODS: We constructed neural network models to model AD polygenic risk and compared them with the widely used weighted polygenic risk score and lasso models. We conducted robust linear regression analysis to investigate the relationship between the AD polygenic risk derived from deep learning methods and AD endophenotypes (i.e., plasma biomarkers and individual cognitive performance). We stratified individuals by applying unsupervised clustering to the outputs from the hidden layers of the neural network model. RESULTS: The deep learning models outperform other statistical models for modeling AD risk. Moreover, the polygenic risk derived from the deep learning models enables the identification of disease-associated biological pathways and the stratification of individuals according to distinct pathological mechanisms. CONCLUSION: Our results suggest that deep learning methods are effective for modeling the genetic risks of AD and other diseases, classifying disease risks, and uncovering disease mechanisms.

Polygenic diseases, such as Alzheimer's disease (AD), are those caused by the interplay between multiple genetic risk factors. Statistical models can be used to predict disease risk based on a person's genetic profile. However, there are limitations to existing methods, while emerging methods such as deep learning may improve risk prediction. Deep learning involves computer-based software learning from patterns in data to perform a certain task, e.g. predict disease risk. Here, we test whether deep learning models can help to predict AD risk. Our models not only outperformed existing methods in modeling AD risk, they also allow us to estimate an individual's risk of AD and determine the biological processes that may be involved in AD. With further testing and optimization, deep learning may be a useful tool to help accurately predict risk of AD and other diseases.

Imaging the metabolic reprograming of fatty acid synthesis pathway enables new diagnostic and therapeutic opportunity for breast cancer.

BACKGROUND: Reprogrammed metabolic network is a key hallmark of cancer. Profiling cancer metabolic alterations with spatial signatures not only provides clues for understanding cancer biochemical heterogeneity, but also helps to decipher the possible roles of metabolic reprogramming in cancer development. METHODS: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technique was used to characterize the expressions of fatty acids in breast cancer tissues. Specific immunofluorescence staining was further carried out to investigate the expressions of fatty acid synthesis-related enzymes. RESULTS: The distributions of 23 fatty acids in breast cancer tissues have been mapped, and the levels of most fatty acids in cancer tissues are significantly higher than those in adjacent normal tissues. Two metabolic enzymes, fatty acid synthase (FASN) and acetyl CoA carboxylase (ACC), which being involved in the de novo synthesis of fatty acid were found to be up-regulated in breast cancer. Targeting the up-regulation of FASN and ACC is an effective approach to limiting the growth, proliferation, and metastasis of breast cancer cells. CONCLUSIONS: These spatially resolved findings enhance our understanding of cancer metabolic reprogramming and give an insight into the exploration of metabolic vulnerabilities for better cancer treatment.

Increasing systemic chronic inflammation mediated the association between poor sleep during pregnancy and gestational cardiovascular health.

OBJECTIVES: This study aimed to examine the association between sleep behaviors and cardiovascular health (CVH) during pregnancy and test whether high-sensitivity C-reactive protein (hs-CRP) mediates this association. METHODS: The study included 4204 pregnant women from the Maternal and Infant Health cohort study in Hefei (MIH-Hefei). Information on sleep (chronotype, sleep duration, snoring, daytime sleepiness, and insomnia) was collected through a touch-screen structured questionnaire at 16-23 weeks' gestation. CVH (body mass index, blood pressure, total cholesterol, glucose, and smoking) and hs-CRP were measured at 24-28 weeks' gestation. The role of hs-CRP in the association between sleep and CVH was explored in a mediation analysis, while adjusting for multiple confounding factors. RESULTS: Poor sleep score was significantly associated with poor gestational CVH metrics, including an RR of 0.872 (95% CI, 0.810, 0.938) for having all ideal (vs. any nonideal) CVH metrics; hs-CRP level was significantly associated with poor gestational CVH metrics, including an RR of 0.531 (95% CI, 0.432, 0.609) for having all ideal (vs. any nonideal) CVH metrics. Sleep scores were positively correlated with hs-CRP level (ß, 0.020, 95% CI, 0.006, 0.034). Mediation analysis revealed that the association between sleep and CVH mediated by hs-CRP was 12.31% (indirect effect, -0.0095, 95% CI, -0.0167, -0.0042). CONCLUSIONS: Poor sleep during pregnancy, particularly late chronotype and snoring, may worsen CVH by increasing systemic chronic inflammation.

High oil content inhibits humification in food waste composting by affecting microbial community succession and organic matter degradation.

Composting is an effective technology to realize resource utilization of food waste in rural China. However, high oil content in food waste limits composting humification. This study investigated the effects of blended plant oil addition at different proportions (0, 10, 20, and 30%) on the humification of food waste composting. Oil addition at 10%-20% enhanced lignocellulose degradation by 16.6%-20.8% and promoted humus formation. In contrast, the high proportion of oil (30%) decreased the pH, increased the electrical conductivity, and reduced the seed germination index to 64.9%. High-throughput sequencing showed that high oil inhibited the growth and reproduction of bacteria (Bacillus, Fodinicurvataceae, and Methylococcaceae) and fungi (Aspergillus), attenuated their interaction, thus, reducing the conversion of organic matter, such as lignocellulose, fat, and total sugar, to humus, consequently leading to negative impacts on composting humification. The results can guide composting parameter optimization and improve effective management of rural food waste.