A gut-derived hormone regulates cholesterol metabolism.

The reciprocal coordination between cholesterol absorption in the intestine and de novo cholesterol synthesis in the liver is essential for maintaining cholesterol homeostasis, yet the mechanisms governing the opposing regulation of these processes remain poorly understood. Here, we identify a hormone, Cholesin, which is capable of inhibiting cholesterol synthesis in the liver, leading to a reduction in circulating cholesterol levels. Cholesin is encoded by a gene with a previously unknown function (C7orf50 in humans; 3110082I17Rik in mice). It is secreted from the intestine in response to cholesterol absorption and binds to GPR146, an orphan G-protein-coupled receptor, exerting antagonistic downstream effects by inhibiting PKA signaling and thereby suppressing SREBP2-controlled cholesterol synthesis in the liver. Therefore, our results demonstrate that the Cholesin-GPR146 axis mediates the inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. This discovered hormone, Cholesin, holds promise as an effective agent in combating hypercholesterolemia and atherosclerosis.

CLCF1 inhibits energy expenditure via suppressing brown fat thermogenesis.

Brown adipose tissue (BAT) is the main site of nonshivering thermogenesis which plays an important role in thermogenesis and energy metabolism. However, the regulatory factors that inhibit BAT activity remain largely unknown. Here, cardiotrophin-like cytokine factor 1 (CLCF1) is identified as a negative regulator of thermogenesis in BAT. Adenovirus-mediated overexpression of CLCF1 in BAT greatly impairs the thermogenic capacity of BAT and reduces the metabolic rate. Consistently, BAT-specific ablation of CLCF1 enhances the BAT function and energy expenditure under both thermoneutral and cold conditions. Mechanistically, adenylate cyclase 3 (ADCY3) is identified as a downstream target of CLCF1 to mediate its role in regulating thermogenesis. Furthermore, CLCF1 is identified to negatively regulate the PERK-ATF4 signaling axis to modulate the transcriptional activity of ADCY3, which activates the PKA substrate phosphorylation. Moreover, CLCF1 deletion in BAT protects the mice against diet-induced obesity by promoting BAT activation and further attenuating impaired glucose and lipid metabolism. Therefore, our results reveal the essential role of CLCF1 in regulating BAT thermogenesis and suggest that inhibiting CLCF1 signaling might be a potential therapeutic strategy for improving obesity-related metabolic disorders.

Calorie Restriction with or without Time-Restricted Eating in Weight Loss.

BACKGROUND: The long-term efficacy and safety of time-restricted eating for weight loss are not clear. METHODS: We randomly assigned 139 patients with obesity to time-restricted eating (eating only between 8:00 a.m. and 4:00 p.m.) with calorie restriction or daily calorie restriction alone. For 12 months, all the participants were instructed to follow a calorie-restricted diet that consisted of 1500 to 1800 kcal per day for men and 1200 to 1500 kcal per day for women. The primary outcome was the difference between the two groups in the change from baseline in body weight; secondary outcomes included changes in waist circumference, body-mass index (BMI), amount of body fat, and measures of metabolic risk factors. RESULTS: Of the total 139 participants who underwent randomization, 118 (84.9%) completed the 12-month follow-up visit. The mean weight loss from baseline at 12 months was -8.0 kg (95% confidence interval [CI], -9.6 to -6.4) in the time-restriction group and -6.3 kg (95% CI, -7.8 to -4.7) in the daily-calorie-restriction group. Changes in weight were not significantly different in the two groups at the 12-month assessment (net difference, -1.8 kg; 95% CI, -4.0 to 0.4; P = 0.11). Results of analyses of waist circumferences, BMI, body fat, body lean mass, blood pressure, and metabolic risk factors were consistent with the results of the primary outcome. In addition, there were no substantial differences between the groups in the numbers of adverse events. CONCLUSIONS: Among patients with obesity, a regimen of time-restricted eating was not more beneficial with regard to reduction in body weight, body fat, or metabolic risk factors than daily calorie restriction. (Funded by the National Key Research and Development Project [No. 2018YFA0800404] and others; ClinicalTrials.gov number, NCT03745612.).

A genome-wide association study identifies candidate genes for sleep disturbances in depressed individuals.

OBJECTIVE: This study aimed to identify candidate loci and genes related to sleep disturbances in depressed individuals and clarify the co-occurrence of sleep disturbances and depression from the genetic perspective. METHODS: The study subjects (including 58,256 self-reported depressed individuals and 6,576 participants with PHQ-9 score ≥ 10, respectively) were collected from the UK Biobank, which were determined based on the Patient Health Questionnaire (PHQ-9) and self-reported depression status, respectively. Sleep related traits included chronotype, insomnia, snoring and daytime dozing. Genome-wide association studies (GWASs) of sleep related traits in depressed individuals were conducted by PLINK 2.0 adjusting age, sex, Townsend deprivation index and 10 principal components as covariates. The CAUSALdb database was used to explore the mental traits associated with the candidate genes identified by the GWAS. RESULTS: GWAS detected 15 loci significantly associated with chronotype in the subjects with self-reported depression, such as rs12736689 at RNASEL (P = 1.00 × 10- 09), rs509476 at RGS16 (P = 1.58 × 10- 09) and rs1006751 at RFX4 (P = 1.54 × 10- 08). 9 candidate loci were identified in the subjects with PHQ-9 ≥ 10, of which 2 loci were associated with insomnia such as rs115379847 at EVC2 (P = 3.50 × 10- 08), and 7 loci were associated with daytime dozing, such as rs140876133 at SMYD3 (P = 3.88 × 10- 08) and rs139156969 at ROBO2 (P = 3.58 × 10- 08). Multiple identified genes, such as RNASEL, RGS16, RFX4 and ROBO2 were reported to be associated with chronotype, depression or cognition in previous studies. CONCLUSION: Our study identified several candidate genes related to sleep disturbances in depressed individuals, which provided new clues for understanding the biological mechanism underlying the co-occurrence of depression and sleep disorders.

Whole-orbit radiomics: machine learning-based multi- and fused- region radiomics signatures for intravenous glucocorticoid response prediction in thyroid eye disease.

BACKGROUND: Radiomics analysis of orbital magnetic resonance imaging (MRI) shows preliminary potential for intravenous glucocorticoid (IVGC) response prediction of thyroid eye disease (TED). The current region of interest segmentation contains only a single organ as extraocular muscles (EOMs). It would be of great value to consider all orbital soft tissues and construct a better prediction model. METHODS: In this retrospective study, we enrolled 127 patients with TED that received 4·5 g IVGC therapy and had complete follow-up examinations. Pre-treatment orbital T2-weighted imaging (T2WI) was acquired for all subjects. Using multi-organ segmentation (MOS) strategy, we contoured the EOMs, lacrimal gland (LG), orbital fat (OF), and optic nerve (ON), respectively. By fused-organ segmentation (FOS), we contoured the aforementioned structures as a cohesive unit. Whole-orbit radiomics (WOR) models consisting of a multi-regional radiomics (MRR) model and a fused-regional radiomics (FRR) model were further constructed using six machine learning (ML) algorithms. RESULTS: The support vector machine (SVM) classifier had the best performance on the MRR model (AUC = 0·961). The MRR model outperformed the single-regional radiomics (SRR) models (highest AUC = 0·766, XGBoost on EOMs, or LR on OF) and conventional semiquantitative imaging model (highest AUC = 0·760, NaiveBayes). The application of different ML algorithms for the comparison between the MRR model and the FRR model (highest AUC = 0·916, LR) led to different conclusions. CONCLUSIONS: The WOR models achieved a satisfactory result in IVGC response prediction of TED. It would be beneficial to include more orbital structures and implement ML algorithms while constructing radiomics models. The selection of separate or overall segmentation of orbital soft tissues has not yet attained its final optimal result.

Caenorhabditis elegans LIN-24, a homolog of bacterial pore-forming toxin, protects the host from microbial infection.

Aerolysin-like pore-forming protein (af-PFP) superfamily members are double-edge swords that assist the bacterial infection but shied bacteria from the host by various mechanisms in some species including the toad Bombina maxima and zebrafish. While members of this family are widely expressed in all kingdoms, especially non-bacteria species, it remains unclear whether their anti-bacterial function is conserved. LIN-24 is an af-PFP that is constitutively expressed throughout the Caenorhabditis elegans lifespan. Here, we observed that LIN-24 knockdown reduced the maximum lifespan of worms. RNA-seq analysis identified 323 differentially expressed genes (DEGs) post-LIN-24 knockdown that were enriched in "immune response" and "lysosome pathway," suggesting a possible role for LIN-24 in resisting microbial infection. In line with this, we found that Pseudomonas aeruginosa 14 (PA14) infection induced LIN-24 expression, and that survival after PA14 infection was significantly reduced by LIN-24 knockdown. In contrast, LIN-24 overexpression (LIN-24-OE) conferred protection against PA14 infection, with worms showing longer survival time and reduced bacterial load. Weighted gene co-expression network analysis of LIN-24-OE worms showed that the highest correlation module was enriched in factors related to immunity and the defense response. Finally, by predicting transcription factors from RNA-seq data and knocking down candidate transcription factors in LIN-24-OE worms, we revealed that LIN-24 may protect worms against bacterial infection by stimulating DAF-16-mediated immune responses. These findings agree with our previous studies showing an anti-microbial role for the amphibian-derived af-PFP complex ßγ-CAT, suggesting that af-PFPs may play a conserved role in combatting microbial infections. Further research is needed to determine the roles this protein family plays in other physio-pathological processes, such as metabolism, longevity, and aging.

Epigenetic analysis suggests aberrant cerebellum brain aging in old-aged adults with autism spectrum disorder and schizophrenia.

The aberrant aging hypothesis of schizophrenia (SCZ) and autism spectrum disorder (ASD) has been proposed, and the DNA methylation (DNAm) clock, which is a cumulative evaluation of DNAm levels at age-related CpGs, could serve as a biological aging indicator. This study evaluated epigenetic brain aging of ASD and SCZ using Horvath's epigenetic clock, based on two public genome-wide DNA methylation datasets of post-mortem brain samples (NASD = 222; NSCZ = 142). Total subjects were further divided into subgroups by gender and age. The epigenetic age acceleration (AgeAccel) for each sample was calculated as the residual value resulting from the regression model and compared between groups. Results showed DNAm age has a strong correlation with chronological age in both datasets across multiple brain regions (P < 0.05). When divided into equally sized age groups, the AgeAccel of the cerebellum (CB) region from people over 45 years of age was greater compared to the control sample (AgeAccel of ASD vs control: 5.069 vs -6.249; P < 0.001). And a decelerated epigenetic aging process was observed in the CB region of individuals with SCZ aged 50-70 years (AgeAccel of SCZ vs control: -3.171 vs 2.418; P < 0.05). However, our results showed no significant difference in AgeAccel between ASD and control groups, and between SCZ and control groups in the total and gender-specific groups (P > 0.05). This study's results revealed some evidence for aberrant epigenetic CB brain aging in old-aged patients with ASD and SCZ, indicating a different pattern of CB aging in older adults with these two diseases. However, further studies of larger ASD and SCZ cohorts are necessary to make definitive conclusions on this observation.

Sex Hormone-Binding Globulin and Risk of Incident Dementia in Middle-Aged to Older Women: Results from the UK Biobank Cohort Study.

INTRODUCTION: The association of serum sex hormone-binding globulin (SHBG) concentrations with dementia risk remains uncertain in middle-aged to older women. We examined associations of serum SHBG levels with incidence of all-cause dementia and its subtypes in middle-aged to older women from the large population-based UK Biobank cohort study. METHODS: Serum total SHBG levels were measured by immunoassay. The incidence of all-cause dementia and its subtypes was recorded. Cox proportional hazards models were used to calculate hazard ratios (HR) for main outcomes. RESULTS: Among 171,482 community-dwelling women (mean [SD] age was 59.9 [5.4] years, median follow-up of 11.8 years), 2,368 developed dementia, including 1,088 from Alzheimer's disease (AD), 451 from vascular dementia (VAD), and 1,609 from other dementia. After multivariable adjustments, higher serum SHBG levels were significantly associated with higher risks of all-cause dementia, AD, and other dementia (all p < 0.05). Compared to those in the lowest quartile of SHBG levels, participants in the highest quartile of SHBG levels had a higher risk of all-cause dementia (HR: 1.34; 95% confidence interval [CI]: 1.16-1.53), AD (HR: 1.32; 95% CI: 1.07-1.62), and other dementia (HR: 1.44; 95% CI: 1.21-1.70). However, this relationship was not significant for VAD (HR: 1.16; 95% CI: 0.86-1.56). CONCLUSION: These findings indicated that higher serum SHBG concentrations were independently associated with higher risks of incident all-cause dementia, as well as AD and other dementia among middle-aged to older women. No association was found for VAD.

Identifying novel chemical-related susceptibility genes for five psychiatric disorders through integrating genome-wide association study and tissue-specific 3'aQTL annotation datasets.

The establishment of 3'aQTLs comprehensive database provides an opportunity to help explore the functional interpretation from the genome-wide association study (GWAS) data of psychiatric disorders. In this study, we aim to search novel susceptibility genes, pathways, and related chemicals of five psychiatric disorders via GWAS and 3'aQTLs datasets. The GWAS datasets of five psychiatric disorders were collected from the open platform of Psychiatric Genomics Consortium (PGC, https://www.med.unc.edu/pgc/ ) and iPSYCH ( https://ipsych.dk/ ) (Demontis et al. in Nat Genet 51(1):63-75, 2019; Grove et al. in Nat Genet 51:431-444, 2019; Genomic Dissection of Bipolar Disorder and Schizophrenia in Cell 173: 1705-1715.e1716, 2018; Mullins et al. in Nat Genet 53: 817-829; Howard et al. in Nat Neurosci 22: 343-352, 2019). The 3'untranslated region (3'UTR) alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) summary datasets of 12 brain regions were obtained from another public platform ( https://wlcb.oit.uci.edu/3aQTLatlas/ ) (Cui et al. in Nucleic Acids Res 50: D39-D45, 2022). First, we aligned the GWAS-associated SNPs of psychiatric disorders and datasets of 3'aQTLs, and then, the GWAS-associated 3'aQTLs were identified from the overlap. Second, gene ontology (GO) and pathway analysis was applied to investigate the potential biological functions of matching genes based on the methods provided by MAGMA. Finally, chemical-related gene-set analysis (GSA) was also conducted by MAGMA to explore the potential interaction of GWAS-associated 3'aQTLs and multiple chemicals in the mechanism of psychiatric disorders. A number of susceptibility genes with 3'aQTLs were found to be associated with psychiatric disorders and some of them had brain-region specificity. For schizophrenia (SCZ), HLA-A showed associated with psychiatric disorders in all 12 brain regions, such as cerebellar hemisphere (P = 1.58 × 10-36) and cortex (P = 1.58 × 10-36). GO and pathway analysis identified several associated pathways, such as Phenylpropanoid Metabolic Process (GO:0009698, P = 6.24 × 10-7 for SCZ). Chemical-related GSA detected several chemical-related gene sets associated with psychiatric disorders. For example, gene sets of Ferulic Acid (P = 6.24 × 10-7), Morin (P = 4.47 × 10-2) and Vanillic Acid (P = 6.24 × 10-7) were found to be associated with SCZ. By integrating the functional information from 3'aQTLs, we identified several susceptibility genes and associated pathways especially chemical-related gene sets for five psychiatric disorders. Our results provided new insights to understand the etiology and mechanism of psychiatric disorders.

Nanosecond heme-to-heme electron transfer rates in a multiheme cytochrome nanowire reported by a spectrally unique His/Met-ligated heme.

Proteins achieve efficient energy storage and conversion through electron transfer along a series of redox cofactors. Multiheme cytochromes are notable examples. These proteins transfer electrons over distance scales of several nanometers to >10 µm and in so doing they couple cellular metabolism with extracellular redox partners including electrodes. Here, we report pump-probe spectroscopy that provides a direct measure of the intrinsic rates of heme-heme electron transfer in this fascinating class of proteins. Our study took advantage of a spectrally unique His/Met-ligated heme introduced at a defined site within the decaheme extracellular MtrC protein of Shewanella oneidensis We observed rates of heme-to-heme electron transfer on the order of 109 s-1 (3.7 to 4.3 Å edge-to-edge distance), in good agreement with predictions based on density functional and molecular dynamics calculations. These rates are among the highest reported for ground-state electron transfer in biology. Yet, some fall 2 to 3 orders of magnitude below the Moser-Dutton ruler because electron transfer at these short distances is through space and therefore associated with a higher tunneling barrier than the through-protein tunneling scenario that is usual at longer distances. Moreover, we show that the His/Met-ligated heme creates an electron sink that stabilizes the charge separated state on the 100-µs time scale. This feature could be exploited in future designs of multiheme cytochromes as components of versatile photosynthetic biohybrid assemblies.

Application Effects of Individualized Diet Nursing Combined with the Modified Glasgow-Blatchford Scoring System in Upper Gastrointestinal Bleeding.

Background: Upper gastrointestinal bleeding encompasses bleeding arising from esophageal, gastric, duodenal, or pancreaticobiliary lesions above the Treitz ligament. Research indicates a close association between improper diet and upper gastrointestinal bleeding. Objective: This study aims to investigate the application effects of individualized diet nursing combined with the modified Glasgow-Blatchford scoring system in patients with upper gastrointestinal bleeding. Design: A randomized controlled study was conducted. Setting: The study took place at the First Hospital of Hebei Medical University. Participants: From January 2021 to October 2022, 80 patients with upper gastrointestinal bleeding were selected at our hospital. Using a random number table, they were divided into a control group and an observation group, each comprising 40 cases. Interventions: The control group received routine nursing, while the observation group received individualized diet nursing based on the Glasgow-Blatchford score in addition to routine nursing. Primary Outcome Measures: (1) bleeding frequency, hemostasis time, and hospital stay; (2) re-bleeding rate; (3) Glasgow-Blatchford scores; (4) quality of life; and (5) nursing satisfaction. Results: In the observation group, bleeding frequency, hemostasis time, and hospital stay significantly reduced compared to the control (P < .05). Post-nursing, the observation group had a lower re-bleeding rate (χ2=11.25, P < .05). Before nursing, no statistical differences existed in Glasgow-Blatchford and quality of life scores between groups (P > .05). Post-nursing, both groups saw reduced Glasgow-Blatchford scores, more so in the observation group (P < .05). Quality of life scores increased in both, more notably in the observation group (P < .05). Overall nursing satisfaction was higher in the observation group (P < .05). Conclusions: Individualized diet nursing, based on the Glasgow-Blatchford score, improves cure rates and quality of life and warrants promotion.

Acetyltransferase P300 Regulates Glucose Metabolic Reprogramming through Catalyzing Succinylation in Lung Cancer.

Aberrant protein post-translational modification is a hallmark of malignant tumors. Lysine succinylation (Ksucc) plays a vital role in cell energy metabolism in various cancers. However, whether succinylation can be catalyzed by acetyltransferase p300 remains unclear. In this study, we unveiled that p300 is a "writer" for succinylation, and p300-mediated Ksucc promotes cell glycometabolism in lung adenocarcinoma (LUAD). Specifically, our succinylome data revealed that EP300 deficiency leads to the systemic reduction of Ksucc, and 79.55% of the p300-succinylated proteins were found in the cytoplasm, which were primarily enriched in the carbohydrate metabolism process. Interestingly, deleting EP300 led to a notable decrease in Ksucc levels on several glycolytic enzymes, especially Phosphoglycerate Kinase 1 (PGK1). Mutation of the succinylated site of PGK1 notably hindered cell glycolysis and lactic acid excretion. Metabolomics in vivo indicated that p300-caused metabolic reprogramming was mainly attributed to the altered carbohydrate metabolism. In addition, 89.35% of LUAD patients exhibited cytoplasmic localization of p300, with higher levels in tumor tissues than adjacent normal tissues. High levels of p300 correlated with advanced tumor stages and poor prognosis of LUAD patients. Briefly, we disclose the activity of p300 to catalyze succinylation, which contributes to cell glucose metabolic reprogramming and malignant progression of lung cancer.

Leukemia inhibitory factor protects against liver steatosis in nonalcoholic fatty liver disease patients and obese mice.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. However, the molecular mechanisms that promote dysregulation of hepatic triglyceride metabolism and lead to NAFLD are poorly understood, and effective treatments are limited. Leukemia inhibitory factor (LIF) is a member of the interleukin-6 cytokine family and has been shown to regulate a variety of physiological processes, although its role in hepatic triglyceride metabolism remains unknown. In the present study, we measured circulating LIF levels by ELISA in 214 patients with biopsy-diagnosed NAFLD as well as 314 normal control patients. We further investigated the potential role and mechanism of LIF on hepatic lipid metabolism in obese mice. We found that circulating LIF levels correlated with the severity of liver steatosis. Patients with ballooning, fibrosis, lobular inflammation, and abnormally elevated liver injury markers alanine transaminase and aspartate aminotransferase also had higher levels of serum LIF than control patients. Furthermore, animal studies showed that white adipose tissue-derived LIF could ameliorate liver steatosis through activation of hepatic LIF receptor signaling pathways. Together, our results suggested that targeting LIF-LIF receptor signaling might be a promising strategy for treating NAFLD.

Assessing the interaction effects of brain structure longitudinal changes and life environmental factors on depression and anxiety.

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome-wide association study datasets of 15 brain structure longitudinal changes (N = 15,640) were obtained from the published study. Genotype and phenotype-related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change-related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex-specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta = -.003, p = .018 for depression; beta = -003, p = .008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta = .088, p = .002 for depression; beta = .070, p = .008 for anxiety). We also observed sex-specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta = -.004, p = .020 for depression; beta = -.005, p = .002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety.

The effect of dietary carbohydrate and calorie restriction on weight and metabolic health in overweight/obese individuals: a multi-center randomized controlled trial.

BACKGROUND: Both low-carbohydrate (LC) and calorie-restricted (CR) diets have been shown to have metabolic benefits. However, the two regimens have yet to be thoroughly compared. We conducted a 12-week randomized trial to compare the effects of these diets separately and in combination on both weight loss and metabolic risk factors in overweight/obese individuals. METHODS: A total of 302 participants were randomized to LC diet (n = 76), CR diet (n = 75), LC + CR diet (n = 76), or normal control (NC) diet (n = 75) using a computer-based random number generator. The primary outcome was the change in body mass index (BMI). The secondary outcomes included body weight, waist circumference, waist-to-hip ratio, body fat, and metabolic risk factors. All participants attended health education sessions during the trial. RESULTS: A total of 298 participants were analyzed. BMI change over 12 weeks was - 0.6 (95% CI, - 0.8 to - 0.3) kg/m2 in NC, - 1.3 (95% CI, - 1.5 to - 1.1) kg/m2 in CR, - 2.3 (95% CI, - 2.6 to - 2.1) kg/m2 in LC, and - 2.9 (95% CI, - 3.2 to - 2.6) kg/m2 in LC + CR. LC + CR diet was more effective than LC or CR diet alone at reducing BMI (P = 0.001 and P < 0.001, respectively). Furthermore, compared with the CR diet, the LC + CR diet and LC diet further reduced body weight, waist circumference, and body fat. Serum triglycerides were significantly reduced in the LC + CR diet group compared with the LC or CR diet alone. Plasma glucose, homeostasis model assessment of insulin resistance, and cholesterol concentrations (total, LDL, and HDL) did not change significantly between the groups during the 12-week intervention. CONCLUSIONS: The reduction of carbohydrate intake without restricting caloric intake is more potent to achieve weight loss over 12 weeks when compared to a calorie-restricted diet in overweight/obese adults. The combination of restricting carbohydrate and total calorie intake may augment the beneficial effects of reducing BMI, body weight, and metabolic risk factors among overweight/obese individuals. TRIAL REGISTRATION: The study was approved by the institutional review board of Zhujiang Hospital of Southern Medical University and registered at the China Clinical Trial Registration Center (registration number: ChiCTR1800015156).

Exome-wide screening identifies novel rare risk variants for major depression disorder.

Despite thousands of common genetic loci of major depression disorders (MDD) have been identified by GWAS to date, a large proportion of genetic variation predisposing to MDD remains unaccounted for. By utilizing the newly released UK Biobank 200,643 exome dataset, we conducted an exome-wide association study to identify rare risk variants contributing to MDD. After quality control, 120,033 participants with MDD polygenic risk scores (PRS) values were included. The individuals with lower 30% quantile of the PRS value were filtered for case and control selecting. Then the cases were set as the individuals with upper 10% quantile of the PHQ depression score and lower 10% quantile were set as controls. Finally, 1612 cases and 1612 controls were included in this study. The variants were annotated by ANNOVRA software. After exclusions, 34,761 qualifying variants, including 148 frameshift variant, 335 non-frameshift variant, 33,758 nonsynonymous, 91 start-loss, 393 stop-gain, 36 stop-loss variants were imported into the SKAT R-package to perform single variants, gene-based burden and robust burden tests with minor allele frequency (MAF) < 0.01. Single variant association testing identified one variant, rs4057749 (P = 5.39 × 10-9), within OR8B4 gene at an exome-wide significance level. The gene-based burden test of the exonic variants identified genome-wide significant associations in OR8B4 (PSKAT = 6.23 × 10-5, PSKAT Robust = 4.49 × 10-5), TRAPPC11 (PSKAT = 0.014, PSKAT Robust = 0.015), SBK3 (PSKAT = 0.020, PSKAT Robust = 0.025) and TNRC6B (PSKAT = 0.026, PSKAT Robust = 0.036). We identified multiple novel rare risk variants contributing to MDD in the individuals with lower PRS of MDD. The findings can help to broaden the genetic insights of the MDD pathogenesis.

Cationic Starch Nanoparticles for Enhancing CpG Oligodeoxynucleotide-Mediated Antitumor Immunity.

CpG ODNs demonstrate a significant promise for immunotherapy. However, their application is limited owing to quick DNase digestion and inadequate cellular internalization. Transportation of CpG ODNs into immune cells is crucial. Although viral vectors exhibit high transfection efficiency, safety risks, high cost, and low carrying capacity remain big obstacles. Herein, a novel CpG ODNs vector was fabricated by using starch. Starch was ultrasonicated and simply aminated (NH2-St) through grafting with diethylenetriamine, which was spherical with a diameter of 50 nm. NH2-St possessed good biocompatibility. Cationic NH2-St encapsulated CpG ODNs well and possessed a high loading capacity of 317 µg/mg. NH2-St protected CpG ODNs from nuclease digestion and significantly enhanced their cellular uptake. NH2-St/CpG induced the potent secretion of antitumor cytokines from macrophages and effectively suppressed the growth of tumor cells. This work highlights the promise of starch for CpG ODNs delivery, which brings new hope for cancer immunotherapy.

Maternal smoking around birth may lower the protective effects of breastfeeding on anxiety, depression and neuroticism in adult offspring: a UK biobank study.

We aim to explore the combined effects of the smoking and breastfeeding on offspring mental health outcomes. We used data from UK biobank (N = 342,846) to evaluate joint effect of breastfeeding and maternal smoke during pregnancy (MSDP) on seven adult offspring mental health outcomes (self-reported depression, depression score, self-reported anxiety, anxiety score, neuroticism score, self-harm, suicide). We stratified individuals to MSDP group and non-MSDP group as well as breastfeeding group and non-breastfeeding group. Multiple linear regression and logistic regressions analysis were performed between independent variables (MSDP or breastfeeding) and dependent variables separately (seven mental health outcomes) in each stratum. Effect estimates were expressed as ß values and OR values. Sex, age, 10 principle components of population structure, smoking, alcohol use, and Townsend deprivation index were examined as covariates. At MSDP grouping level, coefficients (odds ratio [OR]) for association of breastfed as a baby with self-reported anxiety (category variable) were 0.87 (95%CI, (0.82-0.93), P = 1.74 × 10-5) in the MSDP group and 0.83 (95%CI, (0.79-0.87), P = 2.76 × 10-17) in the non-MSDP group. At breastfeeding grouping level, OR for association of MSDP and self-reported anxiety were 1.15 (95%CI, (1.10-1.20), P = 5.36 × 10-11) in breastfeeding group and 1.12(95%CI, (1.06-1.20), P = 2.02 × 10-4) in non-breastfeeding group. At MSDP grouping level, negatively associations were found for breastfeeding and anxiety score (continuable variable) in MSDP group (-0.04 SD change per SD change in MSDP, 95% CI, (- 0.06, - 0.02), P = 2.42 × 10-3) and non-MSDP group (-0.06 SD change per SD change in MSDP, 95%CI, (- 0.07, - 0.04), P = 1.70 × 10-11). At breastfeeding grouping level, positive association was found for MSDP and anxiety score in the breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.06-0.09), P = 1.49 × 10-20) and non-breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.05-0.09), P = 7.19 × 10-8). Compared with non-MSDP group, the protective effect (reflected by coefficients) of breastfeeding on anxiety in the MSDP decreased. Our preliminary study found MSDP may lower the protective effect of breastfeeding on the adult offspring anxiety, depression and neuroticism, providing useful recommendations for health care service via quitting smoking during pregnancy and encouraging prolonged breastfeeding.

Circulating galectin-3 levels are inversely associated with subclinical cardiovascular disease in obese adults.

BACKGROUND: Galectin-3 is a new cytokine that is mainly secreted by activated macrophages. It is involved in apoptosis, inflammation and may play a role in the development of cardiovascular disease (CVD). However, there is little information about the association between circulating galectin-3 and subclinical atherosclerosis in humans. METHODS AND RESULTS: We measured serum galectin-3 in 483 obese adult subjects (aged 40 years and over) who had the measurement of carotid intima-media thickness (CIMT) recruited from the community. Adults with lower levels of circulating galectin-3 had increased CIMT (p < 0.05). In multivariable linear regression analyses, circulating galectin-3 was independently associated with CIMT. The risks of increased CIMT were significantly decreased by 65.1% (OR (95% CI): 0.349 (0.165-0.739)), adjusting for possible confounding factors. Notably, individuals in the lowest quartile of serum galectin-3 were 1.80 times (p < 0.05) more likely to have increased CIMT than those in the highest quartile in multivariable logistic regression analyses; however, such associations with circulating galectin-3 were not noted for carotid plague. CONCLUSIONS: These findings propose that circulating galectin-3 concentrations are inversely associated with increased CIMT in obese adults, which may be a potential biomarker of CVD.

Prevalence and genotype distribution of human papillomavirus infection among female outpatients in Northeast China: a population-based survey of 110,927 women.

PURPOSE: Human papillomavirus (HPV) infection, especially high-risk HPV, is a major etiological factor for cervical cancer. This study aimed to investigate the distribution of human papillomavirus infection among female outpatients in Northeast China. METHODS: A total of 110,927 women aged between 18 and 80 years from Shengjing Hospital of China Medical University, tested with the HPV Geno-Array Test Kit (HybriBio), were enrolled in this study. RESULTS: The overall prevalence of HPV infection in the study population was 16.95% (18,802/110,927). A total of 21 HPV genotypes were identified and the six most prevalent ones were HPV16 (5.78%), HPV58 (2.62%), HPV52 (1.91%), HPV33 (1.55%), HPV53 (1.45%), and HPV18 (1.16%). The prevalence of single HPV was 83.58% (15,714/18802) and that of multiple HPV was 16.42% (3088/18802). HPV16, HPV58, and HPV52 were the most common types of HR-HPV infections, while CP8304, HPV11, and HPV6 were the most common types of LR-HPV infections. Among the multiple infection groups, HPV16 was the most common type of co-infection. Furthermore, the prevalence of HPV infections varied among different age groups. Age-specific prevalence of HPV exhibited two peaks in the youngest age group and in the group aged 50-60 years. CONCLUSION: HPV16, 58, 52, 33, 53, and 18 were the most common types in the general female population. The prevalence of HPV infection varied among different age groups. This study provides guidance for future HPV-based cervical cancer screening tests and prophylactic HPV vaccinations in China.