STEMSIM: a simulator of within-strain short-term evolutionary mutations for longitudinal metagenomic data.

MOTIVATION: As the resolution of metagenomic analysis increases, the evolution of microbial genomes in longitudinal metagenomic data has become a research focus. Some software has been developed for the simulation of complex microbial communities at the strain level. However, the tool for simulating within-strain evolutionary signals in longitudinal samples is still lacking. RESULTS: In this study, we introduce STEMSIM, a user-friendly command-line simulator of short-term evolutionary mutations for longitudinal metagenomic data. The input is simulated longitudinal raw sequencing reads of microbial communities or single species. The output is the modified reads with within-strain evolutionary mutations and the relevant information of these mutations. STEMSIM will be of great use for the evaluation of analytic tools that detect short-term evolutionary mutations in metagenomic data. AVAILABILITY AND IMPLEMENTATION: STEMSIM and its tutorial are freely available online at https://github.com/BoyanZhou/STEMSim.

Ancient DNA and multimethod dating confirm the late arrival of anatomically modern humans in southern China.

The expansion of anatomically modern humans (AMHs) from Africa around 65,000 to 45,000 y ago (ca. 65 to 45 ka) led to the establishment of present-day non-African populations. Some paleoanthropologists have argued that fossil discoveries from Huanglong, Zhiren, Luna, and Fuyan caves in southern China indicate one or more prior dispersals, perhaps as early as ca. 120 ka. We investigated the age of the human remains from three of these localities and two additional early AMH sites (Yangjiapo and Sanyou caves, Hubei) by combining ancient DNA (aDNA) analysis with a multimethod geological dating strategy. Although U-Th dating of capping flowstones suggested they lie within the range ca. 168 to 70 ka, analyses of aDNA and direct AMS 14C dating on human teeth from Fuyan and Yangjiapo caves showed they derive from the Holocene. OSL dating of sediments and AMS 14C analysis of mammal teeth and charcoal also demonstrated major discrepancies from the flowstone ages; the difference between them being an order of magnitude or more at most of these localities. Our work highlights the surprisingly complex depositional history recorded at these subtropical caves which involved one or more episodes of erosion and redeposition or intrusion as recently as the late Holocene. In light of our findings, the first appearance datum for AMHs in southern China should probably lie within the timeframe set by molecular data of ca. 50 to 45 ka.

Immune Regulation of Seminal Plasma on the Endometrial Microenvironment: Physiological and Pathological Conditions.

Seminal plasma (SP) accounts for more than 90% of semen volume. It induces inflammation, regulates immune tolerance, and facilitates embryonic development and implantation in the female reproductive tract. In the physiological state, SP promotes endometrial decidualization and causes changes in immune cells such as macrophages, natural killer cells, regulatory T cells, and dendritic cells. This leads to the secretion of cytokines and chemokines and also results in the alteration of miRNA profiles and the expression of genes related to endometrial tolerance and angiogenesis. Together, these changes modulate the endometrial immune microenvironment and contribute to implantation and pregnancy. However, in pathological situations, abnormal alterations in SP due to advanced age or poor diet in men can interfere with a woman's immune adaptation to pregnancy, negatively affecting embryo implantation and even the health of the offspring. Uterine pathologies such as endometriosis and endometritis can cause the endometrium to respond negatively to SP, which can further contribute to pathological progress and interfere with conception. The research on the mechanism of SP in the endometrium is conducive to the development of new targets for intervention to improve reproductive outcomes and may also provide new ideas for semen-assisted treatment of clinical infertility.

Oral and gastric microbiome in relation to gastric intestinal metaplasia.

Evidence suggests that Helicobacter pylori plays a role in gastric cancer (GC) initiation. However, epidemiologic studies on the specific role of other bacteria in the development of GC are lacking. We conducted a case-control study of 89 cases with gastric intestinal metaplasia (IM) and 89 matched controls who underwent upper gastrointestinal endoscopy at three sites affiliated with NYU Langone Health. We performed shotgun metagenomic sequencing using oral wash samples from 89 case-control pairs and antral mucosal brushing samples from 55 case-control pairs. We examined the associations of relative abundances of bacterial taxa and functional pathways with IM using conditional logistic regression with and without elastic-net penalty. Compared with controls, oral species Peptostreptococcus stomatis, Johnsonella ignava, Neisseria elongata and Neisseria flavescens were enriched in cases (odds ratios [ORs] = 1.29-1.50, P = .004-.01) while Lactobacillus gasseri, Streptococcus mutans, S parasanguinis and S sanguinis were under-represented (ORs = 0.66-0.76, P = .006-.042) in cases. Species J ignava and Filifactor alocis in the gastric microbiota were enriched (ORs = 3.27 and 1.43, P = .005 and .035, respectively), while S mutans, S parasanguinis and S sanguinis were under-represented (ORs = 0.61-0.75, P = .024-.046), in cases compared with controls. The lipopolysaccharide and ubiquinol biosynthesis pathways were more abundant in IM, while the sugar degradation pathways were under-represented in IM. The findings suggest potential roles of certain oral and gastric microbiota, which are correlated with regulation of pathways associated with inflammation, in the development of gastric precancerous lesions.

Uniparental Genetic Analyses Reveal the Major Origin of Fujian Tanka from Ancient Indigenous Daic Populations.

The Fujian Tanka people are officially classified as a southern Han ethnic group, whereas they have customs similar to Daic and Austronesion people. Whether they originated in Han or Daic people, there is no consensus. Three hypotheses have been proposed to explain the origin of this group: (1) the Han Chinese origin, (2) the ancient Daic origin, (3) and the admixture between Daic and Han. This study addressed this issue by analyzing the paternal Y chromosome and maternal mtDNA variation of 62 Fujian Tanka and 25 neighboring Han in Fujian. The southern East Asian predominant haplogroups (e.g., Y-chromosome O1a1a-P203 and O1b1a1a-M95, and mtDNA F2a, M7c1, and F1a1) had relatively high frequencies in Tanka. The interpopulation comparison revealed that the Tanka have a closer affinity with Daic populations than with Han Chinese in paternal lineages but are closely clustered with southern Han populations such as Hakka and Chaoshanese in maternal lineages. Network and haplotype-sharing analyses also support the admixture hypothesis. The Fujian Tanka mainly originate from the ancient indigenous Daic people and have only limited gene flows from Han Chinese populations. Notably, the divergence time inferred by the Tanka-specific haplotypes indicates that the formation of Fujian Tanka was a least 1033.8-1050.6 years before present (the early Northern Song dynasty), indicating that they are an indigenous population, not late Daic migrants from southwestern China.

Molecular genealogy of Tusi Lu's family reveals their paternal relationship with Jochi, Genghis Khan's eldest son.

Genghis Khan's lineage has attracted both academic and general interest because of its mystery and large influence. However, the truth behind the mystery is complicated and continues to confound the scientific study. In this study, we surveyed the molecular genealogy of Northwestern China's Lu clan who claim to be the descendants of the sixth son of Genghis Khan, Toghan. We also investigated living members of the Huo and Tuo clans, who, according to oral tradition, were close male relatives of Lu clan. Using network analysis, we found that the Y-chromosomal haplotypes of Lu clan mainly belong to haplogroup C2b1a1b1-F1756, widely prevalent in Altaic-speaking populations, and are closely related to the Tore clan from Kazakhstan, who claim to be the descendants of the first son of Genghis Khan, Jochi. The most recent common ancestor of the special haplotype cluster that includes the Lu clan and Tore clan lived about 1000 years ago (YA), while the Huo and Tuo clans do not share any Y lineages with the Lu clan. In addition to the reported lineages, such as C3*-Star Cluster, R1b-M343, and Q, our results indicate that haplogroup C2b1a1b1-F1756 might be another candidate of the true Y lineage of Genghis Khan.

Helicobacter Pylori infection of the gallbladder and the risk of chronic cholecystitis and cholelithiasis: A systematic review and meta-analysis.

BACKGROUND: Helicobacter pylori is coexisted with various diseases, including chronic gastritis, ulcer, and gastric cancer. Besides, chronic cholecystitis and cholelithiasis are extremely widespread over the world, which are considered as high health-care cost burdens of digestive diseases. Epidemiologic evidence on Helicobacter pylori infection in gallbladder increasing the risk of biliary diseases has been contradictory. AIM: Conduct a meta-analysis of overall studies and investigate an association between Helicobacter pylori infection of the gallbladder with chronic cholecystitis/cholelithiasis. METHODS: We used PubMed, EMBASE, and Cochrane library databases to identify all published studies before August 2017. Pooled odds ratios (OR) and corresponding 95% confidence intervals (CIs) were obtained using the random effects model. Heterogeneity, sensitivity, and stratified analyses were also performed. RESULTS: Eighteen studies involving 1544 participants and 1061 biliary cases with chronic cholecystitis/cholelithiasis were included. Helicobacter pylori infection of the gallbladder was significantly associated with an increased risk of chronic cholecystitis and cholecystitis (OR = 3.022; 95% CI, 1.897-4.815; I2  = 20.1%). In addition, country-based subgroup analysis also showed a positive association between Helicobacter pylori positivity and chronic cholecystitis/cholelithiasis risk. The ORs (95% CIs) for Asian and non-Asian region studies were 3.75 (1.83-7.71) and 2.25 (1.29-3.89), respectively. CONCLUSION: This meta-analysis suggests that infection of the gallbladder with Helicobacter pylori is closely related to an increased risk of chronic cholecystitis and cholelithiasis.

AntCaller: an accurate variant caller incorporating ancient DNA damage.

Ancient DNA obtained from ancient samples, such as sediments, bones, and teeth, is an important genetic resource that can be used to reconstruct an evolutional history of humans, animals, and plants. The application of high-throughput sequencing enables the research of ancient DNA to be conducted in a whole genome scale. However, post-mortem DNA damage mainly caused by deamination of cytosine to uracil (or methylated cytosine to thymine) may confound the variant calling and downstream analysis. In this article, we develop a Python program to implement a new variant caller, "AntCaller", which extracts the information on nucleotide substitutions from sequencing data and calculates the probability of each genotype based on a Bayesian rule. Through both simulation studies and real data analyses, it was shown that our method reduced the false discovery rate caused by nucleotide misincorporations and outperformed two mainstream variant callers (i.e., GATK and SAMtools) in terms of calling accuracy. In a real application with serious DNA damage, AntCaller still outperformed GATK and SAMtools combined with quality score recalling.

Ginseng Polysaccharide Enhances the Humoral and Cellular Immune Responses to SARS-CoV-2 RBD Protein Subunit Vaccines.

The COVID-19 pandemic remarkably accelerated vaccine research progress. The role of adjuvants in enhancing vaccine immune intensity and influencing immune types has been considered. Ginseng polysaccharide (GPS) has been demonstrated to have strong immunoregulatory properties. It is important to explore the feasibility of adding GPS to vaccine adjuvant components to improve the immune response effect of RBD vaccines. Here, we prepared a SARS-CoV-2 RBD antigen using the Escherichia coli expression system and determined that subcutaneous administration of GPS at a dose of 40 mg/kg could effectively activate dendritic cells (DCs) and macrophages (MΦ) in mice. Compared with the RBD group, the RBD+GPS triggered stronger and persistent antibody responses. It is also notable that higher levels of RBD-specific IgG and IgA were distributed in the lungs of RBD+GPS-immunized BALB/c mice. In addition, the RBD+GPS also resulted in lower percentages of IFN-γ+ CD4+ T cells and higher percentages of IFN-γ+ CD8+ T cells and CD8+ Tcm cells. These results suggest that GPS could be a promising vaccine immuno-enhancer for SARS-CoV-2 RBD subunit vaccines to establish stronger systemic and pulmonary mucosal protective immunity.

Cuproptosis-related gene PDHX and heat stress-related HSPD1 as potential key drivers associated with cell stemness, aberrant metabolism and immunosuppression in esophageal carcinoma.

BACKGROUND: Heat stress is fundamental to esophageal carcinoma (ESCA) oncogenesis and progression. Heat stress damages epithelial structure, causing aberrant 'cell death-repair' patterns of esophagus cells and thereby driving tumor occurrence and progression. However, due to the distinctive functions and crosstalk of regulatory cell death (RCD) patterns, the specific cell deaths in ESCA malignancy are still unclear. METHODS: We analyzed the key regulatory cell death genes involved in heat stress and ESCA progression by using The Cancer Genome Atlas-ESCA database. The least absolute shrinkage and selection operator (LASSO) algorithm was used to filter the key genes. The one-class logistic regression (OCLR) and quanTIseq methods were used to evaluate the cell stemness and immune cell infiltration in ESCA samples. Cell counting kit-8 (CCK8) and wound healing assays were performed to assess the proliferation and migration of cells. RESULTS: We found that cuproptosis may be a potential risk factor of heat stress-related ESCA. Two interrelated genes, HSPD1 and PDHX, were associated with heat stress and cuproptosis and played a role in cell survival, proliferation, migration, metabolism and immunosuppression. CONCLUSIONS: We found that cuproptosis promoted ESCA related to heat stress, offering a new therapeutic opportunity to treat this malignant disorder.

Analysis of the Tomato mTERF Gene Family and Study of the Stress Resistance Function of SLmTERF-13.

Mitochondrial transcription termination factor (mTERF) is a DNA-binding protein that is encoded by nuclear genes, ultimately functions in mitochondria and can affect gene expression. By combining with mitochondrial nucleic acids, mTERF regulates the replication, transcription and translation of mitochondrial genes and plays an important role in the response of plants to abiotic stress. However, there are few studies on mTERF genes in tomato, which limits the in-depth study and utilization of mTERF family genes in tomato stress resistance regulation. In this study, a total of 28 mTERF gene family members were obtained through genome-wide mining and identification of the tomato mTERF gene family. Bioinformatics analysis showed that all members of the family contained environmental stress or hormone response elements. Gene expression pattern analysis showed that the selected genes had different responses to drought, high salt and low temperature stress. Most of the genes played key roles under drought and salt stress, and the response patterns were more similar. The VIGS method was used to silence the SLmTERF13 gene, which was significantly upregulated under drought and salt stress, and it was found that the resistance ability of silenced plants was decreased under both kinds of stress, indicating that the SLmTERF13 gene was involved in the regulation of the tomato abiotic stress response. These results provide important insights for further evolutionary studies and contribute to a better understanding of the role of the mTERF genes in tomato growth and development and abiotic stress response, which will ultimately play a role in future studies of tomato gene function.

Pharmacological antagonism of receptor for advanced glycation end products signaling promotes thermogenesis, healthful body mass and composition, and metabolism in mice.

OBJECTIVE: Optimal body mass and composition as well as metabolic fitness require tightly regulated and interconnected mechanisms across tissues. Disturbances in these regulatory networks tip the balance between metabolic health versus overweight and obesity and their complications. The authors previously demonstrated roles for the receptor for advanced glycation end products (RAGE) in obesity, as global- or adipocyte-specific deletion of Ager (the gene encoding RAGE) protected mice from high-fat diet-induced obesity and metabolic dysfunction. METHODS: To explore translational strategies evoked by these observations, a small molecule antagonist of RAGE signaling, RAGE229, was administered to lean mice and mice with obesity undergoing diet-induced weight loss. Body mass and composition and whole body and adipose tissue metabolism were examined. RESULTS: This study demonstrates that antagonism of RAGE signaling reduced body mass and adiposity and improved glucose, insulin, and lipid metabolism in lean male and female mice and in male mice with obesity undergoing weight loss. In adipose tissue and in human and mouse adipocytes, RAGE229 enhanced phosphorylation of protein kinase A substrates, which augmented lipolysis, mitochondrial function, and thermogenic programs. CONCLUSIONS: Pharmacological antagonism of RAGE signaling is a potent strategy to optimize healthful body mass and composition and metabolic fitness.

DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice.

Atherosclerosis evolves through dysregulated lipid metabolism interwoven with exaggerated inflammation. Previous work implicating the receptor for advanced glycation end products (RAGE) in atherosclerosis prompted us to explore if Diaphanous 1 (DIAPH1), which binds to the RAGE cytoplasmic domain and is important for RAGE signaling, contributes to these processes. We intercrossed atherosclerosis-prone Ldlr-/- mice with mice devoid of Diaph1 and fed them Western diet for 16 weeks. Compared to male Ldlr-/- mice, male Ldlr-/- Diaph1-/- mice displayed significantly less atherosclerosis, in parallel with lower plasma concentrations of cholesterol and triglycerides. Female Ldlr-/- Diaph1-/- mice displayed significantly less atherosclerosis compared to Ldlr-/- mice and demonstrated lower plasma concentrations of cholesterol, but not plasma triglycerides. Deletion of Diaph1 attenuated expression of genes regulating hepatic lipid metabolism, Acaca, Acacb, Gpat2, Lpin1, Lpin2 and Fasn, without effect on mRNA expression of upstream transcription factors Srebf1, Srebf2 or Mxlipl in male mice. We traced DIAPH1-dependent mechanisms to nuclear translocation of SREBP1 in a manner independent of carbohydrate- or insulin-regulated cues but, at least in part, through the actin cytoskeleton. This work unveils new regulators of atherosclerosis and lipid metabolism through DIAPH1.

DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.

Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.

[Analysis of swelling stress and signaling pathway of human lung cancer cells].

Objective To investigate whether swelling stress exists in lung cancer cells by comparing water content and nucleus size as well as mitogen activated protein kinase (MAPK) phosphorylation activation between lung cancer tissues and corresponding paracancerous tissues. Methods Differences in water content between fresh specimens of 10 human lung adenocarcinoma, 12 lung squamous cell carcinoma, and corresponding paracancerous normal lung tissues were examined through "dry and wet" mass comparison. The expressions and phosphorylation activation of mitogen activated protein kinases JNK, ERK1/2, and p38 in 30 lung adenocarcinoma samples, 32 lung squamous cell carcinoma samples, and alveolar epithelial cells and lung bronchial epithelial cells of 10 paracancerous normal tissues samples were detected with their phosphorylated and non-phosphorylated antibodies and by immunohistochemical staining. Nucleus size differences between cancer cells from lung adenocarcinoma and lung squamous cell carcinoma samples and corresponding paracancerous normal lung alveolar epithelial cells or bronchial epithelial cells were estimated by HE staining and analyzed with image analysis software. Results The average water content of lung squamous cell carcinoma and lung adenocarcinoma samples were significantly higher than that of their corresponding paracancerous normal tissues. Immunohistochemistry showed that p38 was highly expressed in all samples of lung adenocarcinoma, lung squamous cell carcinoma, and paracancerous tissues. ERK was weakly expressed in lung adenocarcinoma and squamous cell carcinoma samples, but highly expressed in paracancerous tissues. JNK was weakly expressed in lung adenocarcinoma and paracancerous tissues. JNK, p38 MAPK, and ERK1/2 were not activated through phosphorylation in alveolar or bronchial epithelial tissues. However, JNK, not p38 or ERK1/2, was phosphorylated in lung adenocarcinoma and lung squamous cell carcinoma tissues. The average nucleus size of lung cancer cells was significantly larger than those of their corresponding paracancerous normal lung epithelial cells. Conclusion There is swelling stress in lung cancer cells, and different types of human lung cancer cells have different swelling stress signaling pathways.

Microbial Risk Score for Capturing Microbial Characteristics, Integrating Multi-omics Data, and Predicting Disease Risk.

Background: With the rapid accumulation of microbiome-wide association studies, a great amount of microbiome data are available to study the microbiome's role in human disease and advance the microbiome's potential use for disease prediction. However, the unique features of microbiome data hinder its utility for disease prediction. Methods: Motivated from the polygenic risk score framework, we propose a microbial risk score (MRS) framework to aggregate the complicated microbial profile into a summarized risk score that can be used to measure and predict disease susceptibility. Specifically, the MRS algorithm involves two steps: 1) identifying a sub-community consisting of the signature microbial taxa associated with disease, and 2) integrating the identified microbial taxa into a continuous score. The first step is carried out using the existing sophisticated microbial association tests and pruning and thresholding method in the discovery samples. The second step constructs a community-based MRS by calculating alpha diversity on the identified sub-community in the validation samples. Moreover, we propose a multi-omics data integration method by jointly modeling the proposed MRS and other risk scores constructed from other omics data in disease prediction. Results: Through three comprehensive real data analyses using the NYU Langone Health COVID-19 cohort, the gut microbiome health index (GMHI) multi-study cohort, and a large type 1 diabetes cohort separately, we exhibit and evaluate the utility of the proposed MRS framework for disease prediction and multi-omics data integration. In addition, the disease-specific MRSs for colorectal adenoma, colorectal cancer, Crohn's disease, and rheumatoid arthritis based on the relative abundances of 5, 6, 12, and 6 microbial taxa respectively are created and validated using the GMHI multi-study cohort. Especially, Crohn's disease MRS achieves AUCs of 0.88 ([0.85-0.91]) and 0.86 ([0.78-0.95]) in the discovery and validation cohorts, respectively. Conclusions: The proposed MRS framework sheds light on the utility of the microbiome data for disease prediction and multi-omics integration, and provides great potential in understanding the microbiome's role in disease diagnosis and prognosis.

Microbial risk score for capturing microbial characteristics, integrating multi-omics data, and predicting disease risk.

BACKGROUND: With the rapid accumulation of microbiome-wide association studies, a great amount of microbiome data are available to study the microbiome's role in human disease and advance the microbiome's potential use for disease prediction. However, the unique features of microbiome data hinder its utility for disease prediction. METHODS: Motivated from the polygenic risk score framework, we propose a microbial risk score (MRS) framework to aggregate the complicated microbial profile into a summarized risk score that can be used to measure and predict disease susceptibility. Specifically, the MRS algorithm involves two steps: (1) identifying a sub-community consisting of the signature microbial taxa associated with disease and (2) integrating the identified microbial taxa into a continuous score. The first step is carried out using the existing sophisticated microbial association tests and pruning and thresholding method in the discovery samples. The second step constructs a community-based MRS by calculating alpha diversity on the identified sub-community in the validation samples. Moreover, we propose a multi-omics data integration method by jointly modeling the proposed MRS and other risk scores constructed from other omics data in disease prediction. RESULTS: Through three comprehensive real-data analyses using the NYU Langone Health COVID-19 cohort, the gut microbiome health index (GMHI) multi-study cohort, and a large type 1 diabetes cohort separately, we exhibit and evaluate the utility of the proposed MRS framework for disease prediction and multi-omics data integration. In addition, the disease-specific MRSs for colorectal adenoma, colorectal cancer, Crohn's disease, and rheumatoid arthritis based on the relative abundances of 5, 6, 12, and 6 microbial taxa, respectively, are created and validated using the GMHI multi-study cohort. Especially, Crohn's disease MRS achieves AUCs of 0.88 (0.85-0.91) and 0.86 (0.78-0.95) in the discovery and validation cohorts, respectively. CONCLUSIONS: The proposed MRS framework sheds light on the utility of the microbiome data for disease prediction and multi-omics integration and provides a great potential in understanding the microbiome's role in disease diagnosis and prognosis. Video Abstract.

Gut Microbiota and Subjective Memory Complaints in Older Women.

BACKGROUND: Epidemiological studies that investigate alterations in gut microbial composition associated with cognitive dysfunction are limited. OBJECTIVE: To examine the association between the gut microbiota and subjective memory complaints (SMCs), a self-reported, validated indicator of cognitive dysfunction. METHODS: In this cross-sectional study of 95 older women selected from the New York University Women's Health Study (NYUWHS), we characterized the gut microbial composition using 16S rRNA gene sequencing. We estimated odds ratio (OR) from beta regression which approximates the ratio of mean relative abundances of individual bacterial taxon from phylum to genus levels by binary (2+ versus < 2) and continuous SMCs. RESULTS: Women reporting 2 or more SMCs had higher relative abundances of genus Holdemania and family Desulfovibrionaceae compared with those reporting one or no complaint. Compared with women with < 2 SMCs, the relative abundances of Holdemania and family Desulfovibrionaceae were 2.09 times (OR: 2.09, 95% confidence interval [CI]: 1.38-3.17) and 2.10 times (OR: 2.10, 95% CI: 1.43-3.09) higher in women with 2+ SMCs, respectively (false discovery rate (FDR)-adjusted p = 0.038 and 0.010, respectively). A dose-response association was observed for genus Sutterella and family Desulfovibrionaceae. Every one-unit increase in SMCs was associated with 25% and 27% higher relative abundances of Sutterella (OR: 1.25; 95% CI: 1.11-1.40) and Desulfovibrionaceae (OR: 1.27; 95% CI: 1.13-1.42), respectively (FDR-adjusted p = 0.018 and 0.006, respectively). CONCLUSION: Our findings support an association between alterations in the gut bacterial composition and cognitive dysfunction.

Soluble Receptor for Advanced Glycation End Products (sRAGE) Isoforms Predict Changes in Resting Energy Expenditure in Adults with Obesity during Weight Loss.

Background: Accruing evidence indicates that accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) play a significant role in obesity and type 2 diabetes. The concentrations of circulating RAGE isoforms, such as soluble RAGE (sRAGE), cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE), collectively sRAGE isoforms, may be implicit in weight loss and energy compensation resulting from caloric restriction. Objectives: We aimed to evaluate whether baseline concentrations of sRAGE isoforms predicted changes (∆) in body composition [fat mass (FM), fat-free mass (FFM)], resting energy expenditure (REE), and adaptive thermogenesis (AT) during weight loss. Methods: Data were collected during a behavioral weight loss intervention in adults with obesity. At baseline and 3 mo, participants were assessed for body composition (bioelectrical impedance analysis) and REE (indirect calorimetry), and plasma was assayed for concentrations of sRAGE isoforms (sRAGE, esRAGE, cRAGE). AT was calculated using various mathematical models that included measured and predicted REE. A linear regression model that adjusted for age, sex, glycated hemoglobin (HbA1c), and randomization arm was used to test the associations between sRAGE isoforms and metabolic outcomes. Results: Participants (n = 41; 70% female; mean ± SD age: 57 ± 11 y; BMI: 38.7 ± 3.4 kg/m2) experienced modest and variable weight loss over 3 mo. Although baseline sRAGE isoforms did not predict changes in ∆FM or ∆FFM, all baseline sRAGE isoforms were positively associated with ∆REE at 3 mo. Baseline esRAGE was positively associated with AT in some, but not all, AT models. The association between sRAGE isoforms and energy expenditure was independent of HbA1c, suggesting that the relation was unrelated to glycemia. Conclusions: This study demonstrates a novel link between RAGE and energy expenditure in human participants undergoing weight loss.This trial was registered at clinicaltrials.gov as NCT03336411.