Functions of FACT in Breaking the Nucleosome and Maintaining Its Integrity at the Single-Nucleosome Level.

The human FACT (facilitates chromatin transcription) complex, composed of two subunits SPT16 (Suppressor of Ty 16) and SSRP1 (Structure-specific recognition protein-1), plays essential roles in nucleosome remodeling. However, the molecular mechanism of FACT reorganizing the nucleosome still remains elusive. In this study, we demonstrate that FACT displays dual functions in destabilizing the nucleosome and maintaining the original histones and nucleosome integrity at the single-nucleosome level. We found that the subunit SSRP1 is responsible for maintenance of nucleosome integrity by holding the H3/H4 tetramer on DNA and promoting the deposition of the H2A/H2B dimer onto the nucleosome. In contrast, the large subunit SPT16 destabilizes the nucleosome structure by displacing the H2A/H2B dimers. Our findings provide mechanistic insights by which the two subunits of FACT coordinate with each other to fulfill its functions and suggest that FACT may play essential roles in preserving the original histones with epigenetic identity during transcription or DNA replication.

A c-di-GMP binding effector controls cell size in a cyanobacterium.

Cyclic-di-GMP (c-di-GMP) is a ubiquitous bacterial signaling molecule. It is also a critical player in the regulation of cell size and cell behaviors such as cell aggregation and phototaxis in cyanobacteria, which constitute an important group of prokaryotes for their roles in the ecology and evolution of the Earth. However, c-di-GMP receptors have never been revealed in cyanobacteria. Here, we report the identification of a c-di-GMP receptor, CdgR, from the filamentous cyanobacterium Anabaena PCC 7120. Crystal structural analysis and genetic studies demonstrate that CdgR binds c-di-GMP at the dimer interface and this binding is required for the control of cell size in a c-di-GMP-dependent manner. Different functions of CdgR, in ligand binding and signal transmission, could be separated genetically, allowing us to dissect its molecular signaling functions. The presence of the apo-form of CdgR triggers cell size reduction, consistent with the similar effects observed with a decrease of c-di-GMP levels in cells. Furthermore, we found that CdgR exerts its function by interacting with a global transcription factor DevH, and this interaction was inhibited by c-di-GMP. The lethal effect triggered by conditional depletion of DevH or by the production of several point-mutant proteins of CdgR in cells indicates that this signaling pathway plays critical functions in Anabaena. Our studies revealed a mechanism of c-di-GMP signaling in the control of cell size, an important and complex trait for bacteria. CdgR is highly conserved in cyanobacteria, which will greatly expand our understanding of the roles of c-di-GMP signaling in these organisms.

Gut virome in inflammatory bowel disease and beyond.

OBJECTIVE: The gut virome is a dense community of viruses inhabiting the gastrointestinal tract and an integral part of the microbiota. The virome coexists with the other components of the microbiota and with the host in a dynamic equilibrium, serving as a key contributor to the maintenance of intestinal homeostasis and functions. However, this equilibrium can be interrupted in certain pathological states, including inflammatory bowel disease, causing dysbiosis that may participate in disease pathogenesis. Nevertheless, whether virome dysbiosis is a causal or bystander event requires further clarification. DESIGN: This review seeks to summarise the latest advancements in the study of the gut virome, highlighting its cross-talk with the mucosal microenvironment. It explores how cutting-edge technologies may build upon current knowledge to advance research in this field. An overview of virome transplantation in diseased gastrointestinal tracts is provided along with insights into the development of innovative virome-based therapeutics to improve clinical management. RESULTS: Gut virome dysbiosis, primarily driven by the expansion of Caudovirales, has been shown to impact intestinal immunity and barrier functions, influencing overall intestinal homeostasis. Although emerging innovative technologies still need further implementation, they display the unprecedented potential to better characterise virome composition and delineate its role in intestinal diseases. CONCLUSIONS: The field of gut virome is progressively expanding, thanks to the advancements of sequencing technologies and bioinformatic pipelines. These have contributed to a better understanding of how virome dysbiosis is linked to intestinal disease pathogenesis and how the modulation of virome composition may help the clinical intervention to ameliorate gut disease management.

Autophagy inhibition improves the targeted radionuclide therapy efficacy of 131I-FAP-2286 in pancreatic cancer xenografts.

PURPOSES: Radiotherapy can induce tumor cell autophagy, which might impair the antitumoral effect. This study aims to investigate the effect of autophagy inhibition on the targeted radionuclide therapy (TRT) efficacy of 131I-FAP-2286 in pancreatic cancer. METHODS: Human pancreatic cancer PANC-1 cells were exposed to 131I-FAP-2286 radiotherapy alone or with the autophagy inhibitor 3-MA. The autophagy level and proliferative activity of PANC-1 cells were analyzed. The pancreatic cancer xenograft-bearing nude mice were established by the co-injection of PANC-1 cells and pancreatic cancer-associated fibroblasts (CAFs), and then were randomly divided into four groups and treated with saline (control group), 3-MA, 131I-FAP-2286 and 131I-FAP-2286 + 3-MA, respectively. SPECT/CT imaging was performed to evaluate the bio-distribution of 131I-FAP-2286 in pancreatic cancer-bearing mice. The therapeutic effect of tumor was evaluated by 18F-FDG PET/CT imaging, tumor volume measurements, and the hematoxylin and eosin (H&E) staining, and immunohistochemical staining assay of tumor tissues. RESULTS: 131I-FAP-2286 inhibited proliferation and increased the autophagy level of PANC-1 cells in a dose-dependent manner. 3-MA promoted 131I-FAP-2286-induced apoptosis of PANC-1 cells via suppressing autophagy. SPECT/CT imaging of pancreatic cancer xenograft-bearing nude mice showed that 131I-FAP-2286 can target the tumor effectively. According to 18F-FDG PET/CT imaging, the tumor growth curves and immunohistochemical analysis, 131I-FAP-2286 TRT was capable of suppressing the growth of pancreatic tumor accompanying with autophagy induction, but the addition of 3-MA enabled 131I-FAP-2286 to achieve a better therapeutic effect along with the autophagy inhibition. In addition, 3-MA alone did not inhibit tumor growth. CONCLUSIONS: 131I-FAP-2286 exposure induces the protective autophagy of pancreatic cancer cells, and the application of autophagy inhibitor is capable of enhancing the TRT therapeutic effect.

FACT Remodels the Tetranucleosomal Unit of Chromatin Fibers for Gene Transcription.

In eukaryotes, the packaging of genomic DNA into chromatin plays a critical role in gene regulation. However, the dynamic organization of chromatin fibers and its regulatory mechanisms remain poorly understood. Using single-molecule force spectroscopy, we reveal that the tetranucleosomes-on-a-string appears as a stable secondary structure during hierarchical organization of chromatin fibers. The stability of the tetranucleosomal unit is attenuated by histone chaperone FACT (facilitates chromatin transcription) in vitro. Consistent with in vitro observations, our genome-wide analysis further shows that FACT facilitates gene transcription by destabilizing the tetranucleosomal unit of chromatin fibers in yeast. Additionally, we found that the linker histone H1 not only enhances the stability but also facilitates the folding and unfolding kinetics of the outer nucleosomal wrap. Our study demonstrates that the tetranucleosome is a regulatory structural unit of chromatin fibers beyond the nucleosome and provides crucial mechanistic insights into the structure and dynamics of chromatin fibers during gene transcription.

H2A mono-ubiquitination differentiates FACT's functions in nucleosome assembly and disassembly.

The histone chaperone FACT (FAcilitates Chromatin Transcription) plays an essential role in transcription and DNA replication by its dual functions on nucleosome assembly to maintain chromatin integrity and nucleosome disassembly to destabilize nucleosome and facilitate its accessibility simultaneously. Mono-ubiquitination at Lysine 119 of H2A (ubH2A) has been suggested to repress transcription by preventing the recruitment of FACT at early elongation process. However, up to date, how ubH2A directly affects FACT on nucleosome assembly and disassembly remains elusive. In this study, we demonstrated that the dual functions of FACT are differently regulated by ubH2A. The H2A ubiquitination does not affect FACT's chaperone function in nucleosome assembly and FACT can deposit ubH2A-H2B dimer on tetrasome to form intact nucleosome. However, ubH2A greatly restricts FACT binding on nucleosome and inhibits its activity of nucleosome disassembly. Interestingly, deubiquitination of ubH2A rescues the nucleosome disassembly function of FACT to activate gene transcription. Our findings provide mechanistic insights of how H2A ubiquitination affects FACT in breaking nucleosome and maintaining its integrity, which sheds light on the biological function of ubH2A and various FACT's activity under different chromatin states.

Return to flight duty (RTFD) after posterior lumbar spine surgery for symptomatic lumbar disc herniation (LDH) and lumbar isthmic spondylolisthesis (LIS) in Chinese military pilots.

BACKGROUND: Symptomatic lumbar disc herniation (LDH) and lumbar isthmic spondylolisthesis (LIS) present significant challenges for military pilots, which may result in grounding if not effectively managed. Surgical treatment for LDH and LIS may offer a pathway to return to flight duty (RTFD), but recent data on this crucial topic is lacking. This study seeks to address this gap by investigating the RTFD outcomes among Chinese military pilots who have undergone lumbar spine surgery for symptomatic LDH and LIS. METHODS: A retrospective review was conducted on active-duty military pilots who underwent isolated decompressive or fusion procedures at an authorized military medical center from March 1, 2007, to March 1, 2023. The analysis utilized descriptive statistics to examine demographic, occupational, surgical, and outcome data, with a particular focus on preoperative flight status, recommended clearance by spine surgeons, and actual RTFD outcomes and time. RESULTS: Among the identified cases of active-duty military pilots with LDH or LIS treated by lumbar surgery (n = 24), 70.8% (17 of 24) consistently maintained RTFD status without encountering surgical complications or medical issues during the follow-up period. Of the seven pilots who did not RTFD, one retired within a year of surgery, two had anterior cruciate ligament injuries, three had residual radicular symptoms, and one had chronic low back pain. Excluding pilots who retired and did not RTFD for reasons unrelated to their lumbar conditions, the RTFD rate stood at 81.0% (17 of 21). The median time for recommended clearance by spine surgeons was 143.0 days (inter-quartile range, 116.5-196.0), while the median duration for actual RTFD attainment was 221.0 days (inter-quartile range, 182.0-300.0). The median follow-up post-lumbar surgery was 1.7 years (inter-quartile range, 0.4-2.9). CONCLUSION: Most military pilots diagnosed with symptomatic LDH and LIS can continue their careers and regain active-duty flight status following lumbar spine surgery, as reflected by the high RTFD rate. Lumbar spine surgery can successfully alleviate the physical constraints associated with spinal conditions, facilitating the return of military pilots to their demanding profession.

Chicoric Acid Effectively Mitigated Dextran Sulfate Sodium (DSS)-Induced Colitis in BALB/c Mice by Modulating the Gut Microbiota and Fecal Metabolites.

Chicoric acid (CA) has been reported to exhibit biological activities; it remains unclear, however, whether CA could regulate colitis via modulation of the gut microbiota and metabolites. This study aimed to assess CA's impact on dextran sulfate sodium (DSS)-induced colitis, the gut microbiota, and metabolites. Mice were induced with 2.5% DSS to develop colitis over a 7-day period. CA was administered intragastrically one week prior to DSS treatment and continued for 14 days. The microbial composition in the stool was determined using 16S rRNA sequencing, while non-targeted metabolomics was employed to analyze the metabolic profiles of each mouse group. The results show that CA effectively alleviated colitis, as evidenced by an increased colon length, lowered disease activity index (DAI) and histological scores, and decreased tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) expression levels. CA intervention restored the structure of gut microbiota. Specifically, it decreased the abundance of Bacteroidetes and Cyanobacteria at the phylum level and Bacteroides, Rosiarcus, and unclassified Xanthobacteraceae at the genus level, and increased the abundance of unclassified Lachnospiraceae at the genus level. Metabolomic analysis revealed that CA supplementation reversed the up-regulation of asymmetric dimethylarginine, N-glycolylneuraminic acid, and N-acetylneuraminic acid, as well as the down-regulation of phloroglucinol, thiamine, 4-methyl-5-thiazoleethanol, lithocholic acid, and oxymatrine induced by DSS. Our current research provides scientific evidence for developing CA into an anti-colitis functional food ingredient. Further clinical trials are warranted to elucidate the efficacy and mechanism of CA in treating human inflammatory bowel disease (IBD).

Multicolor Adjustable B-N Molecular Switches: Simple, Efficient, Portable, and Visual Identification of Butanol Isomers.

As intelligent probes, dynamic and controllable molecular switches are useful tools for probing and intervening in life processes. However, the types and properties of molecular switches are still relatively single and often can only make two actions: "off" and "on". Therefore, the development of novel molecular switches with multiple colors and multiple instructions is very challenging. Herein, we propose a novel strategy based on the instability of the Lewis acid-base pair (boron (B) and nitrogen (N)), such as introducing the Schiff base (C═N) group into the aminoborane skeleton and preparing the novel molecular switches BN-HDZ and BN-HDZ-N. These two molecules were found to have good multicolor fluorescence switching capability for methanol. Surprisingly, the compound BN-HDZ-N shows unprecedented visual identification for the butanol isomers and could be made into a portable strip for simple and rapid visual identification of the four isomers of butanol, promising an alternative to conventional Lucas reagents. This provides a novel strategy for the design and fabrication of novel multicolor-tunable molecular switches with visual identification of isomers.

The role of cyanoalanine synthase and alternative oxidase in promoting salt stress tolerance in Arabidopsis thaliana.

BACKGROUND: Cyanide is a toxic chemical that inhibits cellular respiration. In plants, cyanide can be produced by themselves, especially under stressful conditions. Cyanoalanine synthase (CAS) is a key enzyme involved in plant cyanide detoxification. There are three genes encoding CAS in Arabidopsis thaliana, but the roles of these genes in the plant's response to stress are less studied. In addition, it is known that alternative oxidase (AOX) mediates cyanide-resistant respiration, but the relationship between CAS and AOX in regulating the plant stress response remains largely unknown. RESULTS: Here, the effects of the overexpression or mutation of these three CAS genes on salt stress tolerance were investigated. The results showed that under normal conditions, the overexpression or mutation of the CAS genes had no significant effect on the seed germination and growth of Arabidopsis thaliana compared with wild type (WT). However, under 50, 100, and 200 mM NaCl conditions, the seeds overexpressing CAS genes showed stronger salt stress resistance, i.e., higher germination speed than WT seeds, especially those that overexpressed the CYS-C1 and CYS-D1 genes. In contrast, the seeds with CAS gene mutations exhibited salt sensitivity, and their germination ability and growth were significantly damaged by 100 and 200 mM NaCl. Importantly, this difference in salt stress resistance became more pronounced in CAS-OE, WT, and mutant seeds with increasing salt concentration. The CAS-OE seeds maintained higher respiration rates than the WT and CAS mutant seeds under salt stress conditions. The cyanide contents in CAS mutant seeds were approximately 3 times higher than those in WT seeds and more than 5 times higher than those in CAS-OE seeds. In comparison, plants overexpressing CYS-C1 had the fastest detoxification of cyanide and the best salt tolerance, followed by those overexpressing CYS-D1 and CYS-D2. Furthermore, less hydrogen sulfide (H2S) was observed in CAS-OE seedlings than in WT seedlings under long-term salt stress conditions. Nonetheless, the lack of AOX impaired CAS-OE-mediated plant salt stress resistance, suggesting that CAS and AOX interact to improve salt tolerance is essential. The results also showed that CAS and AOX contributed to the reduction in oxidative damage by helping maintain relatively high levels of antioxidant enzyme activity. CONCLUSION: In summary, the findings of the present study suggest that overexpression of Arabidopsis CAS family genes plays a positive role in salt stress tolerance and highlights the contribution of AOX to CAS-mediated plant salt resistance, mainly by reducing cyanide and H2S toxicity.

Recent advances in pulse protein conjugation and complexation with polyphenols: an emerging approach to improve protein functionality and health benefits.

Pulses have attracted much attention in the food industry due to their low cost, high yield, and high protein content, which promises to be excellent alternative protein sources. Recently, techniques for covalent and noncovalent binding of pulse proteins to polyphenols are expected to solve the problem of their poor protein functional properties. Additionally, these conjugates and complexes also show several health benefits. This review summarizes the formation of conjugates and complexes between pulse proteins and polyphenols through covalent and noncovalent binding and the impact of this structural change on protein functionalities and potential health benefits. Recent studies show that pulse protein functionalities can be influenced by polyphenol dose. This is mainly the case for adverse effects on solubility and enhancement in emulsifying capacity. Also, the conjugates/complexes exhibit antioxidant activity and can alter protein digestibility. The antioxidant activity of polyphenols could be retained after binding to proteins, while the effect on digestibility depends on the type or dosage of polyphenols. Considering the link between polyphenols and their potential health benefits, pulse polyphenols would be a good choice for producing the conjugates/complexes due to their low cost and proven potential benefits. Further studies on the structure-function-health benefits relationship of pulse protein-polyphenol conjugates and complexes are still required, as well as the validation of their application as functional foods in the food industry.

Underlying mechanisms and molecular targets of genistein in the management of type 2 diabetes mellitus and related complications.

Diabetes mellitus (DM) is a chronic metabolic disease caused by a complex interaction of genetic and environmental factors and is characterized by persistent hyperglycemia. Long-term hyperglycemia can cause macrovascular and microvascular damage, and compromise the heart, brain, kidney, peripheral nerves, eyes and other organs, leading to serious complications. Genistein, a phytoestrogen derived from soybean, is known for its various biological activities and therapeutic properties. Recent studies found that genistein not only has hypoglycemic activity but can also decrease insulin resistance. In addition, genistein has particular activity in the prevention and treatment of diabetic complications, such as nephropathy, cardiovascular disease, osteoarthrosis, encephalopathy and retinopathy. Therefore, the purpose of this review is to summarize the latest medical research and progress of genistein in DM and related complications and highlights its potential molecular mechanisms and therapeutic targets. Meanwhile, evidence is provided for the development and application of genistein as a potential drug or functional food in the prevention and treatment of diabetes and its related complications.

Edible Osmanthus fragrans flowers: aroma and functional components, beneficial functions, and applications.

Osmanthus fragrans (O. fragrans) has been cultivated in China for over 2,500 years as a traditional fragrant plant. Recently, O. fragrans has drawn increasing attention due to its unique aroma and potential health benefits. In this review, the aroma and functional components of O. fragrans are summarized, and their biosynthetic mechanism is discussed. The beneficial functions and related molecular mechanism of O. fragrans extract are then highlighted. Finally, potential applications of O. fragrans are summarized, and future perspectives are proposed and discussed. According to the current research, O. fragrans extracts and components have great potential to be developed into value-added functional ingredients with preventive effects on certain chronic diseases. However, it is crucial to develop efficient, large-scale, and commercially viable extraction methods to obtain the bioactive components from O. fragrans. Furthermore, more clinical studies are highly needed to explore the beneficial functions of O. fragrans and guide its development into functional food products.

The prognostic, immunological and single-cell features of m6A molecules in cervical cancer.

Cervical cancer (CC) is a growing health concern, emphasizing the need for reliable biomarkers in treatment selection and prognosis assessment. We analyzed gene expression profiles and clinicopathological data from The Cancer Genome Atlas (TCGA) for CC. Using Consensus Cluster Plus, we applied machine learning to cluster the CC cohort. Differential analysis was performed using the edge R package, while weighted correlation network analysis (WGCNA) was conducted using the WGCNA package. Single-sample gene set enrichment analysis (ssGSEA) evaluated immune cell abundance and computed the m6Ascore. Western blot and Q-PCR validated the m6A score in CC. Common copy number variation alterations were observed in the 23 m6A-related genes in CC, and their mutation frequency was summarized in a waterfall chart. Patients were grouped into two clusters, m6AclusterA and m6AclusterB. Improved clinical outcomes were observed in m6AclusterA, while m6AclusterB exhibited higher infiltration of 14 immune cell types. WGCNA analysis generated seven integrated modules, enriched in several biological processes. Prognostic differential genes were used to generate two gene clusters (gene Cluster I and gene Cluster II). Using ssGSEA, the m6Ascore was calculated for each patient. Lower m6Ascore correlated with better clinical outcomes, lower gene mutation frequency, and wild-type status. We investigated the sensitivity of high and low m6Ascore to immunotherapy, visualized through violin and UMAP diagrams showcasing crosstalk among single-cell clusters. The key gene PFKFB4 showed higher expression in CC cell lines and tumor tissues compared to normal cells and tissue. Our study elucidates the role of m6A molecules in predicting prognosis, biological features, and appropriate treatment for CC patients.

Identification of key biomarkers related to epithelial-mesenchymal transition and immune infiltration in ameloblastoma using integrated bioinformatics analysis.

OBJECTIVE: This study aimed to elucidate the underlying mechanisms of ameloblastoma (AM) through integrated bioinformatics analysis. METHODS: We downloaded two microarrays of AMs from the GEO database and identified differentially expressed genes (DEGs) by integrated bioinformatics analysis. The enrichment analysis of DEGs was conducted to characterize GO and KEGG pathways. Protein-protein interaction (PPI) network and hub genes were screened via STRING and Cytoscape. CIBERSORT algorithm was utilized to analyze immune infiltration in AMs. We also verified the diagnostic and therapeutic value of hub genes. RESULTS: Overall, 776 DEGs were identified in AMs through bioinformatics analysis. The function enrichment analysis shed light on pathways involved in AMs. Subsequently, we screened six hub genes via PPI network. Furthermore, we evaluated immune infiltration in AMs and found that macrophages may be participating in the progression of AMs. The upregulated expression of FN1 was related to the macrophages M2 polarization. Finally, ROC analysis indicated that six hub genes had high diagnostic value for AMs and 11 drugs interacted with upregulated hub genes were identified by screening the DGIdb database. CONCLUSION: This study revealed the underlying mechanisms of pathogenesis and biological behavior of AMs and provided candidate targets for the diagnosis and treatment of AMs.

Understanding Psychosocial Determinants of PrEP Uptake Among Cisgender Women Experiencing Heightened HIV Risk: Implications for Multi-Level Communication Intervention.

Pre-exposure prophylaxis (PrEP) is a highly effective daily pill that decreases the likelihood of HIV acquisition by up to 92% among individuals at risk for HIV. PrEP can be discretely used, autonomously controlled, and in place at the time of risk exposure, making it an especially promising method for HIV prevention for cisgender women (CGW). But, PrEP is underutilized by CGW relative to the demonstrable need. We apply the Integrative Model of Behavioral Prediction to identify the critical psychosocial factors that shape CGW's intentions to use PrEP and their relevant underlying beliefs. We surveyed (N = 294) community- and clinic-recruited PrEP eligible CGW to understand the relative importance of attitudes, norms, and efficacy in shaping PrEP intentions. We utilized structural equation modeling to identify the relevant paths. We inspected the summary statistics in relation to three message three selection criteria. We identified beliefs that demonstrated (1) an association with intention, (2) substantial room to move the population, (3) practicality as a target for change through communication intervention. Results show that PrEP awareness was low. When women learned about PrEP, they voiced positive intentions to use it. There were significant and positive direct effects of SE (0.316***), attitudes (0.201**), and subjective norms (0.249***) on intention to initiate PrEP. We illustrate the strategic identification of beliefs within the relevant paths using the 3 belief selection criteria. We also discuss implications for social and structural communication interventions to support women's HIV prevention.

Biosynthesis and the Transcriptional Regulation of Terpenoids in Tea Plants (Camellia sinensis).

Terpenes, especially volatile terpenes, are important components of tea aroma due to their unique scents. They are also widely used in the cosmetic and medical industries. In addition, terpene emission can be induced by herbivory, wounding, light, low temperature, and other stress conditions, leading to plant defense responses and plant-plant interactions. The transcriptional levels of important core genes (including HMGR, DXS, and TPS) involved in terpenoid biosynthesis are up- or downregulated by the MYB, MYC, NAC, ERF, WRKY, and bHLH transcription factors. These regulators can bind to corresponding cis-elements in the promoter regions of the corresponding genes, and some of them interact with other transcription factors to form a complex. Recently, several key terpene synthesis genes and important transcription factors involved in terpene biosynthesis have been isolated and functionally identified from tea plants. In this work, we focus on the research progress on the transcriptional regulation of terpenes in tea plants (Camellia sinensis) and thoroughly detail the biosynthesis of terpene compounds, the terpene biosynthesis-related genes, the transcription factors involved in terpene biosynthesis, and their importance. Furthermore, we review the potential strategies used in studying the specific transcriptional regulation functions of candidate transcription factors that have been discriminated to date.

Evaluation of Autonomic Nervous System Dysfunction in Childhood Obesity and Prader-Willi Syndrome.

The autonomic nervous system (ANS) may play a role in the distribution of body fat and the development of obesity and its complications. Features of individuals with Prader-Willi syndrome (PWS) impacted by PWS molecular genetic classes suggest alterations in ANS function; however, these have been rarely studied and presented with conflicting results. The aim of this study was to investigate if the ANS function is altered in PWS. In this case-control study, we assessed ANS function in 20 subjects with PWS (6 males/14 females; median age 10.5 years) and 27 body mass index (BMI) z-score-matched controls (19 males/8 females; median age 12.8 years). Standardized non-invasive measures of cardiac baroreflex function, heart rate, blood pressure, heart rate variability, quantitative sudomotor axon reflex tests, and a symptom questionnaire were completed. The increase in heart rate in response to head-up tilt testing was blunted (p < 0.01) in PWS compared to controls. Besides a lower heart rate ratio with Valsalva in PWS (p < 0.01), no significant differences were observed in other measures of cardiac function or sweat production. Findings suggest possible altered sympathetic function in PWS.

Gut microbiota composition is associated with SARS-CoV-2 vaccine immunogenicity and adverse events.

OBJECTIVE: The gut microbiota plays a key role in modulating host immune response. We conducted a prospective, observational study to examine gut microbiota composition in association with immune responses and adverse events in adults who have received the inactivated vaccine (CoronaVac; Sinovac) or the mRNA vaccine (BNT162b2; BioNTech; Comirnaty). DESIGN: We performed shotgun metagenomic sequencing in stool samples of 138 COVID-19 vaccinees (37 CoronaVac and 101 BNT162b2 vaccinees) collected at baseline and 1 month after second dose of vaccination. Immune markers were measured by SARS-CoV-2 surrogate virus neutralisation test and spike receptor-binding domain IgG ELISA. RESULTS: We found a significantly lower immune response in recipients of CoronaVac than BNT162b2 vaccines (p<0.05). Bifidobacterium adolescentis was persistently higher in subjects with high neutralising antibodies to CoronaVac vaccine (p=0.023) and their baseline gut microbiome was enriched in pathways related to carbohydrate metabolism (linear discriminant analysis (LDA) scores >2 and p<0.05). Neutralising antibodies in BNT162b2 vaccinees showed a positive correlation with the total abundance of bacteria with flagella and fimbriae including Roseburia faecis (p=0.028). The abundance of Prevotella copri and two Megamonas species were enriched in individuals with fewer adverse events following either of the vaccines indicating that these bacteria may play an anti-inflammatory role in host immune response (LDA scores>3 and p<0.05). CONCLUSION: Our study has identified specific gut microbiota markers in association with improved immune response and reduced adverse events following COVID-19 vaccines. Microbiota-targeted interventions have the potential to complement effectiveness of COVID-19 vaccines.

Ethnicity Associations With Food Sensitization Are Mediated by Gut Microbiota Development in the First Year of Life.

BACKGROUND AND AIMS: Increasing evidence supports the role of early-life gut microbiota in developing atopic diseases, but ecological changes to gut microbiota during infancy in relation to food sensitization remain unclear. We aimed to characterize and associate these changes with the development of food sensitization in children. METHODS: In this observational study, using 16S rRNA amplicon sequencing, we characterized the composition of 2844 fecal microbiota in 1422 Canadian full-term infants. Atopic sensitization outcomes were measured by skin prick tests at age 1 year and 3 years. The association between gut microbiota trajectories, based on longitudinal shifts in community clusters, and atopic sensitization outcomes at age 1 and 3 years were determined. Ethnicity and early-life exposures influencing microbiota trajectories were initially examined, and post-hoc analyses were conducted. RESULTS: Four identified developmental trajectories of gut microbiota were shaped by birth mode and varied by ethnicity. The trajectory with persistently low Bacteroides abundance and high Enterobacteriaceae/Bacteroidaceae ratio throughout infancy increased the risk of sensitization to food allergens, particularly to peanuts at age 3 years by 3-fold (adjusted odds ratio [OR] 2.82, 95% confidence interval [CI] 1.13-7.01). A much higher likelihood for peanut sensitization was found if infants with this trajectory were born to Asian mothers (adjusted OR 7.87, 95% CI 2.75-22.55). It was characterized by a deficiency in sphingolipid metabolism and persistent Clostridioides difficile colonization. Importantly, this trajectory of depleted Bacteroides abundance mediated the association between Asian ethnicity and food sensitization. CONCLUSIONS: This study documented an association between persistently low gut Bacteroides abundance throughout infancy and sensitization to peanuts in childhood. It is the first to show a mediation role for infant gut microbiota in ethnicity-associated development of food sensitization.