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Intestinal farnesoid X receptor (FXR) signaling is involved in the development of obesity, fatty liver disease, and type 2 diabetes. However, the role of intestinal FXR in atherosclerosis and its potential as a target for clinical treatment have not been explored. The serum levels of fibroblast growth factor 19 (FGF19), which is encoded by an FXR target gene, were much higher in patients with hypercholesterolemia than in control subjects and were positively related to circulating ceramide levels, indicating a link between intestinal FXR, ceramide metabolism, and atherosclerosis. Among ApoE-/- mice fed a high-cholesterol diet (HCD), intestinal FXR deficiency (in FxrΔIE ApoE-/- mice) or direct FXR inhibition (via treatment with the FXR antagonist glycoursodeoxycholic acid [GUDCA]) decreased atherosclerosis and reduced the levels of circulating ceramides and cholesterol. Sphingomyelin phosphodiesterase 3 (SMPD3), which is involved in ceramide synthesis in the intestine, was identified as an FXR target gene. SMPD3 overexpression or C16:0 ceramide supplementation eliminated the improvements in atherosclerosis in FxrΔIE ApoE-/- mice. Administration of GUDCA or GW4869, an SMPD3 inhibitor, elicited therapeutic effects on established atherosclerosis in ApoE-/- mice by decreasing circulating ceramide levels. This study identified an intestinal FXR/SMPD3 axis that is a potential target for atherosclerosis therapy.

Archaea are an important component of the gut microbiomes of animals and play a key role in animal health. However, they have been neglected in previous microbial studies, particularly those involving migratory waterbirds. Here, we investigated the gut archaeal communities of Anser erythropus wintering at Shengjin and Caizi Lakes in China using metagenomic analysis of 20 fecal samples (ten samples per lake). The operational taxonomic units (OTUs) in the gut archaea of geese wintering in the two lakes represented 16 phyla, 16 classes, 24 orders, 27 families, and 45 genera, with Euryarchaeota, Thaumarchaeota, and Bathyarchaeota being the dominant gut archaeal phyla. The results of alpha diversity analysis showed a significant difference in composition between the Shengjin and Caizi Lake samples, and orthogonal partial least squares-discriminant analysis (OPLS-DA) analysis indicated that geese were well-matched with their lakes of origin. Stamp analysis revealed a difference of 27 gut archaeal species between A. erythropus wintering at Shengjin Lake and those at Caizi Lake. Archaeal network analysis results fell into four major modules, with Methanolobus psychrotolerans and Thaumarchaeota archaeon as the hub modules. The abundances of several bacterial and fungal genera were significantly correlated with abundances of archaeal genera in pairwise populations, and a positive correlation was observed between archaeal, bacterial, and fungal diversities in the guts of A. erythropus wintering at both Shengjin and Caizi Lakes (R=0.4, p=2.2×10-16; R=0.86, p=2.2×10-16, respectively). This suggests that fecal bacteria and fungi may cooperate with archaea to perform crucial roles in the gut. However, because of the small sample size in this study, further studies are needed to fully investigate the altered archaea in the guts of these geese.

Error-corrected next-generation sequencing (ecNGS) is an emerging technology with the potential to revolutionize the field of genetic toxicology. Here, we present recommendations from an expert working group convened to discuss potential applications, advantages and challenges associated with implementing ecNGS in nonclinical safety studies.Error-corrected next-generation sequencing (ecNGS) is an emerging technology with the potential to revolutionize the field of genetic toxicology. Here, we present recommendations from an expert working group convened to discuss potential applications, advantages and challenges associated with implementing ecNGS in nonclinical safety studies.

Background Heart failure is a common complication of sepsis with a high mortality rate. It has been reported that melatonin can attenuate septic injury due to various properties. On the basis of previous reports, this study will further explore the effects and mechanisms of melatonin pretreatment, posttreatment, and combination with antibiotics in the treatment of sepsis and septic myocardial injury. Methods and results Our results showed that melatonin pretreatment showed an obvious protective effect on sepsis and septic myocardial injury, which was related to the attenuation of inflammation and oxidative stress, the improvement of mitochondrial function, the regulation of endoplasmic reticulum stress (ERS), and the activation of the AMPK signaling pathway. In particular, AMPK serves as a key effector for melatonin-initiated myocardial benefits. In addition, melatonin posttreatment also had a certain degree of protection, while its effect was not as remarkable as that of pretreatment. The combination of melatonin and classical antibiotics had a slight but limited effect. RNA-seq detection clarified the cardioprotective mechanism of melatonin. Conclusion Altogether, this study provides a theoretical basis for the application strategy and combination of melatonin in septic myocardial injury.

Metabolic reprogramming in breast tumors is linked to increases in putative oncogenic metabolites that may contribute to malignant transformation. We previously showed that accumulation of the oncometabolite, 2-hydroxyglutarate (2HG), in breast tumors was associated with MYC signaling, but not with isocitrate dehydrogenase (IDH) mutations, suggesting a distinct mechanism for increased 2HG in breast cancer. Here, we determined that D-2HG is the predominant enantiomer in human breast tumors and show that the D-2HG-producing mitochondrial enzyme, alcohol dehydrogenase, iron-containing protein 1 (ADHFE1), is a breast cancer oncogene that decreases patient survival. We found that MYC upregulates ADHFE1 through changes in iron metabolism while coexpression of both ADHFE1 and MYC strongly enhanced orthotopic tumor growth in MCF7 cells. Moreover, ADHFE1 promoted metabolic reprogramming with increased formation of D-2HG and reactive oxygen, a reductive glutamine metabolism, and modifications of the epigenetic landscape, leading to cellular dedifferentiation, enhanced mesenchymal transition, and phenocopying alterations that occur with high D-2HG levels in cancer cells with IDH mutations. Together, our data support the hypothesis that ADHFE1 and MYC signaling contribute to D-2HG accumulation in breast tumors and show that D-2HG is an oncogenic metabolite and potential driver of disease progression.

Background Depressive symptoms associated with schizophrenia are closely related to stigma and quality of life(QOL). There is, however, no thorough research on the connection between the three. This study sought to investigate the possible factors influencing depressive symptoms in people with schizophrenia (PWS) in rural Chaohu, China, and to further explore the role of depression severity in stigma and lifestyle quality. Methods Eight hundred twenty-one schizophrenia patients accomplished the entire scale, including the 9-item Patient Health Questionnaire (PHQ-9), the Social Impact Scale (SIS), and the World Health Organization on Quality of Life Brief Scale(WHOQOL—BREF). A straightforward mediation model was employed to determine if the intensity of the depression could act as a mediator between stigma and QOL. Results Two hundred seventy-nine schizophrenia patients (34%) had depressive symptoms (PHQ ≥ 10), and 542 patients (66%) did not (PHQ < 10). Logistic regression showed that marital status, job status, physical exercise, standard of living, and stigma contributed to the depressed symptoms of schizophrenia. Depression severity partially mediated the effect between stigma and QOL, with a mediating effect of 48.3%. Conclusions This study discovered a significant incidence of depressed symptoms associated with schizophrenia, with depression severity serving as a mediator variable connecting stigma and QOL and partially moderating the association.

Introduction Helicobacter pylori is a type of Gram-negative microaerobic bacteria that inhabits the gastric mucosal epithelium. It can cause various gastrointestinal diseases including gastritis, peptic ulcer and gastric cancer. White blood cells (WBC) are common immune cells, the increase in whose countoften indicates the presence of an infection. Currently, the relationship between H. pylori and WBC count remains full of controversy. This study aims to further elucidate the effects of H. pylori on WBC count in a population undergoing physical examination.Methods and analysisA total of 864 participants who underwent physical examination and 14C urea breath test (UBT) were retrospectively enrolled in this study from January to June 2021. The overall population was divided into H. pylori-negative (Hp−) and H. pylori-positive (Hp+) groups based on the disintegration per minute (DPM) value detected by UBT. Spearman’s correlation analysis was used to assess the correlation between DPM and WBC count. General linear regression models were applied to assess the potential factors contributing to the increase in WBC count. Generalised additive model (GAM) was performed to identify the non-linear relationship between DPM and WBC count. Additionally, a piecewise linear regression was used to examine the threshold effect of the DPM on WBC count.Results403 subjects were diagnosed with H. pylori infection. The WBC and platelet (PLT) counts in the Hp+ group were significantly higher than those in the Hp− group. Additionally, the prevalence of H. pylori infection gradually increased with the WBC count quartiles (38.89% and 54.67% in quartile 1 and quartile 4, respectively). Spearman’s correlation analysis showed that the DPM value significantly correlated with WBC count (r=0.089, p=0.009) and PLT count (r=0.082, p=0.017). The linear model revealed a positive independent association of H. pylori infection and DPM with WBC count (βHp+=0.398 (95% CI 0.170, 0.625), p<0.001; βDPM=0.002 (95% CI 0.000, 0.0030), p=0.018). The results of the GAM and the piecewise linear regression suggested that the cut-off points of the association between DPM and WBC count were 40 and 155 of DPM, that is, the effect of DPM on WBC count varied with the difference of DPM <40, 40–155, and >155 (βDPM=−0.005 (95% CI −0.017, 0.007), p=0.423; βDPM=0.006 (95% CI 0.002, 0.013), p=0.047; and βDPM=−0.007 (95% CI −0.012, –0.002), p=0.004, respectively).Conclusions H. pylori infection was independently and positively correlated with WBC count; however, the effect of DPM on WBC count varied across different WBC count intervals, suggesting distinct immunological responses at different stages of infection.

A new approach to evolve novel aminoacyl-tRNA synthetase–tRNA pairs with orthogonal substrate specificity is applied to generate a system to site-specifically incorporate phosphothreonine into proteins, enabling functional studies of this post-translational modification. The phosphorylation of threonine residues in proteins regulates diverse processes in eukaryotic cells, and thousands of threonine phosphorylations have been identified. An understanding of how threonine phosphorylation regulates biological function will be accelerated by general methods to biosynthesize defined phosphoproteins. Here we describe a rapid approach for directly discovering aminoacyl-tRNA synthetase–tRNA pairs that selectively incorporate non-natural amino acids into proteins; our method uses parallel positive selections combined with deep sequencing and statistical analysis and enables the direct, scalable discovery of aminoacyl-tRNA synthetase–tRNA pairs with mutually orthogonal substrate specificity. By combining a method to biosynthesize phosphothreonine in cells with this selection approach, we discover a phosphothreonyl-tRNA synthetase–tRNA CUA pair and create an entirely biosynthetic route to incorporating phosphothreonine in proteins. We biosynthesize several phosphoproteins and demonstrate phosphoprotein structure determination and synthetic protein kinase activation.

The dynamic nature of the chromatin epigenetic landscape plays a key role in the establishment and maintenance of cell identity, yet the factors that affect the dynamics of the epigenome are not fully known. Here we find that the ubiquitous nucleosome binding proteins HMGN1 and HMGN2 preferentially colocalize with epigenetic marks of active chromatin, and with cell-type specific enhancers. Loss of HMGNs enhances the rate of OSKM induced reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs), and the ASCL1 induced conversion of fibroblast into neurons. During transcription factor induced reprogramming to pluripotency, loss of HMGNs accelerates the erasure of the MEF-specific epigenetic landscape and the establishment of an iPSCs-specific chromatin landscape, without affecting the pluripotency potential and the differentiation potential of the reprogrammed cells. Thus, HMGN proteins modulate the plasticity of the chromatin epigenetic landscape thereby stabilizing, rather than determining cell identity. HMGN1 and HMGN2 are ubiquitous nucleosome binding proteins. Here the authors provide evidence that HMGN proteins preferentially localize to chromatin regulatory sites to modulate the plasticity of the epigenetic landscape, proposing that HGMNs stabilize, rather than determine, cell identity.

Pyruvate kinase deficiency (PKD) is an autosomal recessive genetic disease caused by mutations in the PKLR gene. To date, the clinical manifestations of PKD are heterogeneous, ranging from fetal anemia, neonatal jaundice, and severe chronic hemolytic anemia to fully compensated hemolytic anemia. Successful cases of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for PKD have been reported, however, the number of cases is very small, and experiences are very limited. Here, we report two successful cases involving our modified conditioning regimen. This approach is suitable for patients with severe transfusion dependence. In conclusion, for PKD patients with severe transfusion dependence, allo-HSCT is an option and is currently a safe and effective way to completely eliminate the need for transfusions of drugs, such as Mitapivat, or genetic therapies and allow the patient to return to normal life.