Search

Epigenetic modifications are plausible molecular sources of phenotypic heterogeneity across schizophrenia patients. The current study investigated biological heterogeneity in schizophrenia using peripheral epigenetic profiles to delineate illness subtypes independent of their phenomenological manifestations. We applied epigenome-wide profiling with a DNA methylation array from blood samples of 63 schizophrenia patients and 59 healthy controls. Non-negative matrix factorization (NMF) and k-means clustering were performed to identify DNA methylation-related patient subtypes. The validity of the partition was tested by assessing the profile of the T cell receptor (TCR) repertoires. The uniqueness of the identified subtypes in relation to brain structural and clinical measures were evaluated. Two distinct patterns of DNA methylation profiles were identified in patients. One subtype (60.3% of patients) showed relatively limited changes in methylation levels and cell composition compared to controls, while a second subtype (39.7% of patients) exhibited widespread methylation level alterations among genes enriched in immune cell activity, as well as a higher proportion of neutrophils and lower proportion of lymphocytes. Differentiation of the two patient subtypes was validated by TCR repertoires, which paralleled the partition based on DNA methylation profiles. The subtype with widespread methylation modifications had higher symptom severity, performed worse on cognitive measures, and displayed greater reductions in fractional anisotropy of white matter tracts and evidence of gray matter thickening compared to the other subtype. Identification of a distinct subtype of schizophrenia with unique molecular, cerebral, and clinical features provide a novel parcellation of the schizophrenia syndrome with potential to guide development of individualized therapeutics.

Increasing Helicobacter pylori resistance to antibiotics has ledthat molecular testing is appropriate as a sub to adoption of seven different bismuth quadruple therapies (BQT) in China without differentiation of first-line or second-line regimens. The objective of this study was to evaluate the efficacy of susceptibility-guided BQT for patients who had experienced previous treatment failures. A total of 133 patients was included and H. pylori was successfully cultured from 101 patients (75.9%) for subsequent antimicrobial susceptibility testing (AST). Based on the AST results, 88 patients completed one of five AST-guided 14-day BQT regimens: esomeprazole and bismuth colloidal pectin, along with either, amoxicillin and clarithromycin (EBAC), amoxicillin and levofloxacin (EBAL), amoxicillin and furazolidone (EBAF), amoxicillin and tetracycline (EBAT), or tetracycline and furazolidone (EBTF). H. pylori eradication rates were 100% for EBAC (5/5), EBAL (13/13), EBAF (14/14), and EBTF (43/43), but 76.9% for EBAT (10/13). The three patients that failed the EBAT regimen were all cured after subsequent treatment with the EBTF regimen. Our study demonstrates the excellent efficacy of the AST-guided BQT for referred H. pylori patients, and that the current EBAT regimen, used in clinics, needs to be optimized. In addition, 57 of the isolates were subjected to whole-genome sequencing. Analysis of the sequences revealed that point mutations in 23S rRNA correlated well with the phenotypic clarithromycin resistance with a concordance of 91.2%, while the concordance between phenotypic levofloxacin resistance and gyrA point mutations was 82.3%. This suggests that molecular testing is appropriate as a substitute for AST as a more rapid and cost-effective method for determining clarithromycin and levofloxacin resistance in Chinese patients.

Epigenetic modifications are plausible molecular sources of phenotypic heterogeneity across schizophrenia patients. The current study investigated biological heterogeneity in schizophrenia using peripheral epigenetic profiles to delineate illness subtypes independent of their phenomenological manifestations. We applied epigenome-wide profiling with a DNA methylation array from blood samples of 63 schizophrenia patients and 59 healthy controls. Non-negative matrix factorization (NMF) and k-means clustering were performed to identify DNA methylation-related patient subtypes. The validity of the partition was tested by assessing the profile of the T cell receptor (TCR) repertoires. The uniqueness of the identified subtypes in relation to brain structural and clinical measures were evaluated. Two distinct patterns of DNA methylation profiles were identified in patients. One subtype (60.3% of patients) showed relatively limited changes in methylation levels and cell composition compared to controls, while a second subtype (39.7% of patients) exhibited widespread methylation level alterations among genes enriched in immune cell activity, as well as a higher proportion of neutrophils and lower proportion of lymphocytes. Differentiation of the two patient subtypes was validated by TCR repertoires, which paralleled the partition based on DNA methylation profiles. The subtype with widespread methylation modifications had higher symptom severity, performed worse on cognitive measures, and displayed greater reductions in fractional anisotropy of white matter tracts and evidence of gray matter thickening compared to the other subtype. Identification of a distinct subtype of schizophrenia with unique molecular, cerebral, and clinical features provide a novel parcellation of the schizophrenia syndrome with potential to guide development of individualized therapeutics.

Increasing

The lipopolysaccharide O-antigen structure expressed by the European Helicobacter pylori model strain G27 encompasses a trisaccharide, an intervening glucan-heptan and distal Lewis antigens that promote immune escape. However, several gaps still remain in the corresponding biosynthetic pathway. Here, systematic mutagenesis of glycosyltransferase genes in G27 combined with lipopolysaccharide structural analysis, uncovered HP0102 as the trisaccharide fucosyltransferase, HP1283 as the heptan transferase, and HP1578 as the GlcNAc transferase that initiates the synthesis of Lewis antigens onto the heptan motif. Comparative genomic analysis of G27 lipopolysaccharide biosynthetic genes in strains of different ethnic origin revealed that East-Asian strains lack the HP1283/HP1578 genes but contain an additional copy of HP1105 and JHP0562. Further correlation of different lipopolysaccharide structures with corresponding gene contents led us to propose that the second copy of HP1105 and the JHP0562 may function as the GlcNAc and Gal transferase, respectively, to initiate synthesis of the Lewis antigen onto the Glc-Trio-Core in East-Asian strains lacking the HP1283/HP1578 genes. In view of the high gastric cancer rate in East Asia, the absence of the HP1283/HP1578 genes in East-Asian H. pylori strains warrants future studies addressing the role of the lipopolysaccharide heptan in pathogenesis., Author summary The human gastric pathogen Helicobacter pylori is the most important aetiological factor for gastric cancer. H. pylori lipopolysaccharide, a major bacterial surface molecule, plays essential roles in host-pathogen interactions. Due to the scattered organisation of the lipopolysaccharide genes in its genome, several key enzymes involved in H. pylori lipopolysaccharide biosynthesis remain to be identified. Here, through systematic mutagenesis of glycosyltransferase genes in the model strain G27 combined with lipopolysaccharide structural analysis, we identified novel glycosyltransferases and established the first complete lipopolysaccharide biosynthetic pathway in G27. Furthermore, we analysed the conservation of the lipopolysaccharide genes across a large panel of H. pylori strains and demonstrated that many of the lipopolysaccharide genes are highly conserved, whereas the genes involved in lipopolysaccharide heptan incorporation are lacking in East-Asian strains. Finally, based on the correlation of lipopolysaccharide structure and gene contents in specific strains, we proposed a lipopolysaccharide biosynthetic model of how East-Asian strains, missing the heptan moiety, attach Lewis antigens onto the conserved Glc-Trio-Core. Future studies are needed to address whether the lack of heptan in lipopolysaccharide of East-Asian H. pylori strains is related to the high gastric cancer rate in East Asia, accounting for almost half of the worldwide gastric cancer cases.

Introduction Gout is a worldwide chronic disease generally caused by high serum levels of uric acid. Using whole exome sequencing, we aimed to explore genetic alterations in hereditary gout. Patients' concerns There were 9 direct descendants diagnosed with gout in total in this family. The patients concerned about the high incidence and inheritance of gout. Diagnosis The youngest propositus was diagnosed as gout in our hospital. Diagnoses of other patients in this family were made on the foundation of history and clinical tests. Interventions Six direct descendants and 3 healthy spouses in 1 family were recruited in our study. Whole-exome sequencing was conducted in all participants. Outcomes Whole-exome sequencing and genetic analysis revealed 2 putative rare inherited deleterious variants, which were detected only in direct descendants. Twelve gout and uric acid (UC)-related nucleotide sequence variants previously reported by GWAS were detected among all subjects. Conclusions In the case of this family, the GWAS identified gout and UC-related nucleotide sequence variants may increase the risk of developing gout, but penetrance was not complete. The rare sequence variants in low-density lipoprotein receptor-related protein 1 (LRP1) and oncoprotein induced transcript 3 (OIT3) may have contributed to inheritance of gout within the 5 generations of family members in this study.