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Research Square Jun 2024Background The family includes many obligate parasitic bacterial species which are etiologically associated with a myriad of zoonotic borrelioses including Lyme disease...
Background The family includes many obligate parasitic bacterial species which are etiologically associated with a myriad of zoonotic borrelioses including Lyme disease and vector-borne relapsing fevers. Infections by the are difficult to detect by both direct and indirect methods, often leading to delayed and missed diagnoses. Efforts to improve diagnoses center around the development of molecular diagnostics (MDx), but due to deep tissue sequestration of the causative spirochaetes and the lack of persistent bacteremias, even MDx assays suffer from a lack of sensitivity. Additionally, the highly extensive genomic heterogeneity among isolates, even within the same species, contributes to the lack of assay sensitivity as single target assays cannot provide universal coverage. This within-species heterogeneity is partly due to differences in replicon repertoires and genomic structures that have likely arisen to support the complex lifecycle in which these parasites have to survive in multiple hosts each with unique immune responses. Results We constructed a family-level pangenome and characterized the phylogenetic relationships among the constituent taxa which supports the recent taxonomy of splitting the family into at least two genera. Gene content profiles were created for the majority of the replicons, providing for the first time their unambiguous molecular typing. Conclusion Our characterization of the pan-genome supports the splitting of the former genus into two genera and provides for the phylogenetic placement of several non-species designated isolates. Mining this family-level pangenome will enable precision diagnostics corresponding to gene content-driven clinical outcomes while also providing targets for interventions.
PubMed: 38947078
DOI: 10.21203/rs.3.rs-4491589/v1 -
Research Square Jun 2024Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to...
Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients. A missense variant in (KLK15 p. Gly226Asp , segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the gene family. To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, mice displayed structural and functional connective tissue defects within multiple organ systems. These findings support gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.
PubMed: 38947032
DOI: 10.21203/rs.3.rs-4547888/v1 -
Research Square Jun 2024Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline...
Prostate cancer (PCa) is highly heritable, with men of African ancestry at greatest risk and associated lethality. Lack of representation in genomic data means germline testing guidelines exclude for African men. Established that structural variations (SVs) are major contributors to human disease and prostate tumourigenesis, their role is under-appreciated in familial and therapeutic testing. Utilising a clinico-methodologically matched African (n = 113) European (n = 57) deep-sequenced PCa resource, we interrogated 42,966 high-quality germline SVs using a best-fit pathogenicity prediction workflow. We identified 15 potentially pathogenic SVs representing 12.4% African and 7.0% European patients, of which 72% and 86% met germline testing standard-of-care recommendations, respectively. Notable African-specific loss-of-function gene candidates include DNA damage repair and and tumour suppressors and . Representing only a fraction of the vast African diaspora, this study raises considerations with respect to the contribution of kilo-to-mega-base rare variants to PCa pathogenicity and African associated disparity.
PubMed: 38947031
DOI: 10.21203/rs.3.rs-4531885/v1 -
Research Square Jun 2024Acute lymphoblastic leukemia (ALL) is the most common cancer in children, yet few environmental risk factors have been identified. We previously found an association...
Acute lymphoblastic leukemia (ALL) is the most common cancer in children, yet few environmental risk factors have been identified. We previously found an association between early-life tobacco smoke exposure and frequency of somatic deletions of 8 leukemia driver genes among childhood ALL patients in the California Childhood Leukemia Study. To expand analysis genome-wide and examine potential mechanisms, we conducted tumor whole-genome sequencing in 35 ALL patients, including 18 with high prenatal tobacco exposure and 17 with low exposure as determined by established epigenetic biomarkers. High tobacco exposure patients had significantly more structural variants (P < .001) and deletions (P = .001) genome-wide than low exposure patients. Investigation of off-target RAG recombination revealed that 41% of deletions in the high tobacco exposure patients were putatively RAG-mediated (full RAG motif identified at one or both breakpoints) compared with only 21% in the low exposure group (P = .001). In a multilevel model, deletions in high tobacco exposure patients were 2.44-fold (95% CI:1.13-5.38) more likely to be putatively RAG-mediated than deletions in low exposure patients. No point mutational signatures were associated with prenatal tobacco exposure. Our findings suggest that early-life tobacco smoke exposure may promote leukemogenesis by driving development of somatic deletions in pre-leukemic lymphocytes via off-target RAG recombination.
PubMed: 38946984
DOI: 10.21203/rs.3.rs-4510345/v1 -
MedRxiv : the Preprint Server For... Jun 2024In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is...
In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. Strikingly, the lncRNAs and are each disrupted in two unrelated cases. Furthermore, in 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of two individuals with BCAs and additionally highlight six individuals with likely developmental etiologies due to lncRNA disruptions.
PubMed: 38946951
DOI: 10.1101/2024.06.16.24307499 -
Cancer Innovation Apr 2024Neuroblastoma is one of the most common extracranial malignant solid tumors in children. AlkB homolog 5 (ALKBH5) is an RNA N6-methyladenosine (m6A) demethylase that...
BACKGROUND
Neuroblastoma is one of the most common extracranial malignant solid tumors in children. AlkB homolog 5 (ALKBH5) is an RNA N6-methyladenosine (m6A) demethylase that plays a critical role in tumorigenesis and development. We assessed the association between single nucleotide polymorphisms (SNPs) in and the risk of neuroblastoma in a case-control study including 402 patients and 473 non-cancer controls.
METHODS
Genotyping was determined by the TaqMan method. The association between polymorphisms (rs1378602 and rs8400) and the risk of neuroblastoma was evaluated using the odds ratio (OR) and 95% confidence interval (CI).
RESULTS
We found no strong association of rs1378602 and rs8400 with neuroblastoma risk. Further stratification analysis by age, sex, primary site, and clinical stage showed that the rs1378602 AG/AA genotype was associated with a lower risk of neuroblastoma in males (adjusted OR = 0.58, 95% CI = 0.35-0.97, = 0.036) and children with retroperitoneal neuroblastoma (adjusted OR = 0.58, 95% CI = 0.34-0.98, = 0.040).
CONCLUSIONS
SNPs do not seem to be associated with neuroblastoma risk. More studies are required to confirm this negative result and reveal the relationship between gene polymorphisms of the m6A modifier and neuroblastoma.
PubMed: 38946930
DOI: 10.1002/cai2.103 -
Frontiers in Microbiology 2024Cotrimoxazole, the combined formulation of sulfamethoxazole and trimethoprim, is one of the treatments of choice for several infectious diseases, particularly urinary...
Cotrimoxazole, the combined formulation of sulfamethoxazole and trimethoprim, is one of the treatments of choice for several infectious diseases, particularly urinary tract infections. Both components of cotrimoxazole are synthetic antimicrobial drugs, and their combination was introduced into medical therapeutics about half a century ago. In Gram-negative bacteria, resistance to cotrimoxazole is widespread, being based on the acquisition of genes from the auxiliary genome that confer resistance to each of its antibacterial components. Starting from previous knowledge on the genotype of resistance to sulfamethoxazole in a collection of cotrimoxazole resistant uropathogenic strains, this work focused on the identification of the genetic bases of the trimethoprim resistance of these same strains. Molecular techniques employed included PCR and Sanger sequencing of specific amplicons, conjugation experiments and NGS sequencing of the transferred plasmids. Mobile genetic elements conferring the trimethoprim resistance phenotype were identified and included integrons, transposons and single gene cassettes. Therefore, strains exhibited several ways to jointly resist both antibiotics, implying different levels of genetic linkage between genes conferring resistance to sulfamethoxazole () and trimethoprim (). Two structures were particularly interesting because they represented a highly cohesive arrangements ensuring cotrimoxazole resistance. They both carried a single gene cassette, or , integrated in two different points of a conserved cluster , carried on transferable plasmids. The results suggest that the pressure exerted by cotrimoxazole on bacteria of our environment is still promoting the evolution toward increasingly compact gene arrangements, carried by mobile genetic elements that move them in the genome and also transfer them horizontally among bacteria.
PubMed: 38946902
DOI: 10.3389/fmicb.2024.1395953 -
Frontiers in Microbiology 2024Salinization damages soil system health and influences microbial communities structure and function. The response of microbial functions involved in the nutrient cycle...
INTRODUCTION
Salinization damages soil system health and influences microbial communities structure and function. The response of microbial functions involved in the nutrient cycle to soil salinization is a valuable scientific question. However, our knowledge of the microbial metabolism functions in salinized soil and their response to salinity in arid desert environments is inadequate.
METHODS
Here, we applied metagenomics technology to investigate the response of microbial carbon (C), nitrogen (N), phosphorus (P), and sulfur (S) cycling and the key genes to salinity, and discuss the effects of edaphic variables on microbial functions.
RESULTS
We found that carbon fixation dominated the carbon cycle. Nitrogen fixation, denitrification, assimilatory nitrate reduction (ANRA), and nitrogen degradation were commonly identified as the most abundant processes in the nitrogen cycle. Organic phosphorus dissolution and phosphorus absorption/transport were the most enriched P metabolic functions, while sulfur metabolism was dominated by assimilatory sulfate reduction (ASR), organic sulfur transformation, and linkages between inorganic and organic sulfur transformation. Increasing salinity inhibited carbon degradation, nitrogen fixation, nitrogen degradation, anammox, ANRA, phosphorus absorption and transport, and the majority of processes in sulfur metabolism. However, some of the metabolic pathway and key genes showed a positive response to salinization, such as carbon fixation (, , ), denitrification (, , , ), ANRA (, ), and organic phosphorus dissolution processes (, , ). High salinity reduced the network complexity in the soil communities. Even so, the saline microbial community presented highly cooperative interactions. The soil water content had significantly correlations with C metabolic genes. The SOC, N, and P contents were significantly correlated with C, N, P, and S network complexity and functional genes. AP, NH4+, and NO3- directly promote carbon fixation, denitrification, nitrogen degradation, organic P solubilization and mineralization, P uptake and transport, ASR, and organic sulfur transformation processes.
CONCLUSION
Soil salinity in arid region inhibited multiple metabolic functions, but prompted the function of carbon fixation, denitrification, ANRA, and organic phosphorus dissolution. Soil salinity was the most important factor driving microbial functions, and nutrient availability also played important roles in regulating nutrient cycling.
PubMed: 38946896
DOI: 10.3389/fmicb.2024.1407760 -
World Journal of Clinical Oncology Jun 2024Lung cancer bone metastasis (LCBM) is a disease with a poor prognosis, high risk and large patient population. Although considerable scientific output has accumulated on...
BACKGROUND
Lung cancer bone metastasis (LCBM) is a disease with a poor prognosis, high risk and large patient population. Although considerable scientific output has accumulated on LCBM, problems have emerged, such as confusing research structures.
AIM
To organize the research frontiers and body of knowledge of the studies on LCBM from the last 22 years according to their basic research and translation, clinical treatment, and clinical diagnosis to provide a reference for the development of new LCBM clinical and basic research.
METHODS
We used tools, including R, VOSviewer and CiteSpace software, to measure and visualize the keywords and other metrics of 1903 articles from the Web of Science Core Collection. We also performed enrichment and protein-protein interaction analyses of gene expression datasets from LCBM cases worldwide.
RESULTS
Research on LCBM has received extensive attention from scholars worldwide over the last 20 years. Targeted therapies and immunotherapies have evolved into the mainstream basic and clinical research directions. The basic aspects of drug resistance mechanisms and parathyroid hormone-related protein may provide new ideas for mechanistic study and improvements in LCBM prognosis. The produced molecular map showed that ribosomes and focal adhesion are possible pathways that promote LCBM occurrence.
CONCLUSION
Novel therapies for LCBM face animal testing and drug resistance issues. Future focus should centre on advancing clinical therapies and researching drug resistance mechanisms and ribosome-related pathways.
PubMed: 38946828
DOI: 10.5306/wjco.v15.i6.765 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Jul 2024To explore the serological characteristics and molecular mechanism underlying an individual with A3 phenotype.
OBJECTIVE
To explore the serological characteristics and molecular mechanism underlying an individual with A3 phenotype.
METHODS
A 27-year-old ethnic Han Chinese woman presented at the Fourth Affiliated Hospital of China Medical University on May 12, 2022 was selected as the study subject. ABO blood type was determined with standard serological techniques. The ABO gene was subjected to direct sequencing of PCR products. Exons 6 and 7 of the ABO gene were sequenced using specific primers to determine the haplotypes. Bioinformatic software was used to analyze the structure of the mutant protein.
RESULTS
Serological typing of the ABO blood group has suggested a rare A3 phenotype. The proband was found to harbor heterozygous c.261delG, c.467C>T and c.745C>T variants by direct sequencing. Single strand sequencing revealed that she has harbored ABO*A3.07 and ABO*O.01.01 alleles. The ABO*A3.07 allele has contained a c.745C>T (p.R249W) variant on the background of an ABO*A1.02 allele. The p.R249W substitution was predicted to be probably damaging by the PolyPhen2 software. The free energy change (ΔΔG) value predicted it to have a destabilizing effect on the GTA protein. Meanwhile, modeling of the 3D structure has predicted that the p.R249W amino acid substitution may alter the hydrogen bond network of the GTA protein.
CONCLUSION
The p.R249W substitution of the α-1,3-N-acetylgalactosaminyltransferase gene may reduce the antigen expression owing to a great destabilizing effect on the structure and function of the GTA protein.
Topics: Humans; Female; ABO Blood-Group System; Adult; Phenotype; Alleles; Glycosyltransferases; N-Acetylgalactosaminyltransferases; Asian People; Base Sequence
PubMed: 38946374
DOI: 10.3760/cma.j.cn511374-20230414-00211