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Frontiers in Veterinary Science 2024Natural cases of prion disease have not been reported in rabbits, and prior attempts to identify a prion conversion agent have been unsuccessful. However, recent...
BACKGROUND
Natural cases of prion disease have not been reported in rabbits, and prior attempts to identify a prion conversion agent have been unsuccessful. However, recent applications of prion seed amplifying experimental techniques have sparked renewed interest in the potential susceptibility of rabbits to prion disease infections. Among several factors related to prion disease, polymorphisms within the prion-like protein gene (), a member of the prion protein family, have been reported as significantly associated with disease susceptibility in various species. Therefore, our study aimed to investigate polymorphisms in the gene of rabbits and analyze their genetic characteristics.
METHODS
Genomic DNA was extracted from 207 rabbit samples to investigate leporine polymorphisms. Subsequently, amplicon sequencing targeting the coding region of the leporine gene was conducted. Additionally, linkage disequilibrium (LD) analysis was employed to assess the connection within and between loci. The impact of non-synonymous single nucleotide polymorphisms (SNPs) on the Doppel protein was evaluated using PolyPhen-2.
RESULTS
We found nine novel SNPs in the leporine gene: c.18A > G, c.76G > C, c.128C > T, c.146C > T, c.315A > G, c.488G > A, c.525G > C, c.544G > A, and c.579A > G. Notably, seven of these SNPs, excluding c.525G > C and c.579A > G, exhibited strong LD values exceeding 0.3. In addition, LD analysis confirmed a robust link between SNP c.234C > T and SNPs at c.525G > C and c.579A > G. Furthermore, according to PolyPhen-2 and SIFT analyses, the four non-synonymous SNPs were predicted to have deleterious effects on the function or structure of the Doppel protein. However, PANTHER and Missense3D did not indicate such effects.
CONCLUSION
In this paper, we have identified novel SNPs in the rabbit gene and predicted their potential detrimental effects on protein function or structure through four non-synonymous SNPs. Additionally, we observed a genetic linkage between SNPs in the and genes. These findings may provide insights into understanding the characteristics of rabbits as partially resistant species. To the best of our knowledge, this study is the first to genetically characterize SNPs in rabbits.
PubMed: 38952802
DOI: 10.3389/fvets.2024.1388339 -
Cureus Jun 2024Background Periodontal disease poses a significant oral health challenge, involving inflammatory conditions impacting tooth-supporting structures. Treponema denticola, a...
Background Periodontal disease poses a significant oral health challenge, involving inflammatory conditions impacting tooth-supporting structures. Treponema denticola, a "red complex" organism, plays a crucial role in periodontal pathogenesis, forming biofilms in subgingival environments and contributing to dysbiosis. Antimicrobial therapy is pivotal in managing periodontal disease, requiring a nuanced understanding of susceptibility patterns exhibited by key pathogens like T. denticola Aims and objectives This study aims to investigate the antimicrobial susceptibility and resistance profiles of Treponema denticola, a prominent bacterium in periodontal disease, by examining its responses to various antimicrobial agents commonly used in periodontal therapy. Methodology Plaque samples were meticulously collected from individuals diagnosed with periodontal disease to ensure a diverse representation of the oral microbiome. All the samples were cultured, and red complex bacteria were isolated under anaerobic culture. Treponema denticola isolates were cultured from these samples under anaerobic conditions, and molecular techniques were employed for species identification. A comprehensive panel of antimicrobial agents was selected to assess the response of Treponema denticola. In vitro antimicrobial susceptibility testing (AST) was conducted using the antimicrobial gradient method, employing a hybrid approach combining elements of disk-diffusion and dilution methods. Results Treponema denticola had exhibited resistance to metronidazole, a commonly used antibiotic effective against anaerobic bacteria, emphasizing limitations in its applicability. However, the bacterium displayed sensitivity to tetracycline, imipenem, cefoperazone, chloramphenicol, clindamycin, and moxifloxacin, offering diverse therapeutic options. The antimicrobial gradient strip test provided detailed minimum inhibitory concentration (MIC) values, contributing to a nuanced understanding of susceptibility and resistance patterns. Conclusion This study significantly advances our understanding of Treponema denticola's antimicrobial susceptibility and resistance profiles in the context of periodontal disease. The findings underscore the importance of tailored treatment strategies and contribute to broader efforts in antimicrobial stewardship, aligning with global initiatives to combat antibiotic resistance. This research lays the foundation for more effective and personalized approaches to periodontal care, emphasizing the intricate microbial dynamics associated with periodontal health and disease.
PubMed: 38952590
DOI: 10.7759/cureus.61497 -
Frontiers in Microbiology 2024Biotic stresses, such as plant viruses, e.g., cotton leaf curl virus (CLCuV), can alter root-associated and leaf-associated microbial diversities in plants. There are...
Biotic stresses, such as plant viruses, e.g., cotton leaf curl virus (CLCuV), can alter root-associated and leaf-associated microbial diversities in plants. There are complex ecological dynamics at play, with each microbe contributing to a multitude of biotic and abiotic interactions, thus deciding the stability of the plant's ecosystem in response to the disease. Deciphering these networks of interactions is a challenging task. The inferential research in microbiome is also at a nascent stage, often constrained by the underlying analytical assumptions and the limitations with respect to the depth of sequencing. There is also no real consensus on network-wide statistics to identify the influential microbial players in a network. Guided by the latest developments in network science, including recently published metrics such as Integrated View of Influence (IVI) and some other centrality measures, this study provides an exposé of the most influential nodes in the rhizospheric and phyllospheric microbial networks of the cotton leaf curl disease (CLCuD) susceptible, partially tolerant, and resistant cotton varieties. It is evident from our results that the CLCuD-resistant possesses an equal share of keystone species, which helps it to withstand ecological pressures. In the resistant variety, the phyllosphere harbors the most influential nodes, whereas in the susceptible variety, they are present in the rhizosphere. Based on hubness score, spreading score, and IVI, the top 10 occurring keystone species in the FDH-228 (resistant) variety include and and were identified as the most influential nodes in the PFV-1 (partially tolerant) variety. In the PFV-2 (susceptible) variety, the keystone species were identified as and . This concept deciphers the diseased and healthy plant's response to viral disease, which may be microbially mediated.
PubMed: 38952448
DOI: 10.3389/fmicb.2024.1381883 -
Computational and Structural... Dec 2024Gene expression plays a pivotal role in various diseases, contributing significantly to their mechanisms. Most GWAS risk loci are in non-coding regions, potentially...
Gene expression plays a pivotal role in various diseases, contributing significantly to their mechanisms. Most GWAS risk loci are in non-coding regions, potentially affecting disease risk by altering gene expression in specific tissues. This expression is notably tissue-specific, with genetic variants substantially influencing it. However, accurately detecting the expression Quantitative Trait Loci (eQTL) is challenging due to limited heritability in gene expression, extensive linkage disequilibrium (LD), and multiple causal variants. The single variant association approach in eQTL analysis is limited by its susceptibility to capture the combined effects of multiple variants, and a bias towards common variants, underscoring the need for a more robust method to accurately identify causal eQTL variants. To address this, we developed an algorithm, CausalEQTL, which integrates + penalized regression with an ensemble approach to localize eQTL, thereby enhancing prediction performance precisely. Our results demonstrate that CausalEQTL outperforms traditional models, including LASSO, Elastic Net, Ridge, in terms of power and overall performance. Furthermore, analysis of heart tissue data from the GTEx project revealed that eQTL sites identified by our algorithm provide deeper insights into heart-related tissue eQTL detection. This advancement in eQTL mapping promises to improve our understanding of the genetic basis of tissue-specific gene expression and its implications in disease. The source code and identified causal eQTLs for CausalEQTL are available on GitHub: https://github.com/zhc-moushang/CausalEQTL.
PubMed: 38952424
DOI: 10.1016/j.csbj.2024.05.050 -
BMC Veterinary Research Jun 2024The aim of this research was to estimate the immunopotentiation effect of brown algae Padina boergesenii water extract on Nile tilapia, Oreochromis niloticus through...
The aim of this research was to estimate the immunopotentiation effect of brown algae Padina boergesenii water extract on Nile tilapia, Oreochromis niloticus through resistance to Pseudomonas putida infection. Gas Chromatography Mass Spectrometry was utilized to characterize the seaweed phytoconstituents. One hundred and twenty-six fish were divided in triplicates into two equal groups corresponding to two diet variants that used to feed Nile tilapia for 20 successive days: a basal (control), and P. boergesenii water extract supplemented group. Fish samples were collected at 10-days intervals throughout the experiment. Serum biochemical constituents, total antioxidant capacity (TAC), and some immune related genes expression of the spleen and intestinal tissues of experimental fish were studied, as well as histological examination of fish immune tissues. Moreover, following 20 days of feeding, the susceptibility of Nile tilapia to P. putida infection was evaluated to assess the protective effect of the used extract. The findings indicated that the studied parameters were significantly increased, and the best immune response profiles were observed in fish fed P. boergesenii water extract for 20 successive days. A bacterial challenge experiment using P. putida resulted in higher survival within the supplemented fish group than the control. Thus, the lowered post-challenge mortality of the fish may be related to the protection provided by the stimulation of the innate immune system, reduced oxidative stress by higher activity of TAC, and elevated levels of expression of iterleukin-1beta (IL-1β), beta-defensin (β-defensin), and natural killer-lysin (NKl). Moreover, the constituents of the extract used showed potential protective activity for histological features of the supplemented fish group when compared to the control. Collectively, this study presents a great insight on the protective role of P. boergesenii water extract as an additive in Nile tilapia feed which suggests its potential for improving the immune response against P. putida infection.
Topics: Animals; Pseudomonas putida; Fish Diseases; Cichlids; Animal Feed; Pseudomonas Infections; Dietary Supplements; Phaeophyceae; Diet; Disease Resistance; Plant Extracts
PubMed: 38951863
DOI: 10.1186/s12917-024-04115-7 -
BMC Genomics Jun 2024Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous...
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.
METHODS
Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.
RESULTS
A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10; OR = 4.73, p = 2 × 10; OR = 2.3, p = 7.49 × 10, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10).
CONCLUSIONS
In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.
Topics: Amyotrophic Lateral Sclerosis; Humans; Genetic Predisposition to Disease; Male; Female; Ethnicity; Genetic Variation
PubMed: 38951798
DOI: 10.1186/s12864-024-10538-1 -
Cardiovascular Diabetology Jun 2024Glucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose...
BACKGROUND
Glucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction.
METHODS
Using publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR).
RESULTS
Genetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57-46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78-4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54-0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results.
CONCLUSIONS
Impaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.
Topics: Mendelian Randomization Analysis; Humans; Genome-Wide Association Study; Adaptor Proteins, Signal Transducing; Risk Factors; Genetic Predisposition to Disease; Risk Assessment; Blood Glucose; Glucokinase; Biomarkers; Lipids; Phenotype; Carrier Proteins; Polymorphism, Single Nucleotide; Time Factors; Dyslipidemias; Fatty Liver
PubMed: 38951793
DOI: 10.1186/s12933-024-02321-z -
BMC Plant Biology Jun 2024Hybrid genotypes can provide significant yield gains over conventional inbred varieties due to heterosis or hybrid vigor. However, hybrids can also display unintended...
Hybrid genotypes can provide significant yield gains over conventional inbred varieties due to heterosis or hybrid vigor. However, hybrids can also display unintended negative attributes or phenotypes such as extreme pathogen susceptibility. The necrotrophic pathogen Pyrenophora teres f. maculata (Ptm) causes spot form net blotch, which has caused significant yield losses to barley worldwide. Here, we report on a non-transgressive hybrid susceptibility locus in barley identified between the three parental lines CI5791, Tifang and Golden Promise that are resistant to Ptm isolate 13IM.3. However, F progeny from CI5791 × Tifang and CI5791 × Golden Promise crosses exhibited extreme susceptibility. The susceptible phenotype segregated in a ratio of 1 resistant:1 susceptible representing a genetic segregation ratio of 1 parental (res):2 heterozygous (sus):1 parental (res) suggesting a single hybrid susceptibility locus. Genetic mapping using a total of 715 CI5791 × Tifang F individuals (1430 recombinant gametes) and 149 targeted SNPs delimited the hybrid susceptibility locus designated Susceptibility to Pyrenophora teres 2 (Spt2) to an ~ 198 kb region on chromosome 5H of the Morex V3 reference assembly. This single locus was independently mapped with 83 CI5791 × Golden Promise F individuals (166 recombinant gametes) and 180 genome wide SNPs that colocalized to the same Spt2 locus. The CI5791 genome was sequenced using PacBio Continuous Long Read technology and comparative analysis between CI5791 and the publicly available Golden Promise genome assembly determined that the delimited region contained a single high confidence Spt2 candidate gene predicted to encode a pentatricopeptide repeat-containing protein.
Topics: Hordeum; Plant Diseases; Chromosome Mapping; Ascomycota; Disease Resistance; Phenotype; Polymorphism, Single Nucleotide; Hybridization, Genetic; Hybrid Vigor; Genotype
PubMed: 38951756
DOI: 10.1186/s12870-024-05303-1 -
Nature Communications Jul 2024Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it...
Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.
Topics: Humans; Schizophrenia; Multifactorial Inheritance; Genetic Predisposition to Disease; Coronary Artery Disease; Risk Factors; Female; Precision Medicine; Male; Genome-Wide Association Study; Middle Aged; Polymorphism, Single Nucleotide
PubMed: 38951512
DOI: 10.1038/s41467-024-49338-2 -
The Pharmacogenomics Journal Jun 2024There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent...
There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.
Topics: Humans; Adolescent; Anthracyclines; Cancer Survivors; Young Adult; Male; Female; Genetic Predisposition to Disease; Cardiotoxicity; Adult; Myocytes, Cardiac; Polymorphism, Single Nucleotide; Neoplasms; Heart Diseases; Antibiotics, Antineoplastic; Risk Factors
PubMed: 38951505
DOI: 10.1038/s41397-024-00343-0