Despite the availability of a vaccine against hepatitis B virus (HBV), this infection still causes public health problems, particularly in susceptible populations. In Portugal, universal free ...vaccination started in 1994, and most HBV infections are diagnosed in immigrants from high-prevalence countries. Our aim was to assess the pattern of HBV genotypes/subgenotypes in samples collected between 2017 and 2021 from a convenience sample of 70 infected residents in Portugal. The HBV pol/HBsAg region was amplified and sequenced, allowing the analysis of RT sequences submitted to phylogenetic analysis and mutations assessment. A total of 37.1% of samples were from native Portuguese, aged 25–53 years (mean: 36.7 years), and the remaining samples were from individuals born outside of Portugal. A high diversity of HBV was identified: subgenotypes A1–A3 in 41.0% (16/39); D1, D3, and D4 in 30.7% (12/39); E in 23.1% (9/39); and F4 in 2.6% (1/39). Besides genotypes A and D, Portuguese were also infected with genotypes E and F, which are prevalent in Africa and South America, respectively. Resistance mutations in RT sequences were not found. The findings provide valuable insights for updating the HBV molecular epidemiology in Portugal. However, successful strategies to prevent and control the infection are still needed in the country, especially among susceptible and vulnerable populations.
Humans vary substantially in their willingness to take risks. In a combined sample of over 1 million individuals, we conducted genome-wide association studies (GWAS) of general risk tolerance, ...adventurousness, and risky behaviors in the driving, drinking, smoking, and sexual domains. Across all GWAS, we identified hundreds of associated loci, including 99 loci associated with general risk tolerance. We report evidence of substantial shared genetic influences across risk tolerance and the risky behaviors: 46 of the 99 general risk tolerance loci contain a lead SNP for at least one of our other GWAS, and general risk tolerance is genetically correlated (Formula: see text ~ 0.25 to 0.50) with a range of risky behaviors. Bioinformatics analyses imply that genes near SNPs associated with general risk tolerance are highly expressed in brain tissues and point to a role for glutamatergic and GABAergic neurotransmission. We found no evidence of enrichment for genes previously hypothesized to relate to risk tolerance.
Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one
(cystic fibrosis transmembrane conductance ...regulator) allele, but it has not been evaluated in children <12 years of age.
To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with
-minimal function or
-
genotypes.
In this 24-week open-label phase 3 study, children (
= 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h).
The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV
(10.2 percentage points; 95% confidence interval CI, 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index
(-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age
-score increased over the 24-week treatment period when compared with the pretreatment baseline.
Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one
allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).
We studied symbiotic performance of factorial combinations of diverse rhizobial genotypes (G
) and East African common bean varieties (G
) that comprise Andean and Mesoamerican genetic groups. An ...initial wide screening in modified Leonard jars (LJ) was followed by evaluation of a subset of strains and genotypes in pots (contained the same, sterile medium) in which fixed nitrogen was also quantified. An additive main effect and multiplicative interaction (AMMI) model was used to identify the contribution of individual strains and plant genotypes to the G
× G
interaction. Strong and highly significant G
× G
interaction was found in the LJ experiment but with little evidence of a relation to genetic background or growth habits. The interaction was much weaker in the pot experiment, with all bean genotypes and
strains having relatively stable performance. We found that
strain CFN42 and
strains CIAT899 and NAK91 were effective across bean genotypes but with the latter showing evidence of positive interaction with two specific bean genotypes. This suggests that selection of bean varieties based on their response to inoculation is possible. On the other hand, we show that symbiotic performance is not predicted by any
grouping, limiting the scope for more general recommendations. The fact that the strength and pattern of G
× G
depended on growing conditions provides an important cautionary message for future studies.
The existence of genotype-by-strain (G
× G
) interaction has implications for the expected stability of performance of legume inoculants and could represent both challenges and opportunities for improvement of nitrogen fixation. We find that significant genotype-by-strain interaction exists in common bean (
L.) but that the strength and direction of this interaction depends on the growing environment used to evaluate biomass. Strong genotype and strain main effects, combined with a lack of predictable patterns in G
× G
, suggests that at best individual bean genotypes and strains can be selected for superior additive performance. The observation that the screening environment may affect experimental outcome of G
× G
means that identified patterns should be corroborated under more realistic conditions.
Late blight caused by
Phytophthora infestans
is an economically important disease of potato and tomato worldwide. In Canada, an increase in late blight incidence and severity coincided with changes ...in genetic composition of
P. infestans
. We monitored late blight incidence on tomato and potato in Pacific western and eastern Canada between 2019 and 2022, identified genotypes of
P
.
infestans
, and examined their population genetic diversity. We identified four major existing genotypes US11, US17, US8, and US23 as well as 25 new genotypes. The US11 genotype was dominant in Pacific western Canada, accounting for 59% of the total population. We discovered the US17 genotype for the first time in Canada. We revealed a higher incidence of late blight and quite diverse genotypes of
P
.
infestans
in Pacific western Canada than in eastern Canada. We found high genetic diversity of
P. infestans
population from Pacific western Canada, as evidenced by the high number of multilocus genotypes, high values of genetic diversity indices, and emergence of 25 new genotypes. Considering the number of disease incidence, the detection of diverse known genotypes, the emergence of novel genotypes, and the high number of isolates resistant to metalaxyl-m (95%) from Pacific western Canada, the region could play a role in establishing sexual recombination and diverse populations, which could ultimately pose challenges for late blight management. Therefore, continuous monitoring of
P. infestans
populations in Pacific western region and across Canada is warranted.
Key points
• Genotypes of P. infestans in Pacific western were quite diverse than in eastern Canada.
• We
discovered US17 genotype for the first time in Canada and identified 26 novel genotypes.
• Approximately 95% of P. infestans isolates were resistant to metalaxyl-m.
The use of whole-genome sequence data can lead to higher accuracy in genome-wide association studies and genomic predictions. However, to benefit from whole-genome sequence data, a large dataset of ...sequenced individuals is needed. Imputation from SNP panels, such as the Illumina BovineSNP50 BeadChip and Illumina BovineHD BeadChip, to whole-genome sequence data is an attractive and less expensive approach to obtain whole-genome sequence genotypes for a large number of individuals than sequencing all individuals. Our objective was to investigate accuracy of imputation from lower density SNP panels to whole-genome sequence data in a typical dataset for cattle.
Whole-genome sequence data of chromosome 1 (1737 471 SNPs) for 114 Holstein Friesian bulls were used. Beagle software was used for imputation from the BovineSNP50 (3132 SNPs) and BovineHD (40 492 SNPs) beadchips. Accuracy was calculated as the correlation between observed and imputed genotypes and assessed by five-fold cross-validation. Three scenarios S40, S60 and S80 with respectively 40%, 60%, and 80% of the individuals as reference individuals were investigated.
Mean accuracies of imputation per SNP from the BovineHD panel to sequence data and from the BovineSNP50 panel to sequence data for scenarios S40 and S80 ranged from 0.77 to 0.83 and from 0.37 to 0.46, respectively. Stepwise imputation from the BovineSNP50 to BovineHD panel and then to sequence data for scenario S40 improved accuracy per SNP to 0.65 but it varied considerably between SNPs.
Accuracy of imputation to whole-genome sequence data was generally high for imputation from the BovineHD beadchip, but was low from the BovineSNP50 beadchip. Stepwise imputation from the BovineSNP50 to the BovineHD beadchip and then to sequence data substantially improved accuracy of imputation. SNPs with a low minor allele frequency were more difficult to impute correctly and the reliability of imputation varied more. Linkage disequilibrium between an imputed SNP and the SNP on the lower density panel, minor allele frequency of the imputed SNP and size of the reference group affected imputation reliability.
Newcastle disease virus (NDV) is among the most important viruses of poultry; however, variants also cause clinical diseases in birds of the family Columbidae. From 2014 onwards, notable mortality ...rates have been observed in racing and rock pigeons, with a correlation to subgenotypes XXI.1.1 and XXI.1.2 of genotype XXI in Pakistan. In this study, we performed isolation and genetic characterization of 29 pigeon-derived NDV isolates of sub-genotypes XXI.1.1, XXI.1.2 and VII.2. Phylogenetic analysis based on complete fusion gene sequences classified seven (n = 7) isolates into sub-genotype XXI.1.1 and they were genetically closely related to isolates previously characterized in Pakistan (0.05-0.43% nucleotide divergence), and in Iran, Russia, Egypt, Nigeria, Kazakhstan and Ukraine (3.75% to 6.67% nucleotide divergence) in the period from 2005-2018. In addition, nineteen (n = 19) isolates were clustered with viruses previously isolated in Pakistan (2014-2018) in sub-genotype XXI.1.2. In addition, three (n = 3) F-gene sequences assigned to subgenotype VII.2 were identified along with viruses repeatedly isolated (2011-2020) from several poultry and non-poultry avian species in Pakistan. The analysis showed that all isolates of sub-genotypes XXI.1.1 and XXI.1.2 were mesogenic (1.42-1.49) and the isolates belonging to sub-genotype VII.2 were velogenic (1.63-1.71) in nature according to the intracerebral pathogenicity index (ICPI). This study delivers a comprehensive description of the prevalence of sub-genotypes XXI.1.1 and XXI.1.2 in Pakistan since 2014. Additionally, it underscores the role of free-range pigeons as effective carriers of virulent sub-genotype VII.2 viruses, impacting both poultry and non-poultry avian species reared in open environments.
Virulent NDV genotypes were repeatedly isolated from pigeons.
Evidence of epidemiological links among viruses isolated from various locations.
Distinct phylogenetic branches suggest separate, simultaneous evolution of NDVs.
Study information could be helpful in the development of an effective vaccine.
Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., ...minor allele frequency MAF <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prions are infectious agents that cause neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD). The absence of a human cell culture model that replicates human prions has hampered prion ...disease research for decades. In this paper, we show that astrocytes derived from human induced pluripotent stem cells (iPSCs) support the replication of prions from brain samples of CJD patients. For experimental exposure of astrocytes to variant CJD (vCJD), the kinetics of prion replication occur in a prion protein codon 129 genotype-dependent manner, reflecting the genotype-dependent susceptibility to clinical vCJD found in patients. Furthermore, iPSC-derived astrocytes can replicate prions associated with the major sporadic CJD strains found in human patients. Lastly, we demonstrate the subpassage of prions from infected to naive astrocyte cultures, indicating the generation of prion infectivity in vitro. Our study addresses a long-standing gap in the repertoire of human prion disease research, providing a new in vitro system for accelerated mechanistic studies and drug discovery.
Abstract
Enzymes can evolve new catalytic activity when environmental changes present them with novel substrates. Despite this seemingly straightforward relationship, factors other than the direct ...catalytic target can also impact adaptation. Here, we characterize the catalytic activity of a recently evolved bacterial methyl-parathion hydrolase for all possible combinations of the five functionally relevant mutations under eight different laboratory conditions (in which an alternative divalent metal is supplemented). The resultant adaptive landscapes across this historical evolutionary transition vary in terms of both the number of “fitness peaks” as well as the genotype(s) at which they are found as a result of genotype-by-environment interactions and environment-dependent epistasis. This suggests that adaptive landscapes may be fluid and molecular adaptation is highly contingent not only on obvious factors (such as catalytic targets), but also on less obvious secondary environmental factors that can direct it towards distinct outcomes.
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