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Lactase persistence (LP) - the genetic trait that determines the continued expression of the enzyme lactase into adulthood - has undergone recent, rapid positive selection since the advent of animal domestication and dairying in some human populations. While underlying evolutionary explanations have been widely posited and studied, the molecular basis of LP remains less so. This review considers the genetic and epigenetic bases of LP. Multiple single-nucleotide polymorphisms (SNPs) in an LCT enhancer in intron 13 of the neighbouring MCM6 gene are associated with LP. These SNPs alter binding of transcription factors (TFs) and likely prevent age-related increases in methylation in the enhancer, maintaining LCT expression into adulthood to cause LP. However, the complex relationship between the genetics and epigenetics of LP is not fully characterised, and the mode of action of methylation quantitative trait loci (meQTLs) (SNPs affecting methylation) generally remains poorly understood. Here, we examine published LP data to propose a model describing how methylation in the LCT enhancer is prevented in LP adults. We argue that this occurs through altered binding of the TF Oct-1 (encoded by the gene POU2F1) and neighbouring TFs GATA-6 (GATA6), HNF-3A (FOXA1) and c-Ets1 (ETS1) acting in concert. We therefore suggest a plausible new model for LCT downregulation in the context of LP, with wider relevance for future work on the mechanisms of other meQTLs., (© 2024 The Author(s). Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.)

Background: Dementia has no pharmacological cure. Therefore, lifestyle interventions targeting modifiable risk factors to reduce cognitive decline are of interest. This study examines the cross‐sectional relationships between two potentially protective behaviours: Mediterranean diet (MediDiet) adherence and physical activity (PA). Method: Participants were recruited from the Sax Institute's 45 and Up Study into the Maintain Your Brain trial. MediDiet adherence was assessed using the validated Mediterranean Diet and Culinary Index (MediCul) tool. The 50‐item tool consists of 17 sub‐categories focusing on key aspects of the MediDiet. Leisure time PA was assessed by a standard questionnaire and intensity was quantified using the BORG Rating of Perceived Exertion (RPE) scale, modified for strength and aerobic activities. Associations between the MediDiet and PA were investigated using hierarchical linear regression and analysis of covariance. Result: 6236 participants [55‐77 years; mean (SD)=65.0 (5.8)] completed baseline assessments and were included. Mean (SD) MediCul score was 53.2 (13.0)/100), indicating low adherence to the MediDiet. Only 5% of participants achieved a score consistent with better cognitive outcomes in The PREDIMED study. Almost one‐half of participants (48.4%) met aerobic PA (150 min/week) but less than one‐quarter (24.2%) met resistance training (RT) recommendations (2 days/week). Unadjusted MediCul score explained a small but significant amount of the variance for light (1.0%) and moderate‐vigorous (MV) (3.1%) PA, both p<0.001. For light PA, the final model, including MediCul, age, sex, BMI, CAGE (alcohol use) score and diabetes explained 2.8% of the variance. For MV PA, the final model including MediCul, age, sex, BMI, CAGE, depression, diabetes and education explained 10.9% of the variance. A 10‐point higher MediCul score was associated with an additional 3.3 seconds of light PA/wk and additional 7.5 seconds of MV aerobic PA/wk (both p<0.001). Additionally, MediCul score was significantly higher in participants engaging in 2+days/wk of RT compared to 1 or fewer days/wk (56.6/100 vs. 52.2/100, respectively; p<0.001). Conclusion: Both aerobic and RT PA are significantly but weakly associated with better diet, but the clinical meaningfulness, as well as any causal nature, of these relationships requires further exploration. The outcomes of the MYB trial will contribute substantively to this question. [ABSTRACT FROM AUTHOR]

Background: The Mediterranean‐style diet (MD) is promoted as one of the healthiest dietary patterns and has been shown to reduce cognitive decline in some randomised controlled trials (RCTs). This pattern is plant‐based with a focus on vegetables, legumes, fish, and olive oil, with low intake of red meats and foods high in sugar and saturated fats. The Maintain Your Brain (MYB) study is an online multi‐domain RCT targeting modifiable risk factors for dementia, including diet. This study investigated cross‐sectional associations between adherence to a MD pattern and cognition. Methods: Participants enrolled in MYB were recruited from the Sax Institute's larger 45 and Up Study, and included those with all baseline MYB assessments (n=6236). Diet was assessed using the validated Mediterranean Diet and Culinary Index tool. This 50‐item tool assesses intake of nine desirable and four undesirable features of the MD diet and allows derivation of the Mediterranean Diet Adherence Screener (MEDAS). Computerised cognitive tests, administered through the MYB digital platform, were used to assess domains of executive function, complex attention, learning and memory and global cognition. Results: Participants were 46% male, with mean (SD) age 65.0 (5.8) years, BMI 26.6 (4.9) kg/m2 and well educated (46% with tertiary education). Higher MEDAS scores were associated with being female, younger, better educated and having a lower BMI (all p<0.001). Overall participant adherence to a MD pattern was low; MEDAS score 6.1 (2.1)/14. After covariate adjustment and correction for multiple analyses in hierarchical linear regression models, better MEDAS scores were significantly associated with worse (lower) z‐scores for executive function (β ‐0.018, p=0.003). For every 1‐point higher MEDAS score, executive function z‐scores were 0.018 lower. This unexpected negative association was clinically very small. There were no significant associations with other cognitive domains. Conclusion: Adherence to a MD was sub‐optimal in this well‐educated Australian sample. The one unexpected finding is likely not clinically meaningful given its size. Additionally, as this was a cross‐sectional study, reverse causality cannot be ruled out. Results from the main MYB RCT will provide data on MD acceptance and impact in a Western dietary environment. [ABSTRACT FROM AUTHOR]

The development of sensitive and specific diagnostic tools for hepatitis B virus (HBV) and hepatitis C virus (HCV) remains crucial for effective disease management and control. In this study, we utilized CRISPR‐Cas12 and CRISPR‐Cas13 systems for the detection of HBV (DNA virus) and HCV (RNA virus), respectively. We designed and tested multiple guide RNAs (gRNAs) targeting both viruses, confirming successful cleavage of target sequences through gel electrophoresis and a fluorescent reporter assay. Using optimized gRNAs, we developed a lateral flow assay (LFA) for sensitive detection of HBV and HCV, demonstrating a concentration‐dependent signal increase. Importantly, no cross‐reactivity was observed with other viral targets. To further enhance sensitivity, we employed a dual‐enzyme approach, combining Cas12 and Cas13 in a single reaction, which significantly improved detection limits for both viruses. Finally, we developed a dual antigen detection LFA strip capable of simultaneously detecting both HBV and HCV in a single sample. This approach holds promise for point‐of‐care (POC) diagnostics where the specific viral infection is unknown. This study addresses the current limitations in CRISPR‐Cas based diagnostics, namely, the need for ultrasensitive detection methods and the ability to detect multiple antigens using a single test strip. Our findings demonstrate the feasibility of using CRISPR‐Cas systems for highly sensitive and specific detection of HBV and HCV, paving the way for potential POC application. [ABSTRACT FROM AUTHOR]

Codon‐based analyses of the PPARGC1A gene across 38 vertebrate species were deployed to elucidate patterns of evolutionary change. Employing maximum likelihood assessments through MEGA, we scrutinized 447 codon positions addressing the entire coding region, excluding positions mired by gaps or missing data. Distinct codons manifested variance in selection pressures, particularly codons 4, 11, 66, and 123, which exhibited positive dN‐dS values suggestive of positive selection. Codon 137 displayed the most pronounced dN‐dS value, signifying intensified selective advantage. Meanwhile, codons 30 and 90 portrayed near‐neutral scores, indicative of purifying selection. Complementary computational methods (IFEL, REL, FUBAR, and SLAC) confirmed positive selection at specific codon sites, with varying degrees of corroboration. The integration of mixed‐effect modeling (MEME) identified episodic diversifying selection, pinpointing codons that underwent selection episodes in certain lineages. Refined codon model selection lent insight into substitution rates, revealing nuanced degrees of evolutionary conservation among different codons. Supporting these genetic insights, the phylogenetic analysis highlighted relationships among the PPARGC1A sequences and domain analysis confirmed conserved features across species, while protein–protein interaction networks suggested a complex web of functional interdependencies. These findings advance our understanding of the PPARGC1A gene's evolutionary trajectory and underscore the gene's potential adaptive significance within diverse vertebrate lineages. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) has rapidly escalated into a global pandemic that primarily affects older and immunocompromised individuals due to underlying clinical conditions and suppressed immune responses. Furthermore, COVID‐19 patients exhibit a spectrum of neurological symptoms, indicating that COVID‐19 can affect the brain in a variety of manners. Many studies, past and recent, suggest a connection between viral infections and an increased risk of neurodegeneration, raising concerns about the neurological effects of COVID‐19 and the possibility that it may contribute to Alzheimer's disease (AD) onset or worsen already existing AD pathology through inflammatory processes given that both COVID‐19 and AD share pathological features and risk factors. This leads us to question whether COVID‐19 is a risk factor for AD and how these two conditions might influence each other. Considering the extensive reach of the COVID‐19 pandemic and the devastating impact of the ongoing AD pandemic, their combined effects could have significant public health consequences worldwide. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the concentrations of neutrophil extracellular traps (NET) and salivary cytokines (IL‐1β, IL‐6, IL‐8/CXCL8, TNF, and TGF‐β1) in patients undergoing chemotherapy and their associations with oral mucositis (OM) and Candida infection. Materials and Methods: This prospective longitudinal study performed at a Brazilian service included 60 adults diagnosed with hematolymphoid diseases. Saliva samples were collected on days D0, D3, D10, and D15. Cytokines were analyzed by ELISA and NET formation by identification of the myeloperoxidase‐DNA complex. Oral Candida spp. was cultured. Results: OM occurred in 43.3% of patients and oral candidiasis in 20%. However, 66% of individuals had positive cultures for C. albicans. Higher concentrations of IL‐6, IL‐8/CXCL8, and TNF and lower concentrations of TGF‐β1 were observed in patients with OM. C. albicans infection contributed to the increase in IL‐8/CXCL8, TGF‐β1, and TNF. Individuals with OM or with oral candidiasis had significant reductions in NET formation. In contrast, individuals with C. albicans and with concomitant C. albicans and OM exhibited higher NET formation. Conclusion: The kinetics of cytokine levels and NET formation in chemotherapy‐induced OM appears to be altered by Candida infection, even in the absence of clinical signs of oral candidiasis. [ABSTRACT FROM AUTHOR]

The question of how local adaptation takes place remains a fundamental question in evolutionary biology. The variation of allele frequencies in genes under selection over environmental gradients remains mainly theoretical and its empirical assessment would help understanding how adaptation happens over environmental clines. To bring new insights to this issue we set up a broad framework which aimed to compare the adaptive trajectories over environmental clines in two domesticated mammal species co‐distributed in diversified landscapes. We sequenced the genomes of 160 sheep and 161 goats extensively managed along environmental gradients, including temperature, rainfall, seasonality and altitude, to identify genes and biological processes shaping local adaptation. Allele frequencies at putatively adaptive loci were rarely found to vary gradually along environmental gradients, but rather displayed a discontinuous shift at the extremities of environmental clines. Of the 430 candidate adaptive genes identified, only 6 were orthologous between sheep and goats and those responded differently to environmental pressures, suggesting different putative mechanisms involved in local adaptation in these two closely related species. Interestingly, the genomes of the 2 species were impacted differently by the environment, genes related to signatures of selection were most related to altitude, slope and rainfall seasonality for sheep, and summer temperature and spring rainfall for goats. The diversity of candidate adaptive pathways may result from a high number of biological functions involved in the adaptations to multiple eco‐climatic gradients, and a differential role of climatic drivers on the two species, despite their co‐distribution along the same environmental gradients. This study describes empirical examples of clinal variation in putatively adaptive alleles with different patterns in allele frequency distributions over continuous environmental gradients, thus showing the diversity of genetic responses in adaptive landscapes and opening new horizons for understanding genomics of adaptation in mammalian species and beyond. [ABSTRACT FROM AUTHOR]

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BACKGROUND: The widespread use of chemical herbicides and the growing issue of weed resistance pose significant challenges in agriculture. To address these problems, there is a pressing need to develop biological herbicides based on bacterial metabolites. RESULTS: In this study, we investigated the impact of the cell‐free culture filtrate (CFCF) from the ZT isolate, a bacilliform bacterium obtained from diseased wheat seeds, on the germination and seedling growth of various plant species, including wild oat, ryegrass, redroot, wheat, and chickpea. The results revealed that CFCF had a detrimental effect on the fresh and dry weight of stems and roots in most of the studied plants, except chickpeas. The CFCF was further subjected to separation into aqueous and organic phases using chloroform, followed by the division of the aqueous phase into 13 fractions using an alumina column. Notably, both the aqueous phase (20%) and all 13 fractions (ranging from 50% to 83%) displayed the ability to reduce the root length of ryegrass, a monocotyledonous weed. Liquid chromatography–mass spectrometry (LC–MS) analysis identified that fractions 3 and 7, which were effective against ryegrass but not redroot, contained Cry family proteins, including Cry10 Aa, Cry4 Ba, and Cry4 Aa. Additionally, 16s rRNA gene sequencing revealed that the ZT isolate is closely related (98.27%) to Bacillus wiedmannii. CONCLUSION: Conclusively, metabolites from the ZT bacterium hold promise for monocotyledonous weed‐targeted herbicides, providing a constructive strategy to confront agricultural issues tied to chemical herbicides and weed resistance. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Whole genome sequencing (WGS) plays an important role in the advanced characterization of pathogen transmission and is widely used in studies of major bacterial and viral diseases. Although protozoan parasites cause serious diseases in humans and animals, WGS data on them are relatively scarce due to the large genomes and lack of cultivation techniques for some. In this review, we have illustrated bioinformatic analyses of WGS data and their applications in studies of the genomic epidemiology of apicomplexan parasites. WGS has been used in outbreak detection and investigation, studies of pathogen transmission and evolution, and drug resistance surveillance and tracking. However, comparative analysis of parasite WGS data is still in its infancy, and available WGS data are mainly from a few genera of major public health importance, such as Plasmodium, Toxoplasma, and Cryptosporidium. In addition, the utility of third‐generation sequencing technology for complete genome assembly at the chromosome level, studies of the biological significance of structural genomic variation, and molecular surveillance of pathogens has not been fully exploited. These issues require large‐scale WGS of various protozoan parasites of public health and veterinary importance using both second‐ and third‐generation sequencing technologies. [ABSTRACT FROM AUTHOR]

As an invaluable Chinese sheep germplasm resource, Hu sheep are renowned for their high fertility and beautiful wavy lambskins. Their distinctive characteristics have evolved over time through a combination of artificial and natural selection. Identifying selection signatures in Hu sheep can provide a straightforward insight into the mechanism of selection and further uncover the candidate genes associated with breed‐specific traits subject to selection. Here, we conducted whole‐genome resequencing on 206 Hu sheep individuals, each with an approximate 6‐fold depth of coverage. And then we employed three complementary approaches, including composite likelihood ratio, integrated haplotype homozygosity score and the detection of runs of homozygosity, to detect selection signatures. In total, 10 candidate genomic regions displaying selection signatures were simultaneously identified by multiple methods, spanning 88.54 Mb. After annotating, these genomic regions harbored collectively 92 unique genes. Interestingly, 32 candidate genes associated with reproduction were distributed in nine genomic regions detected. Out of them, two stood out as star candidates: BMPR1B and GNRH2, both of which have documented associations with fertility, and a HOXA gene cluster (HOXA1‐5, HOXA9, HOXA10, HOXA11 and HOXA13) had also been linked to fertility. Additionally, we identified other genes that are related to hair follicle development (LAMTOR3, EEF1A2), ear size (HOXA1, KCNQ2), fat tail formation (HOXA10, HOXA11), growth and development (FAF1, CCNDBP1, GJB2, GJA3), fat deposition (ACOXL, JAZF1, HOXA3, HOXA4, HOXA5, EBF4), immune (UBR1, FASTKD5) and feed intake (DAPP1, RNF17, NPBWR2). Our results offer novel insights into the genetic mechanisms underlying the selection of breed‐specific traits in Hu sheep and provide a reference for sheep genetic improvement programs. [ABSTRACT FROM AUTHOR]

The recent high incidence of Mycoplasma pneumoniae (Mp) infections has raised widespread public health concerns. Therefore, rapid and accurate diagnosis of respiratory pathogenic microbial infections is of paramount importance to provide clinicians with accurate diagnostic insights and guide clinical medication. In response to this urgent need, we developed a one-tube Palm CRISPR/Cas12a Diagnostic (PaCD) method. This method facilitates the rapid detection of Mp infections, as well as three other prevalent respiratory pathogens, Chlamydia pneumoniae (Cp), Haemophilus influenzae (Hi), and Streptococcus pneumoniae (SP). In addition, 3D printing was employed to fabricate a compact detection device that includes a temperature control module set at 39°C and a blue light irradiation module, significantly enhancing the feasibility of point-of-care testing. The PaCD diagnostic process takes only 30 min with a detection limit of 50 copies/test, making it suitable for analysis of sputum and throat swab samples. PaCD demonstrated 100% concordance (72/72) with next-generation sequencing and exhibited high concordance with computed tomography test results. These findings demonstrate the clinical feasibility of PaCD for the rapid and accurate diagnosis of infections caused by four prevalent respiratory pathogens, offering theoretical insights into the versatile application of point-of-care tests for the detection of other respiratory pathogens in various clinical scenarios. [ABSTRACT FROM AUTHOR]

As a respiratory tract‐transmitted disease, coronavirus disease 2019 (COVID‐19) exerts a profound immune injury effect, leading not only to pulmonary impairment but also to cardiac complications. We present a case of a 79‐year‐old woman, who had previously contracted COVID‐19 and subsequently developed sinus arrest (SA) following her second infection. The longest asystole time detected by Holter monitoring was 7.2 seconds. Although the patient met criteria for permanent pacemaker implantation, her family declined this intervention and conservative management was pursued instead. However, after a period of observation, the patient's SA resolved. The present case study describes a patient who experienced SA upon reinfection with COVID‐19, which was not present during the initial infection. It emphasizes the impact of COVID‐19 on cardiac health, particularly its potential to induce arrhythmias. In addition, it is worth noting that the arrhythmia induced by a COVID‐19 infection may show reversibility, suggesting that a permanent pacemaker might not be the priority option if further pacing therapy is being considered. [ABSTRACT FROM AUTHOR]

The use of novel high‐throughput sequencing (HTS) technologies to examine the responses of natural multidomain microbial communities to scrubber effluent discharges to the marine environment is still limited. Thus, we applied metabarcoding sequencing targeting the planktonic unicellular eukaryotic and prokaryotic fraction (phytoplankton, bacterioplankton, and protozooplankton) in mesocosm experiments with natural microbial communities from a polluted and an unpolluted site. Furthermore, metagenomic analysis revealed changes in the taxonomic and functional dominance of multidomain marine microbial communities after scrubber effluent additions. The results indicated a clear shift in the microbial communities after such additions, which favored bacterial taxa with known oil and polycyclic aromatic hydrocarbons (PAHs) biodegradation capacities. These bacteria exhibited high connectedness with planktonic unicellular eukaryotes employing variable trophic strategies, suggesting that environmentally relevant bacteria can influence eukaryotic community structure. Furthermore, Clusters of Orthologous Genes associated with pathways of PAHs and monocyclic hydrocarbon degradation increased in numbers at treatments with high scrubber effluent additions acutely. These genes are known to express enzymes acting at various substrates including PAHs. These indications, in combination with the abrupt decrease in the most abundant PAHs in the scrubber effluent below the limit of detection—much faster than their known half‐lives—could point toward a bacterioplankton‐initiated rapid ultimate biodegradation of the most abundant toxic contaminants of the scrubber effluent. The implementation of HTS could be a valuable tool to develop multilevel biodiversity indicators of the scrubber effluent impacts on the marine environment, which could lead to improved impact assessment. Environ Toxicol Chem 2024;43:1012–1029. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Systematic evolution of ligands by exponential enrichment (SELEX) has been used to discover thousands of aptamers since its development in 1990. Aptamers are short single‐stranded oligonucleotides capable of binding to targets with high specificity and selectivity through structural recognition. While aptamers offer advantages over other molecular recognition elements such as their ease of production, smaller size, extended shelf‐life, and lower immunogenicity, they have yet to show significant success in real‐world applications. By analyzing the importance of structured library designs, reviewing different SELEX methodologies, and the effects of chemical modifications, we provide a comprehensive overview on the production of aptamers for applications in drug delivery systems, therapeutics, diagnostics, and molecular imaging. [ABSTRACT FROM AUTHOR]

Young children and adolescents in subsistence societies forage for a wide range of resources. They often target child‐specific foods, they can be very successful foragers, and they share their produce widely within and outside of their nuclear family. At the same time, while foraging, they face risky situations and are exposed to diseases that can influence their immune development. However, children's foraging has largely been explained in light of their future (adult) behavior. Here, we reinterpret findings from human behavioral ecology, evolutionary medicine and cultural evolution to center foraging children's contributions to life history evolution, community resilience and immune development. We highlight the need to foreground immediate alongside delayed benefits and costs of foraging, including inclusive fitness benefits, when discussing children's food production from an evolutionary perspective. We conclude by recommending that researchers carefully consider children's social and ecological context, develop cross‐cultural perspectives, and incorporate children's foraging into Indigenous sovereignty discourse. [ABSTRACT FROM AUTHOR]

Agricultural intensification at field and landscape scales, including increased use of agrochemicals and loss of semi‐natural habitats, is a major driver of insect declines and other community changes. Efforts to understand and mitigate these effects have traditionally focused on ecological responses. At the same time, adaptations to pesticide use and habitat fragmentation in both insects and flowering plants show the potential for rapid evolution. Yet we lack an understanding of how such evolutionary responses may propagate within and between trophic levels with ensuing consequences for conservation of species and ecological functions in agroecosystems. Here, we review the literature on the consequences of agricultural intensification on plant and animal evolutionary responses and interactions. We present a novel conceptualization of evolutionary change induced by agricultural intensification at field and landscape scales and emphasize direct and indirect effects of rapid evolution on ecosystem services. We exemplify by focusing on economically and ecologically important interactions between plants and pollinators. We showcase available eco‐evolutionary theory and plant–pollinator modelling that can improve predictions of how agricultural intensification affects interaction networks, and highlight available genetic and trait‐focused methodological approaches. Specifically, we focus on how spatial genetic structure affects the probability of propagated responses, and how the structure of interaction networks modulates effects of evolutionary change in individual species. Thereby, we highlight how combined trait‐based eco‐evolutionary modelling, functionally explicit quantitative genetics, and genomic analyses may shed light on conditions where evolutionary responses impact important ecosystem services. [ABSTRACT FROM AUTHOR]

The growth of shrimp production through aquaculture has led to efforts to optimize processes such as nutrition during the prematuration and reproductive phases. This study sought an optimal culture system and diet to enhance the reproductive characteristics of male Litopenaeus vannamei during prematuration: this compared biofloc with clear water, and an experimental pellet (EP) with a mix of fresh food. Effects were measured in terms of shrimp survival, sperm quality, immunological parameters including prophenoloxidase (ProPO) and hemocyte count, nutritional condition measured as metabolites in hemolymph, hepatopancreas, and reproductive tract, oxidative stress biomarkers in the hepatopancreas and reproductive tract, and relative expression of superoxide dismutase, catalase, glutathione peroxidase, ProPO, alpha2‐macroglobulin and caspase in reproductive tract. Survival was higher with pellets (100%) than with fresh food (87%). Shrimp that were fed pellets had a higher hepatosomatic index, higher nutrient concentration in the hepatopancreas, and a higher antioxidant activity in the reproductive tract. Notably, sperm quality remained similar regardless of culture system or diet. These promising results should be ratified with a bioeconomic study to check the feasibility of hatcheries to use monosex tanks and feeding the males with EPs. [ABSTRACT FROM AUTHOR]

Population genetic simulation has emerged as a common tool for investigating increasingly complex evolutionary and demographic models. Software capable of handling high‐level model complexity has recently been developed, and the advancement of tree sequence recording now allows simulations to merge the efficiency and genealogical insight of coalescent simulations with the flexibility of forward simulations. However, frameworks utilizing these features have not yet been compared and benchmarked. Here, we evaluate various simulation workflows using the coalescent simulator msprime and the forward simulator SLiM, to assess resource efficiency and determine an optimal simulation framework. Three aspects were evaluated: (1) the burn‐in, to establish an equilibrium level of neutral diversity in the population; (2) the forward simulation, in which temporally fluctuating selection is acting; and (3) the final computation of summary statistics. We provide typical memory and computation time requirements for each step. We find that the fastest framework, a combination of coalescent and forward simulation with tree sequence recording, increases simulation speed by over twenty times compared to classical forward simulations without tree sequence recording, although it does require six times more memory. Overall, using efficient simulation workflows can lead to a substantial improvement when modelling complex evolutionary scenarios—although the optimal framework ultimately depends on the available computational resources. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) often shows disrupted brain connectivity and autonomic dysfunctions, progressing alongside with motor and cognitive decline. Recently, PD has been linked to a reduced sensitivity to cardiac inputs, that is, cardiac interoception. Altogether, those signs suggest that PD causes an altered brain–heart connection whose mechanisms remain unclear. Our study aimed to explore the large‐scale network disruptions and the neurophysiology of disrupted interoceptive mechanisms in PD. We focused on examining the alterations in brain–heart coupling in PD and their potential connection to motor symptoms. We developed a proof‐of‐concept method to quantify relationships between the co‐fluctuations of brain connectivity and cardiac sympathetic and parasympathetic activities. We quantified the brain–heart couplings from electroencephalogram and electrocardiogram recordings from PD patients on and off dopaminergic medication, as well as in healthy individuals at rest. Our results show that the couplings of fluctuating alpha and gamma connectivity with cardiac sympathetic dynamics are reduced in PD patients, as compared to healthy individuals. Furthermore, we show that PD patients under dopamine medication recover part of the brain–heart coupling, in proportion with the reduced motor symptoms. Our proposal offers a promising approach to unveil the physiopathology of PD and promoting the development of new evaluation methods for the early stages of the disease. [ABSTRACT FROM AUTHOR]

Background. Natural medicinal products are commonly used as a remedy against malaria infections in African populations and have become a major source of information for the screening of new and more effective antiplasmodial molecules. Therefore, in vitro studies are needed to validate the efficacy of these medicinal products and to explore the potential effects of such drugs on the genetic diversity of Plasmodium falciparum. The current study has investigated the impact of some Beninese plant extracts with antiplasmodial activity on the genetic diversity of P. falciparum. Method. Five (5) ethanolic plant extracts (Dissotis rotundifolia, Ehretia cymosa Thonn, Hibiscus surattensis L., Cola millenii K. Shum, and Costus afer Ker Gawl) and a compound extracted from Ehretia cymosa Thonn (encoded CpE2) were tested against asexual stage parasites of a culture-adapted strain of P. falciparum. Subsequently, the P. falciparum Msp1 and Msp2 markers were genotyped, and the number of allelic variants and the multiplicity of infection (MOI) were compared between drug-exposed and unexposed parasites. Results. All plant extracts have shown inhibitory activity against asexual P. falciparum and selected new allelic variants of the Msp1 and Msp2 genes compared to unexposed parasites. The newly selected allelic variants were K1_100bp and RO33_300bp of the Msp1 gene and FC27_150bp, FC27_300bp, FC27_400bp, and FC27_600bp of the Msp2 gene. However, there was no significant difference in MOI between drug-exposed and unexposed parasites. Conclusion. Our study highlights a source for the selection of new Msp1 and Msp2 alleles after exposure to antimalarial drugs. These findings pave the way for further studies investigating the true roles of these newly selected alleles in P. falciparum. [ABSTRACT FROM AUTHOR]

Background: Although antioxidants are largely used in subfertile men with oligo‐astheno‐teratozoospermia (OAT), the choice among different molecules is challenged by the lack of comparative head‐to‐head studies. The network meta‐analysis (NMA) can overcome limitations of pairwise meta‐analyses, since it incorporates direct and indirect evidence into a single model generating an effectiveness hierarchy. Objective: To assess with a NMA the effects of antioxidants in improving seminal parameters in idiopathic OAT. Materials and methods: PubMed, Scopus, Cinahl, and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing any antioxidant treatment to each other or placebo in men with at least one idiopathic seminal abnormality. Data were included in a random‐effects NMA, where efficacy of treatments was ranked by surface under the cumulative ranking curve (SUCRA). Results: 29 RCTs provided information on 2045 men (mean age: 33.5 years) with idiopathic OAT and 19 antioxidant preparations. Compared to placebo, l‐carnitine, especially in combination with l‐acetyl‐carnitine (LAC), had the highest SUCRA for sperm concentration, progressive motility, and morphology. Folate was the only other compound effective on sperm concentration. Vitamin E+selenium or zinc had the highest SUCRA for total motility. A contribution on progressive motility was revealed for pentoxifylline and vitamin E+CoQ10. [ABSTRACT FROM AUTHOR]

Pathogen genomic epidemiology has the potential to provide a deep understanding of population dynamics, facilitating strategic planning of interventions, monitoring their impact, and enabling timely responses, and thereby supporting control and elimination efforts of parasitic tropical diseases. Plasmodium vivax, responsible for most malaria cases outside Africa, shows high genetic diversity at the population level, driven by factors like sub‐patent infections, a hidden reservoir of hypnozoites, and early transmission to mosquitoes. While Latin America has made significant progress in controlling Plasmodium falciparum, it faces challenges with residual P. vivax. To characterize genetic diversity and population structure and dynamics, we have analyzed the largest collection of P. vivax genomes to date, including 1474 high‐quality genomes from 31 countries across Asia, Africa, Oceania, and America. While P. vivax shows high genetic diversity globally, Latin American isolates form a distinctive population, which is further divided into sub‐populations and occasional clonal pockets. Genetic diversity within the continent was associated with the intensity of transmission. Population differentiation exists between Central America and the North Coast of South America, vs. the Amazon Basin, with significant gene flow within the Amazon Basin, but limited connectivity between the Northwest Coast and the Amazon Basin. Shared genomic regions in these parasite populations indicate adaptive evolution, particularly in genes related to DNA replication, RNA processing, invasion, and motility – crucial for the parasite's survival in diverse environments. Understanding these population‐level adaptations is crucial for effective control efforts, offering insights into potential mechanisms behind drug resistance, immune evasion, and transmission dynamics. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer is one of the most common cancer types in males and rs12621278:A > G has been suggested to be associated with this disease by previous genome‐wide association studies. One thousand genomes project data analysis indicated that rs12621278:A > G is within two long‐core haplotypes. However, the origin, causal variant(s), and molecular function of these haplotypes were remaining unclear. Materials and Methods: Population genetics analysis and functional genomics work was performed for this locus. Results: Phylogeny analysis verified that the rare haplotype is derived from Neanderthal introgression. Genome annotation suggested that three genetic variants in the core haplotypes, rs116108611:G > A, rs139972066:AAAAAAAA > AAAAAAAAA, and rs3835124:ATTTATT > ATT, are located in functional regions. Luciferase assay indicated that rs139972066:AAAAAAAA > AAAAAAAAA and rs116108611:G > A are not able to alter ITGA6 (integrin alpha 6) and ITGA6 antisense RNA 1 expression, respectively. In contrast, rs3835124:ATTTATT > ATT can significantly influence PDK1 (pyruvate dehydrogenase kinase 1) expression, which was verified by expression quantitative trait locus analysis. This genetic variant can alter transcription factor cut like homeobox 1 interaction efficiency. The introgressed haplotype was observed to be subject to positive selection in East Asian populations. The molecular function of the haplotype suggested that Neanderthal should be with lower PDK1 expression and further different energy homeostasis from modern human. Conclusion: This study provided new insight into the contribution of Neanderthal introgression to human phenotypes. [ABSTRACT FROM AUTHOR]

Snowmelt floods are highly hazardous meteorological disasters that can potentially threaten human lives and property. Hence, snowmelt susceptibility mapping (SSM) plays an important role in flood prevention systems and aids emergency responders and flood risk managers. In this paper, a method of identifying snowmelt flood hazards is proposed, and a large‐scale snowmelt flood hazard zonation scheme based on historical recordings and multisource remote sensing data is established. To assess the quality of our approach, the proposed model was tested in the cold and arid region of Xinjiang, China. Overall, 140 historical snowmelt flood events and 27 explanatory factors were selected to construct a geospatial dataset for SSM of the contemporary period. GridSearchCV was used to comprehensively search the candidate parameters from the grid of given parameters obtained with the random forest (RF) algorithm. Then, the geospatial dataset was divided into two subsets: 70% for training and 30% for testing. Next, SSM results were obtained with the RF algorithm using optimized parameters. The results indicate that our optimized RF classifier performs well for the task of SSM, with a high AUC value (0.975) for the test dataset. The validation and analysis suggest that the proposed method can efficiently identify snowmelt flood hazards in undersampled arid areas at a regional scale. [ABSTRACT FROM AUTHOR]

3′ untranslated regions (3′ UTRs) of mRNAs have many functions, including mRNA processing and transport, translational regulation, and mRNA degradation and stability. These different functions require cis‐elements in 3′ UTRs that can be either sequence motifs or RNA structures. Here we review the role of secondary structures in the functioning of 3′ UTRs and discuss some of the trans‐acting factors that interact with these secondary structures in eukaryotic organisms. We propose potential participation of 3′‐UTR secondary structures in cytoplasmic polyadenylation in the model organism Drosophila melanogaster. Because the secondary structures of 3′ UTRs are essential for post‐transcriptional regulation of gene expression, their disruption leads to a wide range of disorders, including cancer and cardiovascular diseases. Trans‐acting factors, such as STAU1 and nucleolin, which interact with 3′‐UTR secondary structures of target transcripts, influence the pathogenesis of neurodegenerative diseases and tumor metastasis, suggesting that they are possible therapeutic targets. [ABSTRACT FROM AUTHOR]

Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19). It is estimated that more than half of new infections are transmitted by asymptomatic people; therefore, the isolation of symptomatic people is not enough to control the spread of the disease. Methods. A total of 171 unvaccinated young adults (18–35 years) from Sonora, Mexico, who underwent a structured survey to identify prior COVID-19 infections, were included in this study. A qualitative determination of anti-SARS-CoV-2 antibodies in serum was performed by lateral flow immunoassay (Certum IgG/IgM Rapid Test™ cassette kit) and neutralizing antibodies were also determined (GenScript cPass assay). Results. A total of 36 people reported a history of COVID-19 infection, and 135 reported no history of COVID-19. In contrast, 49.6% (67/135) of individuals who had not reported a previous SARS-CoV-2 infection were seropositive to the rapid anti-SARS-CoV-2 antibody test, and 48.1% (65/135) of them had neutralizing antibodies. Conclusions. These results suggest that in young adults, SARS-CoV-2 infections could be asymptomatic in a high percentage of individuals, which could contribute in part to the slow control of the current pandemic due to the large number of asymptomatic cases that are contagious and that could be a silent spread of the virus. [ABSTRACT FROM AUTHOR]

Antagonistic selection between pathogens and their hosts can drive rapid evolutionary change and leave distinct molecular footprints of past and ongoing selection in the genomes of the interacting species. Despite an increasing availability of tools able to identify signatures of selection, the genetic mechanisms underlying coevolutionary interactions and the specific genes involved are still poorly understood, especially in heterogeneous natural environments. We searched the genomes of two species of Epichloe plant pathogen for evidence of recent selection. The Epichloe genus includes highly host‐specific species that can sterilize their grass hosts. We performed selection scans using genome‐wide SNP data from seven natural populations of two co‐occurring Epichloe sibling species specialized on different hosts. We found evidence of recent (and ongoing) selective sweeps across the genome in both species. However, selective sweeps were more abundant in the species with a larger effective population size. Sweep regions often overlapped with highly polymorphic AT‐rich regions supporting the role of these genome compartments in adaptive evolution. Although most loci under selection were specific to individual populations, we could also identify several candidate genes targeted by selection in sweep regions shared among populations. The genes encoded small secreted proteins typical of fungal effectors and cell wall‐degrading enzymes. By investigating the genomic signatures of selection across multiple populations and species, this study contributes to our understanding of complex adaptive processes in natural plant pathogen systems. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is an autosomal dominant disease with an estimated prevalence of 1 in 200-250 individuals. Patients with FH are at increased risk of premature coronary artery disease. Early diagnosis and treatment are essential for improving clinical outcomes. In many cases, however, the genetic diagnosis is not confirmed. At present, routine genetic testing does not analyze the 3 ′ UTR regions of LDLR and PCSK9. However, 3 ′ UTR-single nucleotide variants could be of interest because they can modify the target sequence of miRNAs that regulate the expression of these genes. Our study fully characterizes the 3 ′ UTR regions of LDLR and PCSK9 in 409 patients with a suspected diagnosis of FH using next-generation sequencing. In 30 of the 409 patients, we found 21 variants with an allelic frequency of <1%; 14 of them at 3 ′ UTR-LDLR and 8 at 3 ′ UTR-PCSK9. The variants' pathogenicity was studied in silico; subsequently, a number of the variants were functionally validated using luciferase reporter assays. LDLR: c. ∗ 653 G > C showed a 41% decrease in luciferase expression, while PCSK9: c. ∗ 950 C > T showed a 41% increase in PCSK9 expression, results that could explain the hypercholesterolemia phenotype. In summary, the genetic analysis of the 3 ′ UTR regions of LDLR and PCSK9 could improve the genetic diagnosis of FH. [ABSTRACT FROM AUTHOR]

Porcine reproductive and respiratory syndrome (PRRS) is a significant pig disease causing substantial annual losses exceeding half a billion dollars to the United States pork industry. The cocirculation and emergence of genetically distinct PRRSV-2 viruses hinder PRRS control, especially vaccine development. Similar to other viral infections like seasonal flu and SARS-CoV-2, predictive tools for identifying potential emerging viral variants may prospectively aid in preemptive disease mitigation. However, such predictions have not been made for PRRSV-2, despite the abundance of relevant data. In this study, we analyzed a decade's worth of virus ORF5 sequences (n = 20,700) and corresponding metadata to identify phylogenetic-based early indicators for short-term (12 months) and long-term (24 months) variant emergence. Our analysis focuses on PRRSV-2 Lineage 1, which was the predominant lineage within the U.S. during this period. We evaluated population expansion, spatial distribution, and genetic diversity as key success metrics for variant emergence. Our findings indicate that successful variants were best characterized as those that underwent population expansion alongside widespread geographical spread but had limited genetic diversification. Conditional logistic regression revealed the local branching index as the sole informative indicator for predicting population expansion (balanced accuracy (BA) = 0.75), while ancestral branch length was strongly linked to future genetic diversity (BA = 0.79). Predicting spatial dispersion relied on the branch length and putative antigenic difference (BA = 0.67), but their causal relationships remain unclear. Although the predictive models effectively captured most emerging variants (sensitivity = 0.58–0.81), they exhibited relatively low positive predictive value (PPV = 0.09–0.16). This initial step in PRRSV-2 prediction is a crucial step for more precise prevention strategies against PRRS in the future. [ABSTRACT FROM AUTHOR]

Cancer is the second most common cause of death globally and is a major public health concern. Managing this disease is difficult due to its multiple stages and numerous genetic and epigenetic changes. Traditional cancer diagnosis and treatment methods have limitations, making it crucial to develop new modalities to combat the increasing burden of cancer. The clustered regularly interspaced short palindromic repeats (CRISPR)‐CRISPR‐associated protein 9 (Cas9) system has transformed genetic engineering due to its simplicity, specificity, low cytotoxicity, and cost‐effectiveness. It has been proposed as an effective technology to enhance cancer diagnosis and treatment strategies. This article presents the most recent discoveries regarding the structure, mechanism, and delivery methods of the highly powerful genome editing tool, CRISPR‐Cas9. In terms of diagnosis, the article examines the role of CRISPR‐Cas9 in detecting microRNAs and DNA methylation, and discusses two popular gene detection techniques that utilize the CRISPR‐Cas system: DNA endonuclease‐targeted CRISPR trans reporter and specific high sensitivity enzymatic reporter unlocking. Regarding treatment, the article explores several genes that have been identified and modified by CRISPR‐Cas9 for effective tumorigenesis of common cancers such as breast, lung, and colorectal cancer. The present review also addresses the challenges and ethical issues associated with using CRISPR‐Cas9 as a diagnostic and therapeutic tool. Despite some limitations, CRISPR‐Cas9‐based cancer diagnosis has the potential to become the next generation of cancer diagnostic tools, and the continuous progress of CRISPR‐Cas9 can greatly aid in cancer treatment. [ABSTRACT FROM AUTHOR]

The accessibility to CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR‐associated protein) genetic tools has given rise to applications beyond site‐directed genome editing for the detection of DNA and RNA. These tools include precise diagnostic detection of human disease pathogens, such as SARS‐CoV‐2 and Zika virus. Despite the technology being rapid and cost‐effective, the use of CRISPR/Cas tools in the surveillance of the causative agents of wildlife diseases has not been prominent. This study presents the development of a minimally invasive, field‐applicable and user‐friendly CRISPR/Cas‐based biosensor for the detection of Pseudogymnoascus destructans (Pd), the causative fungal agent of white‐nose syndrome (WNS), an infectious disease that has killed more than five million bats in North America since its discovery in 2006. The biosensor assay combines a recombinase polymerase amplification (RPA) step followed by CRISPR/Cas12a nuclease cleavage to detect Pd DNA from bat dermal swab and guano samples. The biosensor had similar detection results when compared to quantitative PCR in distinguishing Pd‐positive versus negative field samples. Although bat dermal swabs could be analysed with the biosensor without nucleic acid extraction, DNA extraction was needed when screening guano samples to overcome inhibitors. This assay can be applied to help with more rapid delineation of Pd‐positive sites in the field to inform management decisions. With further optimization, this technology has broad translation potential to wildlife disease‐associated pathogen detection and monitoring applications. [ABSTRACT FROM AUTHOR]

Objective. The reproductive system can be adversely affected by anemia, characterized by elevated free radical production and lipid peroxidation. Conversely, the pistachio is well-known for its antioxidant capabilities. In this study, a mouse model was employed to investigate the safeguarding effects of the aqueous extract of pistachio (Pistacia vera) against oxidative stress induced by phenylhydrazine (PHZ)-triggered hemolytic anemia. Materials and methods. Forty-eight male mice were distributed into six distinct experimental groups (n = 8): control, PHZ, PHZ + 20Pis, PHZ + 80Pis, PHZ + 160Pis, and 80Pis groups. The experimental groups were administered a PHZ dose of 80 mg/kg/48 hr, along with pistachio doses of 20, 80, and 160 mg/kg/day, delivered intraperitoneally. After a period of 35 days, an assessment of sperm count, motility, morphology, and viability was conducted. Additionally, sperm chromatin quality was evaluated through Chromomycin A3, aniline blue, and toluidine blue staining. Hematoxylin–eosin staining was performed to examine the total diameter of seminiferous tubes and spermatogenic cells. Hormonal levels (FSH, LH, T) and antioxidant levels were analyzed using standard kits. Results. The PHZ groups exhibited a noteworthy decrease in various sperm parameters, as well as diminished chromatin quality assays and reduced levels of sex hormones when compared to the control group. Moreover, the morphometric evaluation indicated a substantial reduction in spermatogonia cell number, spermatid count, tubule count, seminiferous diameters, and seminiferous area in the PHZ group. Notably, the Pis group demonstrated the highest concentration of antioxidant contents. Conclusion. The protective impact of P. vera extract against PHZ-induced anemia on the male reproductive system in mice may be attributed to its abundant antioxidant components, which possess therapeutic properties at elevated levels. [ABSTRACT FROM AUTHOR]

Celtic‐Iberian pig breeds were majority in Spain and Portugal until the first half of the 20th century. In the 1990s, they were nearly extinct as a result of the introduction of foreign improved pig breeds. Despite its historical importance, the genetic background of the Celtic‐Iberian pig strain is poorly documented. In this study, we have identified genomic regions that might contain signatures of selection peculiar of the Celtic‐Iberian genetic lineage. A total of 153 DNA samples of Celtic‐Iberian pigs (Spanish Gochu Asturcelta and Portuguese Bísara breeds), Iberian pigs (Spanish Iberian and Portuguese Alentejano breeds), Cinta Senese pig, Korean local pig and Cosmopolitan pig (Hampshire, Landrace and Large White individuals) were analysed. A pairwise‐comparison approach was applied: the Gochu Asturcelta and the Bísara samples as test populations and the five other pig populations as reference populations. Three different statistics (XP‐EHH, FST and ΔDAF) were computed on each comparison. Strict criteria were used to identify selection sweeps in order to reduce the noise brought on by the Gochu Asturcelta and Bísara breeds' severe population bottlenecks. Within test population, SNPs used to construct potential candidate genomic areas under selection were only considered if they were identified in four of ten two‐by‐two pairwise comparisons and in at least two of three statistics. Genomic regions under selection constructed within test population were subsequently overlapped to construct candidate regions under selection putatively unique to the Celtic‐Iberian pig strain. These genomic regions were finally used for enrichment analyses. A total of 39 candidate regions, mainly located on SSC5 and SSC9 and covering 3130.5 kb, were identified and could be considered representative of the ancient genomic background of the Celtic‐Iberian strain. Enrichment analysis allowed to identify a total of seven candidate genes (NOL12, LGALS1, PDXP, SH3BP1, GGA1, WIF1, and LYPD6). Other studies reported that the WIF1 gene is associated with ear size, one of the characteristic traits of the Celtic‐Iberian pig strain. The function of the other candidate genes could be related to reproduction, adaptation and immunity traits, indirectly fitting with the rusticity of a non‐improved pig strain traditionally exploited under semi‐extensive conditions. [ABSTRACT FROM AUTHOR]

Background: Increased oxidative stress (OS), resulting from the delicate balance between reactive oxygen species (ROS) production and antioxidant defense, is closely linked to sperm abnormalities and male subfertility. Elevated ROS levels particularly affect sperm quality. The vulnerability of spermatozoa to ROS is due to the absence of DNA repair mechanisms and the high presence of polyunsaturated fatty acids in their membranes. Methods: This article updates and advances our understanding of the molecular damage caused by OS in spermatozoa, including lipid peroxidation, DNA damage, motility, and functionality. Additionally, the review discusses the challenges in diagnosing OS in semen and recommends accurate and sensitive testing methods. Case studies are utilized to demonstrate the effective management of male infertility caused by OS. Main findings: Highlighting the need to bridge the gap between research and clinical practice, this review suggests strategies for clinicians, such as lifestyle and dietary changes and antioxidant therapies. The review emphasizes lifestyle modifications and personalized care as effective strategies in managing male infertility caused by OS. Conclusion: This review calls for early detection and intervention and interdisciplinary collaboration to improve patient care in male infertility cases related to increased OS. [ABSTRACT FROM AUTHOR]

Rapid identification of organisms is essential for many biological and medical disciplines, from understanding basic ecosystem processes, disease diagnosis, to the detection of invasive pests. CRISPR‐based diagnostics offers a novel and rapid alternative to other identification methods and can revolutionize our ability to detect organisms with high accuracy. Here we describe a CRISPR‐based diagnostic developed with the universal cytochrome‐oxidase 1 gene (CO1). The CO1 gene is the most sequenced gene among Animalia, and therefore our approach can be adopted to detect nearly any animal. We tested the approach on three difficult‐to‐identify moth species (Keiferia lycopersicella, Phthorimaea absoluta and Scrobipalpa atriplicella) that are major invasive pests globally. We designed an assay that combines recombinase polymerase amplification (RPA) with CRISPR for signal generation. Our approach has a much higher sensitivity than real‐time PCR assays and achieved 100% accuracy for identification of all three species, with a detection limit of up to 120 fM for P. absoluta and 400 fM for the other two species. Our approach does not require a sophisticated laboratory, reduces the risk of cross‐contamination, and can be completed in less than 1 h. This work serves as a proof of concept that has the potential to revolutionize animal detection and monitoring. [ABSTRACT FROM AUTHOR]

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The aim of this study was to compare nonrandom associations between physically adjacent single methylation polymorphism loci among rheumatoid arthritis (RA) and normal subjects for investigating RA‐risk methylation haplotypes (meplotype). With 354 ACPA‐positive RA patients and 335 normal controls selected from a case–control study based on Swedish population, we conducted the first RA epigenome‐wide meplotype association study using our software EWAS2.0, mainly including (i) converted the β value to methylation genotype (menotype) data, (ii) identified methylation disequilibrium (MD) block, (iii) calculated frequent of each meplotypes in MD block and performed case–control association test and (iv) screened for RA‐risk meplotypes by odd ratio (OR) and p‐values. Ultimately, 545 meplotypes on 334 MD blocks were identified significantly associated with RA (p‐value <.05). These meplotypes were mapped to 329 candidate genes related to RA. Subsequently, combined with gene optimization, eight RA‐risk meplotypes were identified on three risk genes: HLA‐DRB1, HLA‐DRB5 and HLA‐DQB1. Our results reported the relationship between DNA methylation pattern on HLA‐DQB1 and the risk of RA for the first time, demonstrating the co‐demethylation of 'cg22984282' and 'cg13423887' on HLA‐DQB1 gene (meplotype UU, p‐value = 2.90E − 6, OR = 1.68, 95% CI = [1.35, 2.10]) may increase the risk of RA. Our results demonstrates the potential of methylation haplotype analysis to identify RA‐related genes from a new perspective and its applicability to the study of other disease. [ABSTRACT FROM AUTHOR]