Genetic Groups Research Articles

HMX3 is a critical vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia.

KMT2A::MLLT3 acute myelomonocytic leukemia (AML) comes in two clinically and biologically different subtypes. One is characterized by inferior outcome, older age, and MECOM oncogene expression. The other is mainly observed in children and young adults, associates with better clinical outcome, but lacks MECOM. To identify cell fate determining transcription factors downstream of KMT2A::MLLT3, we applied a bioinformatic algorithm that integrates gene and enhancer expression from primary MECOM-positive and -negative KMT2A::MLLT3 AML samples. This identified MECOM to be most influential in the MECOM-positive group, while neuronal transcription factor HMX3 was most influential in the MECOM-negative group. In large AML cohorts, HMX3 expression associated with a unique gene expression profile, younger age (p < 0.002) and KMT2A-rearranged and KAT6A-CREBBP leukemia (p < 0.00001). HMX3 was not expressed in other major genetic risk groups and healthy blood cells. RNA-sequencing analyses following forced HMX3 expression in healthy CD34+ cells and its silencing in KMT2A::MLT3 cells showed that HMX3 drives cancer-associated E2F and MYC gene programs (p < 0.001). HMX3 expression in healthy CD34+ cells blocked monocytic but not granulocytic colony formation. Strikingly, HMX3 silencing in KMT2A::MLLT3 patient cells resulted in cell cycle arrest, monocytic differentiation and apoptosis. Thus, the neuronal transcription factor HMX3 is a leukemia-specific vulnerability in KMT2A::MLLT3 AML.

Using multiplexed functional data to reduce variant classification inequities in underrepresented populations

BackgroundMultiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene of interest. The resulting saturation-style functional data may help resolve variant classification disparities between populations, especially for Variants of Uncertain Significance (VUS).MethodsWe analyzed clinical significance classifications in 213,663 individuals of European-like genetic ancestry versus 206,975 individuals of non-European-like genetic ancestry from All of Us and the Genome Aggregation Database. Then, we incorporated clinically calibrated MAVE data into the Clinical Genome Resource’s Variant Curation Expert Panel rules to automate VUS reclassification for BRCA1, TP53, and PTEN.ResultsUsing two orthogonal statistical approaches, we show a higher prevalence (p ≤ 5.95e − 06) of VUS in individuals of non-European-like genetic ancestry across all medical specialties assessed in all three databases. Further, in the non-European-like genetic ancestry group, higher rates of Benign or Likely Benign and variants with no clinical designation (p ≤ 2.5e − 05) were found across many medical specialties, whereas Pathogenic or Likely Pathogenic assignments were increased in individuals of European-like genetic ancestry (p ≤ 2.5e − 05). Using MAVE data, we reclassified VUS in individuals of non-European-like genetic ancestry at a significantly higher rate in comparison to reclassified VUS from European-like genetic ancestry (p = 9.1e − 03) effectively compensating for the VUS disparity. Further, essential code analysis showed equitable impact of MAVE evidence codes but inequitable impact of allele frequency (p = 7.47e − 06) and computational predictor (p = 6.92e − 05) evidence codes for individuals of non-European-like genetic ancestry.ConclusionsGeneration of saturation-style MAVE data should be a priority to reduce VUS disparities and produce equitable training data for future computational predictors.

Assessment of breeding nuclei contributions to the genetic diversity and population structure of the Cyprus Chios sheep

Cyprus, facing climate change and desertification, has Europe’s second highest population growth. Halloumi cheese’s Protected Designation of Origin status boosted goat and sheep milk demand. Optimizing primary sector production is key to balancing food production and environmental sustainability. The present study aims to explore the genetic diversity and population structure of Cyprus Chios sheep, as well as the impact of existing breeding nuclei on the breed’s gene pool. Two breeding nuclei aiming to preserve genetic diversity and boost local milk production and four private farms were sampled. Genome-wide data using Illumina 50 K arrays were generated, analyzing over 1000 animals from six farms. At least three distinct genetic groups were identified, two of which are represented by the nuclei’s distinct genetic profiles and a third was found in private farms. Calculated metrics indicate a negative correlation of gene flow with geographic distance in case of the Eastern nucleus. Presented results support recent, though limited inbreeding (mean FROH=0.046), compared to other commercial breeds. Estimated effective population size reveals a stabilizing trend to a relatively high number (Ne ~ 200) which indicates relatively high diversity that allows further genetic improvement. Revealed genomic diversity highlights the necessity of such exploration before effectively implementing genomic evaluation programs.

Genome-wide association study identified QTLs and genes underlying early seedling vigour in aus rice (Oryza sativa L.).

Early seedling vigour (ESV) is a key trait that enhances early establishment, stress tolerance, and grain yield in rice, especially in direct-seeded rice (DSR) systems. The aus varietal groups is known for its high seedling vigour. The screening of aus diversity panel for ESV traits and subsequent genome-wide association study (GWAS) can lead to the identification of genetic components of ESV. Here, we report the genetic variation in seven ESV traits along with days to 50% flowering and grain yield in a panel of 181 aus accessions evaluated under field conditions. We observed significant variations in the studied traits. The vegetative vigour, scored visually, was significantly correlated with most of the traits, suggesting its impact on overall plant performance. Comparative analysis of aus genetic groups revealed significant variations, and the subpopulation that includes early maturing drought tolerant genotypes was the most vigorous, and thus ideal for donor selection. GWAS using 918, 863 single nucleotide polymorphism (SNP) markers identified 14 significant QTLs, including seven novel ones, linked to vegetative vigour, average growth rate and seedling biomass. Candidate genes like OsPDR1, NCKAP1, and OsSAUR10, involved in jasmonic acid biosynthesis, ABA signaling, and brassinosteroid pathways, were identified to be associated with ESV regulation. This study provides insights into the genetic basis of ESV in aus rice, identifying promising germplasm and genes that could improve seedling vigour and yield in DSR systems. Future research should validate these findings and integrate them into breeding programs for enhanced rice performance in various environments.

Spatial variation in toll-like receptor diversity in koala populations across their geographic distribution

The koala (Phascolarctos cinereus) is an iconic Australian species that is listed as endangered in the northern parts of its range due to loss of habitat, disease, and road deaths. Diseases contribute significantly to the decline of koala populations, primarily Chlamydia and koala retrovirus. The distribution of these diseases across the species’ range, however, is not even. Toll-like receptors (TLRs) play a crucial role in innate immunity by recognising and responding to various pathogens. Variations in TLR genes can influence an individual’s susceptibility or resistance to infectious diseases. The aim of this study was to identify koala TLR diversity across the east coast of Australia using 413 re-sequenced genomes at 30 × coverage. We identified 45 single-nucleotide polymorphisms (SNP) leading to 51 alleles within ten TLR genes. Our results show that the diversity of TLR genes in the koala forms four distinct genetic groups, which are consistent with the diversity of the koala major histocompatibility complex (MHC), another key immune gene family. The bioinformatics approach presented here has broad applicability to other threatened species with existing genomic resources.

Physically-based digital geomorphological mapping: Case study of glacial and karst topography

Digital geomorphological mapping is considered here as a semi-automated procedure of division the land surface into genetically meaningful objects. The basis is automatic segmentation into elementary forms, the smallest and indivisible elements of the land surface, should be geometrically clearly identifiable, with maximal internal homogeneity and clear discontinuities at their boundaries. These elements can then be combined into more complex genetically homogeneous composite forms. Given the crucial role of gravitational energy in landform formation, it should also be considered in elementary land surface segmentation . This research builds on the theoretical foundation of physical geomorphometry, which explores the relationship between gravitational energy and geomorphometric variables. Specifically, we apply the recently published algorithm for physically-based elementary land surface segmentation by Minár et al. (2024), which utilizes dynamic least squares (DLS) generalization within a GEOBIA framework. The algorithm was initially tested in structurally fluvial hilly terrain using nine physically interpretable gravity-specific point-based variables (elevation, slope aspect and gradient, three basic curvatures, and three changes in curvature). In this study, we extend the application of this algorithm to two different areas of the Western Carpathians: the glacial topography of its highest part and a karst plateau. By using a slightly simplified and specifically modified version of the physically-based algorithm, we achieved plausible and genetically interpretable results in both case studies, which confirms the value of physical geomorphometry in geomorphological mapping. Additionally, a novel concept of physical-geomorphometric signature was applied in both case studies as a support for the physical-geomorphometric analysis. The physical-geomorphometric signature is very helpful in the quantitative comparison between various genetic groups of landforms.

Associations between the life's essential 8, genetic risk and breast cancer incidence in premenopausal and postmenopausal women: a prospective study in UK Biobank.

The combined effect of cardiovascular risk factors on breast cancer in women is unknown. The relationship between genetic risk combined with cardiovascular health (CVH) levels and breast cancer has not been confirmed. This study aims to explore the relationship between CVH level based on life's essential 8 (LE8) score and breast cancer risk in women with different menopausal statuses and to estimate further the effect of CVH level combined with genetic susceptibility on breast cancer risk. A total of 118,911 women from UK Biobank were included in the study, including 22,676 premenopausal women and 96,235 postmenopausal women. The association between the CVH level and the risk of breast cancer in women with different menopausal statuses was assessed using the Cox proportional hazards regression models, with the healthiest CVH group as the reference. In addition, risk ratios (HRs) and 95% confidence intervals (95% CIs) for the joint effect of the CVH level and polygenic risk score (PRS) were calculated using the PRS from the UK Biobank. During a mean follow-up period of 13.8years, we observed 733 cases and 3,645 cases of breast cancer in premenopausal and postmenopausal women, respectively. In premenopausal women, the risk of breast cancer was significantly increased in the intermediate CVH group (HR, 1.28; 95%CI 1.08-1.52) and the low CVH group (HR, 1.44; 95%CI 1.13-1.85). In postmenopausal women, the risk of incidence was also significantly increased in the intermediate CVH group (HR, 1.20; 95%CI 1.07-1.32) and the low CVH group (HR, 1.34; 95%CI 1.17-1.54). In the joint effect analysis, the risk of breast cancer for women in the low CVH group and the high genetic risk group was highest in both premenopausal (HR, 8.26; 95%CI 4.44-15.35) and postmenopausal (HR, 8.10; 95%CI 5.50-11.93) women. Women with lower LE8 scores and higher genetic susceptibility have the higher risk of breast cancer. This suggests that women with lower levels of CVH and higher genetic susceptibility have an increased risk of breast cancer under different menopausal statuses.

Association of imaging biomarkers with molecular subtypes of medulloblastoma.

Background and purpose: The World Health Organization (WHO) subdivided medulloblastoma into genetic and histopathological groups, each with a specific therapeutic intervention and different clinical outcomes. These subtypes may present with distinct imaging features. Therefore, the current study aimed to identify magnetic resonance imaging (MRI) biomarkers to predict the precise pathological characteristics of medulloblastoma. Methods: This study included 28 patients with a first diagnosis of medulloblastoma who underwent preoperative brain MRI with subsequent surgical resection and histopathological confirmation at our hospital between 2010 and 2022. Conventional MRI parameters, including apparent diffusion coefficient (ADC) mean values, were correlated with molecular subtypes to identify distinct MRI biomarkers. Results: Out of 28 tumors, two (7.1%) tumors exhibited wingless (WNT) activation, thirteen (46.4%) exhibited sonic hedgehog (SHH) activation, and thirteen (46.4%) exhibited non-WNT/non-SHH activation (Group 3 or 4). Statistical analysis revealed a significant association of SHH-activated tumors with paramidline/cerebellar location and the presence of peritumoral edema (p value = <0.0001). No significant correlations were found between the genetic subtypes and the other MRI parameters. A distinctive distribution of the ADC-mean values among the various genetic subtypes with recognizable tendencies was identified. However, it was statistically insignificant. Conclusion: Conventional MRI features of the paramidline/hemispheric location and the presence of peritumoral edema were significantly correlated with the SHH activated pathway and hence can be used to facilitate the preoperative implementation of SHH-targeted therapeutic intervention. Although the ADC-mean measurements were not statistically significant, a recognizable distribution of values among the various genetic subtypes was identified.

Assessment of genomic diversity within and between two cryptic shiners, the West Texas shiner (Notropis megalops) and the Texas shiner (Notropis amabilis).

The presence of cryptic species can hinder effective conservation planning and implementation, as has been the case for speciose groups of freshwater fishes that are difficult to differentiate due to conserved morphologies. The West Texas shiner Notropis megalops and the Texas shiner Notropis amabilis are a cryptic pair of leuciscids (minnows) that co-occur in spring-fed tributaries of the Rio Grande in Texas and Mexico. Both N. megalops and N. amabilis are listed as Species of Greatest Conservation Need by the Texas Parks and Wildlife Department. Notropis amabilis is widespread and listed as apparently secure by Texas Parks and Wildlife Department whereas N. megalops has a very limited distribution and has not been ranked by Texas Parks and Wildlife Department because of data deficiency. Morphological differences between these species have been described; however, proper identification in situ remains problematic. Furthermore, given their range of overlap there is potential for hybridization, and limited genetic data have been collected comparing the species. Therefore, reduced representation genomic and mitochondrial sequencing data were used to reassess the distinctness of the species, screen for hybridization, and characterize their relative frequencies throughout their range of overlap. Genomic analyses recovered two distinct genetic groups corresponding to the species (F'CT = 0.89) with no evidence of admixture or introgression. The species were found to co-occur at three sampling locations, two in the Devils River and one in the Pecos, but not in equal frequencies. Overall, these results provide data and tools for further research on N. megalops needed for accurate conservation policies and management practices.

Molecular Diversity and Distribution of Whiteflies (Bemisia tabaci) in Cassava Fields Across South West and North Central, Nigeria.

Whitefly Bemisia tabaci (Gennadium, Hemiptera) causes severe damage to cassava plants through excessive feeding on leaves and transmitting viruses, such as African cassava mosaic virus (ACMV), East African cassava mosaic virus (EACMV), and ipomoviruses that cause cassava brown streak disease. Currently, little is known about the molecular diversity and distribution of whitefly species in the major cassava-growing zones of Nigeria. This study aimed to address the knowledge gap by assessing the genetic diversity, distribution, and associated cassava mosaic begomoviruses (CMBs) in whiteflies across South West and North Central, Nigeria. Whitefly samples were systematically collected from cassava plants during georeferenced epidemiological surveys in 2017, 2020, and 2022. The samples were genotyped using the mitochondrial cytochrome oxidase I (mtCOI) marker, and CMBs were detected by PCR with virus-specific primers. Phylogenetic analyses revealed four distinct genetic groups of B. tabaci: Sub-Saharan Africa 1 (SSA1; 84.8%), SSA2 (1.4%), SSA3 (13.1%), and Mediterranean (MED) (0.7%). The SSA1 group was the predominant and most widely distributed genotype across the surveyed zones, with three subgroups identified: SSA1-SG1, SSA1-SG3, and SSA1-SG5. The second most frequently identified genotype, SSA3, was restricted to the North Central zone, along with the SSA2 group, which was only identified in two North Central states (Niger and Plateau). African cassava mosaic virus (ACMV) was detected in SSA1-SG1, SSA1-SG5, and SSA3, whereas EACMV was found in only the SSA1-SG3. The findings of this study will aid in developing better whitefly management strategies to reduce the impact of CMD on cassava production in Nigeria.

Combined Effect of Air Pollution and Genetic Risk on Incident Cardiovascular Diseases.

Whether genetic susceptibility to cardiovascular diseases (CVDs) enhances the vulnerability to adverse cardiovascular outcomes by air pollution is unknown. We assessed the combined effect of air pollution and genetic predispositions on CVD risk. From the UK Biobank cohort, we selected genetically unrelated White British participants without CVD. Levels of ambient particulate matter with a diameter of <2.5 μm (PM2.5) and <10 μm were estimated using land use regression models. An individual's genetic predisposition to CVDs was determined by polygenic risk scores for coronary artery disease, myocardial infarction, stroke, ischemic stroke, heart failure, and atrial fibrillation. We stratified mortality and CVD risk by PM2.5 exposure across high and low genetic risk groups. A total of 249 082 participants (aged 56.9±8.0 years, 46.8% men) were followed for a median of 10.8 years. The combined effect of PM2.5 exposure and the genetic predisposition of CVD demonstrated the highest risk of cardiovascular death in the high genetic risk group with the greatest PM2.5 exposure (adjusted hazard ratios ranging from 1.73 to 2.12 across the polygenic risk score of each CVD). The combination of higher exposure to ambient PM2.5 and high genetic risk was associated with higher incidence of all CVDs, although no significant interactions were observed between genetic risk and PM2.5 exposure on cardiovascular death or CVD events. A combination of greater PM2.5 exposure and higher genetic predisposition to particular CVDs was modestly associated with elevated risks of cardiovascular death and CVDs. Not only alleviating PM2.5 exposure in the general population but also implementing individualized preventive approach for those at high genetic risk might be beneficial.

Dimensionality reduction distills complex evolutionary relationships in seasonal influenza and SARS-CoV-2.

Public health researchers and practitioners commonly infer phylogenies from viral genome sequences to understand transmission dynamics and identify clusters of genetically-related samples. However, viruses that reassort or recombine violate phylogenetic assumptions and require more sophisticated methods. Even when phylogenies are appropriate, they can be unnecessary or difficult to interpret without specialty knowledge. For example, pairwise distances between sequences can be enough to identify clusters of related samples or assign new samples to existing phylogenetic clusters. In this work, we tested whether dimensionality reduction methods could capture known genetic groups within two human pathogenic viruses that cause substantial human morbidity and mortality and frequently reassort or recombine, respectively: seasonal influenza A/H3N2 and SARS-CoV-2. We applied principal component analysis, multidimensional scaling (MDS), t-distributed stochastic neighbor embedding (t-SNE), and uniform manifold approximation and projection to sequences with well-defined phylogenetic clades and either reassortment (H3N2) or recombination (SARS-CoV-2). For each low-dimensional embedding of sequences, we calculated the correlation between pairwise genetic and Euclidean distances in the embedding and applied a hierarchical clustering method to identify clusters in the embedding. We measured the accuracy of clusters compared to previously defined phylogenetic clades, reassortment clusters, or recombinant lineages. We found that MDS embeddings accurately represented pairwise genetic distances including the intermediate placement of recombinant SARS-CoV-2 lineages between parental lineages. Clusters from t-SNE embeddings accurately recapitulated known phylogenetic clades, H3N2 reassortment groups, and SARS-CoV-2 recombinant lineages. We show that simple statistical methods without a biological model can accurately represent known genetic relationships for relevant human pathogenic viruses. Our open source implementation of these methods for analysis of viral genome sequences can be easily applied when phylogenetic methods are either unnecessary or inappropriate.

Abstract 4137717: Atrial Fibrillation in Valvular Heart Disease: Assessing the Impact of Genetics in the UK Biobank

Background: Atrial fibrillation (AF) in valvular heart disease (VHD) is typically linked to pressure or volume overload resulting in atrial remodeling. However, the independent contribution of genetics to AF in VHD beyond abnormal hemodynamics and other risk factors remains unclear. Objective: To study the role of a previously developed Polygenic Risk Score (PRS) for AF in predicting AF across different VHDs in the UK Biobank cohort. Methods: We analyzed UK Biobank data between 2000 and 2022. ICD codes were used to define incident AF and VHD status, including mitral valve (MV) disease [prolapse (MVP), regurgitation (MR) and stenosis (MS)] and aortic (AV) disease [stenosis (AS) and regurgitation (AR)]. Prior AF was excluded. Participants were divided into quintiles based on the PRS: the top quintile was defined as high genetic AF risk, second through fourth as intermediate genetic risk, and bottom quintile as low genetic risk. Results: Among 452841 participants with available PRS, 2238 had at least one VHD (385 MVP, 1058 MR, 81 MS, 421 AR, and 509 AS). AF incidence was 9.9%, 13.6%, and 19% in the low, intermediate and high genetic risk groups respectively, compared to 1.4%, 2.8%, and 5.7% in the general population (all p&lt;0.05) - Figure 1A . Cox regression models adjusted for cardiovascular risk factors showed different genetic effects on AF across VHD types. Censoring patients at death, including valve intervention as a time-dependent variable, and excluding AF within 30 days post-intervention, PRS independently predicted AF in MV disease (hazard ratio [HR] 1.7, p=0.03 for the intermediate risk/mid PRS; HR 2.3, p=0.002 for the high risk PRS), particularly in those with MVP (HR 3.1, p=0.03 for the high PRS). However, in those with AV disease, PRS was not significantly associated with AF (p=0.93 and p=0.07) - Figure 1B. Conclusion: In patients with VHD, AF PRS is significantly associated with an increased risk of developing AF. However, the genetic impact varies across different VHD. In AV disease, there is a minimal genetic contribution, and the elevated AF risk may be predominantly due to pressure or volume overload. In contrast, in MV disease, particularly in MVP, there is a substantial genetic influence on AF risk.

Abstract 4120763: Predicting Disease Risk Among Variants in Cardiomyopathy-Associated Genes Across Diverse Genetic Ancestries

Background: Many cases of cardiomyopathy (CM) are genetically inherited, and the expansion of broad genomic sequencing has opened the door for predicting those at risk for developing disease. However, genetic tools that help determine variant pathogenicity employ genetic data from predominantly European genetic ancestries. Understanding the full diversity of genetic variants in cardiomyopathy genes is central to identifying which variants will cause disease. Hypothesis: Participants of non-European genetic ancestry will have a higher burden of cardiomyopathy gene variants with "VUS" designation in ClinVar but will have equivalent/less penetrance of clinical cardiomyopathy compared to a European ancestry group. Methods: Participants in the AllofUs database with exome sequencing (ES) were queried and a cohort of 230,013 participants were retained after sample quality control filters. Participant genetic ancestry was based on the designated ancestry group determined via AllofUs as previously described (1). Participants were queried for variants in genes with definitive or moderate evidence of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic cardiomyopathy (ACM) in ClinGen. Variants were filtered by ClinVar status (1* and above P/LP, 1* and above B/LB, and VUS). Participant CM disease status was determined via ICD-9/10 code. Results: For each ancestry group, prevalence of cardiomyopathy ranged from 0.34% in the Latino/admixed American ancestry group to 1.09% in the African group, with an average prevalence of 0.91% across all groups. The European group had a statistically significant lower percentage of ClinVar VUS variants at 26%, while all other non-European ancestry groups had a combined VUS prevalence rate of 35% (****p&lt;0.0001). The penetrance of CM in participants with CM VUS variants was lower in combined non-European ancestry groups (0.84%) than European ancestry (1.02%) (*p=0.0156). Conclusion: Prevalence of ClinVar VUS variants varies across different genetic ancestry groups, with European ancestry having a lower burden of VUS variants compared to non-European groups. However, non-European ancestry groups with increased burden of VUS variants have lower disease penetrance. Citations: (1) The All of Us Research Program Genomics Investigators. Genomic data in the All of Us Research Program. Nature 627 , 340–346 (2024). https://doi.org/10.1038/s41586-023-06957-x

Morphological characterization of cacao (Theobroma cacao L.) criollo type in Mexico

Objective: Achieve the morphological characterization of Criollo-type cocoa from Mexico. Design/methodology/approach: For morphological characterization, 17 Criollo-type cocoa accessions and 30 varietal descriptors were proposed by Avendaño et al., (2014), and this was carried out on five-year-old trees in the Rosario Izapa Experimental Field of INIFAP during two production cycles. Results: With the first three principal components, 47.3% of the variation was explained and the variables that most explained this variation were the color of the young leaf, anthocyanin pigmentation of the pedicel, basal constriction of the fruit, shape of the fruit apex and length/diameter ratio of the fruit; sepal length, sepal width length, fruit length, fruit exocarp thickness, seed width, seed length/diameter ratio and cotyledon color. The cluster analysis allowed us to differentiate two groups where the color of the unripe fruit was one of the descriptors that contributed the most to forming the groups. Limitations on study/implications: Knowledge of the diversity of Mexican Criollo-type cocoas allows for establishing strategies for conserving and using this type of cocoa. Findings/conclusions: In Mexico, the Criollo cacao genetic group presents a wide morphological variation in the descriptors of leaf, flower, fruit and seed. The shape of the apex of the leaf, the anthocyanin pigmentation in the flower, the color in the mature and immature state, and the shape and basal constriction of the fruit, as well as the color of the cotyledon, are the descriptors that allowed us to differentiate the Criollo cocoas studied.

Investigation of the Effects of Biotinidase Deficiency on Plasma Cholinesterase Activity

Purpose: Biotinidase deficiency (BD) is a rare autosomal recessive metabolic disorder that impairs the body's ability to recycle biotin, a crucial coenzyme for carboxylase enzymes involved in various metabolic processes. This study aims to evaluate the effects of biotinidase deficiency on cholinesterase activity in plasma, hypothesizing that the metabolic disruptions caused by inadequate biotin recycling may lead to alterations in cholinesterase function. Materials and methods: Plasma samples were collected from 73 individuals categorized into four genetic groups: wild type (n = 12), heterozygous (n = 30), homozygous (n = 19), and compound heterozygous (n = 12). Cholinesterase activity was measured using a colorimetric method. Results: The study discovered that the cholinesterase activity of the Heterozygous group was higher than the homozygous group (p = 0.0356). Additionally, cholinesterase activity was significantly lower in homozygous and compound heterozygous people than in wild and heterozygous groups (p = 0.0272). The statistically significant changes suggested a relationship between biotinidase deficiency and altered cholinergic activity. Conclusion: The findings indicate that biotinidase deficiency, particularly in its severe variants, may cause considerable reductions in cholinesterase activity, contributing to the neurological symptoms found in affected patients. More studies are needed to investigate the processes behind this association and develop strategies for reducing the effects of BD on cholinesterase activity and neurological health.

Outcomes with intensive treatment for acute myeloid leukemia: an analysis of two decades of data from the HARMONY Alliance.

Since 2017, targeted therapies combined with conventional intensive chemotherapy have started to improve outcome of patients with acute myeloid leukemia (AML). However, even before these innovations outcomes with intensive chemotherapy have improved, which has not yet been extensively studied. Thus, we used a large pan-European multicenter dataset of the HARMONY Alliance to evaluate treatment-time dependent outcomes over two decades. In 5359 AML patients, we compared the impact of intensive induction therapy on outcome over four consecutive 5-year calendar periods from 1997 to 2016. During that time, the 5- year survival of AML patients improved significantly, also across different genetic risk groups. In particular, the 60-day mortality rate has dropped from 13.0% to 4.7% over time. The independent effect of calendar periods on outcome was confirmed in multivariate models. Improvements were documented both for patients.

Genetic Diversity and Ecogeographical Niche Overlap Among Hybridising Ox-Eye Daisies (Leucanthemum, Asteraceae) in the Carpathian Mountains: The Impact of Anthropogenic Disturbances.

Climate change and human influence are transforming mountain ecosystems, significantly impacting species distributions and biodiversity. Among these changes, the upward migration of lowland species into mountain regions stands out. This study examines the ecogeographical niche overlap and genetic diversity among three Leucanthemum species distributed along an altitudinal gradient in the Carpathian Mountains: the lowland L. ircutianum (4x), the montane L. rotundifolium (2x) and the alpine L. gaudinii (2x). By genotyping over 600 individuals using SNP analysis, followed by principal coordinate analysis (PCoA), Neighbour-Net Network and Structure clustering, we reveal not just distinct genetic groups but also hybridisation across all species, suggesting the potential for triple hybrids. Genetic admixture is further supported by environmental background and niche overlap analyses that reveal substantial overlap among species, particularly in line with their vertical distribution. Climate envelope plots indicate a likely reduction in available habitat for mountainous species due to climate change, leading to an increase in competition and an intensification of hybridisation. Anthropogenic influences are further intensifying these hybridisation trends. Among the studied species, L. gaudinii is most at risk of overwhelming hybridisation, whereas L. ircutianum may experience habitat expansion. By providing a comprehensive genetic and ecological overview, our research highlights the significance of hybridisation in biodiversity conservation and the challenges posed by environmental changes and anthropogenic activities in mountain environments. This study not only contributes to the understanding of genetic diversity in the Carpathians but also underscores the broader implications for molecular ecology and conservation strategies in mountain ecosystems.

Unlocking Spanish pear genetic diversity: strategies for construction of a national core collection

Spanish pear germplasm collections are crucial for preservation, research, and breeding efforts. However, genetic diversity and structure is unknown at national level. A coordinated national project analyzed 1251 accessions from 7 Spanish pear collections using an internationally recognized set of 14 SSRs to enhance the utilization of these collections. Key findings included the identification of 760 unique genotypes (490 diploids and 270 triploids). Notably, genotypes represented by a single accession accounted for 49% of the total, indicating high vulnerability of this material. Using a Bayesian clustering method revealed two main genetic groups, G1 containing most foreign cultivars and G2 retaining local Spanish cultivars, which were further divided into two other subgroups using a nested approach, revealing moderate but significant differentiation among them. The populations were renamed according to the origin of the reference samples assigned to each group as ‘South’ (G1.1), ‘Western Europe-1’ (G1.2), ‘Western Europe-2’ (G2.1) and ‘No-Pyrus communis’ (G2.2). The results led to the creation of a ‘generalist’ collection, aiming to maximize genetic diversity representativeness, starting with 68 genotypes but expanding to 111 to achieve better allele recovery. This core collection is a valuable resource for genetic studies and conservation, enhancing efforts to preserve pear biodiversity.

Effect of vaccination against Mycoplasma hyopneumoniae on divergent pig genetic groups

The bacterium Mycoplasma hyopneumoniae (Mhp) causes a chronic infectious respiratory disease in pigs, leading to important economic losses. This study aimed to compare the immune response of the local Piau breed and a commercial line to Mhp vaccination. For this, two phases were carried out. In the first, gene expression of toll-like receptors (TLR2, TLR4, TLR6, and TLR10) and cytokines (IL2, IL6, IL8, IL10, IL12, IL13, TNFα, and TGFβ) was assessed in porcine blood mononuclear cells (PBMC) from the two genetic groups before and after vaccination. In the second experiment, nitric oxide production, specific antibodies, and gene expression of toll-like receptors and cytokines were evaluated in bronchoalveolar lavage fluid (BALF) cells of vaccinated and unvaccinated pigs. After vaccination against Mhp, TLR2, TLR4, TLR6, TLR10, IL6, TNFα, and TGFβ expression levels were elevated in PBMC from commercial animals, and TLR6, TLR10, and TGFβ expression levels were elevated in PBMC from the Piau group. Vaccination also increased the production of Mhp-specific IgG antibodies in BALF cells in the Piau breed. Comparison of the two genetic groups revealed differences in TNFα and IL10 expression in BALF cells. These results show that Piau pigs have different immune responses to vaccination compared with commercial animals. It is worth noting that these genetic differences between both genetic groups may be related to phenotypic differences in Mhp resistance or susceptibility.