Non-genetic Factors Research Articles

8039 Role Of Genetics In The Age-Related Testosterone Decline In Men: A UK Biobank Study

Abstract Disclosure: L. Ogoniak: None. S. Sandmann: None. J. Varghese: None. A.S. Busch: None. Background: Age-related decline in circulating serum testosterone concentrations is a well-established phenomenon in men. While the decline is partially linked to comorbidities such as obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD), healthy ageing men present with rather stable levels. Recent genetic mapping studies demonstrated a large influence of common genetic variation on testosterone levels in men. However, increasing incidence rates of comorbidities in the ageing population are posing a challenge for the disentanglement of effects. Objective: Our study aims to investigate the genetic component of age-dependent testosterone decline in men. We hypothesize that the decline in testosterone levels in ageing men is primarily influenced by comorbidities, without significant alterations in the genetic architecture of testosterone levels. Material and Methods: We included 6,406 men with baseline and follow-up measurements of circulating serum concentrations of total testosterone (T), bioavailable testosterone (BAT) and sex hormone-binding globulin (SHBG) representing an independent sub-cohort of the UK Biobank study. We 1) assessed the association of baseline levels with the decline in sex steroids and 2) developed and verified polygenic risk score (PRS) models for T, BAT and SHBG based on 183,909 men from the UK Biobank (sub cohorts: 70% base, 15% target and 15% validation, follow-up cohort excluded for PRS development). Results: In the follow-up sub cohort, mean age (SD) at baseline was 58.2 yrs ( 7.5) and mean (SD) follow-up period was 4.3 (1.0) yrs. Mean (SD) BAT at baseline were 5.2 (1.32) nmol/L with a mean (SD) decline of 1.6 (24.4) % at follow-up. Baseline BAT, T and SHBG levels were significantly associated with the relative change of the respective biomarker at follow-up (-7.8, -2.9 and -0.4% per nmol/L, respectively, all p <0.001). After correcting for age at baseline, follow-up period and principal components 1-10, PGSTestosterone and PGSBAT were not associated with relative decline of the respective biomarker (both p = n.s.). Conclusion: Our study did not find evidence supporting a genetic component in the age-related decline of circulating serum T or BAT concentrations. Instead, in accordance to previous observational studies, our results suggest that rather non-genetic factors, e.g. increasing incidence rates of comorbidities, drive the age-related decline in sex steroid levels in men. Our study contributes to understanding the intricate relationship between genetic and non-genetic factors with age-related testosterone decline in men and offers valuable insights for potential interventions targeting age-related hormonal changes and associated health outcomes. Presentation: 6/2/2024

9240 Role Of Genetics In The Age-Related Testosterone Decline In Men: A UK Biobank Study

Abstract Disclosure: L. Ogoniak: None. S. Sandmann: None. J. Varghese: None. A.S. Busch: None. Background: Age-related decline in circulating serum testosterone concentrations is a well-established phenomenon in men. While the decline is partially linked to comorbidities such as obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD), healthy ageing men present with rather stable levels. Recent genetic mapping studies demonstrated a large influence of common genetic variation on testosterone levels in men. However, increasing incidence rates of comorbidities in the ageing population are posing a challenge for the disentanglement of effects. Objective: Our study aims to investigate the genetic component of age-dependent testosterone decline in men. We hypothesize that the decline in testosterone levels in ageing men is primarily influenced by comorbidities, without significant alterations in the genetic architecture of testosterone levels. Material and Methods: We included 6,406 men with baseline and follow-up measurements of circulating serum concentrations of total testosterone (T), bioavailable testosterone (BAT) and sex hormone-binding globulin (SHBG) representing an independent sub-cohort of the UK Biobank study. We 1) assessed the association of baseline levels with the decline in sex steroids and 2) developed and verified polygenic risk score (PRS) models for T, BAT and SHBG based on 183,909 men from the UK Biobank (sub cohorts: 70% base, 15% target and 15% validation, follow-up cohort excluded for PRS development). Results: In the follow-up sub cohort, mean age (SD) at baseline was 58.2 yrs ( 7.5) and mean (SD) follow-up period was 4.3 (1.0) yrs. Mean (SD) BAT at baseline were 5.2 (1.32) nmol/L with a mean (SD) decline of 1.6 (24.4) % at follow-up. Baseline BAT, T and SHBG levels were significantly associated with the relative change of the respective biomarker at follow-up (-7.8, -2.9 and -0.4% per nmol/L, respectively, all p <0.001). After correcting for age at baseline, follow-up period and principal components 1-10, PGSTestosterone and PGSBAT were not associated with relative decline of the respective biomarker (both p = n.s.). Conclusion: Our study did not find evidence supporting a genetic component in the age-related decline of circulating serum T or BAT concentrations. Instead, in accordance to previous observational studies, our results suggest that rather non-genetic factors, e.g. increasing incidence rates of comorbidities, drive the age-related decline in sex steroid levels in men. Our study contributes to understanding the intricate relationship between genetic and non-genetic factors with age-related testosterone decline in men and offers valuable insights for potential interventions targeting age-related hormonal changes and associated health outcomes. Presentation: 6/2/2024

8039 Role Of Genetics In The Age-Related Testosterone Decline In Men: A UK Biobank Study

Abstract Disclosure: L. Ogoniak: None. S. Sandmann: None. J. Varghese: None. A.S. Busch: None. Background: Age-related decline in circulating serum testosterone concentrations is a well-established phenomenon in men. While the decline is partially linked to comorbidities such as obesity, type 2 diabetes (T2D), and cardiovascular disease (CVD), healthy ageing men present with rather stable levels. Recent genetic mapping studies demonstrated a large influence of common genetic variation on testosterone levels in men. However, increasing incidence rates of comorbidities in the ageing population are posing a challenge for the disentanglement of effects. Objective: Our study aims to investigate the genetic component of age-dependent testosterone decline in men. We hypothesize that the decline in testosterone levels in ageing men is primarily influenced by comorbidities, without significant alterations in the genetic architecture of testosterone levels. Material and Methods: We included 6,406 men with baseline and follow-up measurements of circulating serum concentrations of total testosterone (T), bioavailable testosterone (BAT) and sex hormone-binding globulin (SHBG) representing an independent sub-cohort of the UK Biobank study. We 1) assessed the association of baseline levels with the decline in sex steroids and 2) developed and verified polygenic risk score (PRS) models for T, BAT and SHBG based on 183,909 men from the UK Biobank (sub cohorts: 70% base, 15% target and 15% validation, follow-up cohort excluded for PRS development). Results: In the follow-up sub cohort, mean age (SD) at baseline was 58.2 yrs ( 7.5) and mean (SD) follow-up period was 4.3 (1.0) yrs. Mean (SD) BAT at baseline were 5.2 (1.32) nmol/L with a mean (SD) decline of 1.6 (24.4) % at follow-up. Baseline BAT, T and SHBG levels were significantly associated with the relative change of the respective biomarker at follow-up (-7.8, -2.9 and -0.4% per nmol/L, respectively, all p <0.001). After correcting for age at baseline, follow-up period and principal components 1-10, PGSTestosterone and PGSBAT were not associated with relative decline of the respective biomarker (both p = n.s.). Conclusion: Our study did not find evidence supporting a genetic component in the age-related decline of circulating serum T or BAT concentrations. Instead, in accordance to previous observational studies, our results suggest that rather non-genetic factors, e.g. increasing incidence rates of comorbidities, drive the age-related decline in sex steroid levels in men. Our study contributes to understanding the intricate relationship between genetic and non-genetic factors with age-related testosterone decline in men and offers valuable insights for potential interventions targeting age-related hormonal changes and associated health outcomes. Presentation: 6/2/2024

8244 Genetic Evaluation Using Next-Generation Sequencing of Children with Short Stature < A Single Tertiary Center Experience

Abstract Disclosure: J. Park: None. S. Kim: None. E. Joo: None. J. Lee: None. Purpose: We aimed to investigate the genetic causes of suspected genetic short stature in 37 patients using next-generation sequencing (NGS) and describe their phenotypes and various genetic spectra. Methods: We reviewed the medical records of 50 patients who underwent genetic testing using NGS for suspected genetic short stature from June 2019 to December 2022. Patients with short stature caused by non-genetic factors or common chromosomal abnormalities were excluded. Thirty-seven patients from 35 families were enrolled in this study. We administered one of three genetic tests (targeted panel sequencing using two different panels or whole exome sequencing) to patients according to their phenotypes. Results: Clinical and molecular diagnoses were confirmed in 15 of the 37 patients, and the overall diagnostic yield was 40.5 %. Fifteen pathogenic/likely pathogenic variants were identified in 13 genes (ACAN, ANKRD11, ARID1B, CEP152, COL10A1, COL1A2, EXT1, FGFR3, NIPBL, NRAS, PTPN11, SHOX, SLC16A2). The diagnostic rate was high in the patients with small for gestational age (7/11, 63.6 %). Conclusions: Genetic evaluation using NGS can be helpful in patients with suspected genetic short stature who have clinical and genetic heterogeneity. Further studies are needed to develop patient selection algorithms and panels containing growth-related genes. Keywords: Dwarfism, Growth Hormone, Next-Generation Sequencing Presentation: 6/2/2024

Influence of Genetic and Non-Genetic Factors on the Physical and Mechanical Properties of Mongolian Cashmere Fiber Properties

Cashmere is widely acclaimed as one of the most luxurious textile fibers. Mongolia, a major player in cashmere production and processing, is key to this industry. Despite the rich history of cashmere, there is limited research on cashmere fiber properties, which are essential in producing high-quality garments. This study aims to improve our understanding of cashmere fibers’ physical and mechanical properties and to assess how genetic and non-genetic factors affect these characteristics. We analyzed key fiber characteristics, including scale morphology, and the physical and mechanical properties (such as fineness, length parameters, stress, and strain) in 11 samples from Mongolian goats of varying areas, breeds, ages, and genders. Through detailed statistical analysis, our experimental results revealed that both genetic and non-genetic factors significantly affect fiber fineness and the specific energy of rupture. Additionally, we observed that the influence of these factors can inform better classification systems for raw cashmere and enhance the determination of the fiber’s spinability limit.

The Multifaceted Nongenetic Risk Factors for Primary Open-angle Glaucoma—An Overview of Systematic Reviews

TopicA synthesis of the current knowledge on risk factors for primary open-angle glaucoma (POAG). MethodWe conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library to identify relevant systematic reviews (SR) published in English after 2012. The inclusion criteria focused on SRs investigating risk factors for POAG. We registered the study prospectively in the PROSPERO database (CRD42022351372) and used Covidence and the Risk Of Bias In Systematic reviews (ROBIS) tool to manage article selection and assess the risk of bias in the included SRs. Data was extracted independently by two authors. ResultsAfter removing duplicate SRs, we assessed 2,542 SRs. Of these, 2,396 were determined to be irrelevant, leaving 138 for a full text review. Following this, 78 were excluded with reasons, resulting in 57 SRs. Of these, 30 had a low risk of bias. In our bias assessment, SRs categorized as high risk of bias were characterized by 1) lack of sufficient detail in the bias assessment of the SR and 2) insufficient information or missing calculations of heterogeneity among the included studies. In our study, we identified 22 risk factors associated with POAG. The SRs covered a wide range of risk factors for POAG. Among these, the strongest associations with glaucoma, based on effect size, were observed in two SRs related to obstructive sleep apnea (OSA), with a pooled odds ratio (OR) of 3.66 (95% CI: 1.70-7.90) and an adjusted OR of 2.46 (95% CI: 1.32-4.59). Similarly, two SRs investigating Helicobacter pylori (H. pylori) infections showed significant associations, with pooled ORs of 2.08 (95% CI: 1.48-2.93) and 2.08 (95% CI: 1.42-3.04), respectively. ConclusionThis article summarizes the current knowledge on risk factors for POAG from published SRs. Our findings highlight the complexity of the disease and the nature of the factors that may affect various populations.Among the reported associations with low risk of bias, we found the highest effect estimates for OSA and H. pylori infections in relation to POAG. Our review helps advance understanding, guide future research and inform strategies for the prevention and treatment of POAG.

Nongenetic and Genetic Factors Associated with White Matter Brain Aging: Exposome-Wide and Genome-Wide Association Study.

Human brain aging is a complex process that affects various aspects of brain function and structure, increasing susceptibility to neurological and psychiatric disorders. A number of nongenetic (e.g., environmental and lifestyle) and genetic risk factors are found to contribute to the varying rates at which the brain ages among individuals. In this paper, we conducted both an exposome-wide association study (XWAS) and a genome-wide association study (GWAS) on white matter brain aging in the UK Biobank, revealing the multifactorial nature of brain aging. We applied a machine learning algorithm and leveraged fractional anisotropy tract measurements from diffusion tensor imaging data to predict the white matter brain age gap (BAG) and treated it as the marker of brain aging. For XWAS, we included 107 variables encompassing five major categories of modifiable exposures that potentially impact brain aging and performed both univariate and multivariate analysis to select the final set of nongenetic risk factors. We found current tobacco smoking, dietary habits including oily fish, beef, lamb, cereal, and coffee intake, length of mobile phone use, use of UV protection, and frequency of solarium/sunlamp use were associated with the BAG. In genetic analysis, we identified several SNPs on chromosome 3 mapped to genes IP6K1, GMNC, OSTN, and SLC25A20 significantly associated with the BAG, showing the high heritability and polygenic architecture of human brain aging. The critical nongenetic and genetic risk factors identified in our study provide insights into the causal relationship between white matter brain aging and neurodegenerative diseases.

РОЛЬ КОНСТИТУЦИОНАЛЬНОЙ ПРИНАДЛЕЖНОСТИ В ГЕНЕЗЕ ОЖИРЕНИЯ У ДЕТЕЙ И ПОДРОСТКОВ 7-17 ЛЕТ

Obesity in children and adolescents is becoming a pressing issue that can be classified as a disease associated with the interaction of genetic and non-genetic factors. There are numerous causes of this disease. The most important ones are hereditary predisposition and the intake of a large number of calories along with reduced physical activity. In children of different somatotypes aged 7-17 years, there is a wave-like change in the growth of the bone, muscle and fat body components. There are periods when growth processes and hormonal changes lead to the maximum increase in the F, M, L components of body weight. Children of the MD, DM, and D body types are at risk of excess fat deposition. The natural age-related increase in the fat component accompanied by negative exogenous and endogenous factors can lead to hormonal failure and a substantial increase in fat mass.

Mapping biological influences on the human plasma proteome beyond the genome

Broad-capture proteomic platforms now enable simultaneous assessment of thousands of plasma proteins, but most of these are not actively secreted and their origins are largely unknown. Here we integrate genomic with deep phenomic information to identify modifiable and non-modifiable factors associated with 4,775 plasma proteins in ~8,000 mostly healthy individuals. We create a data-driven map of biological influences on the human plasma proteome and demonstrate segregation of proteins into clusters based on major explanatory factors. For over a third (N = 1,575) of protein targets, joint genetic and non-genetic factors explain 10–77% of the variation in plasma (median 19.88%, interquartile range 14.01–31.09%), independent of technical factors (median 2.48%, interquartile range 0.78–6.41%). Together with genetically anchored causal inference methods, our map highlights potential causal associations between modifiable risk factors and plasma proteins for hundreds of protein–disease associations, for example, COL6A3, which possibly mediates the association between reduced kidney function and cardiovascular disease. We provide a map of biological and technical influences on the human plasma proteome to help contextualize findings from proteomic studies.

Meat tenderness in Australian lamb: Data editing, environmental variation and their effects in genetic parameter estimation

Breeding for meat quality increases the value of lambs and requires reliable genetic parameters to achieve balanced genetic progress. Meat tenderness, accomplished by selecting for lower shear force, is an important eating quality trait because of its relationship with consumer satisfaction. Factors influencing shear force, include the pH and temperature decline post-mortem which can contribute towards higher shear force values and increased variation across contemporary groups. This study explored if genetic parameters for shear force change when post slaughter covariates and heterogeneous variance are corrected for, using data from 32,223 animals from different sheep breeds. Results showed that removing extreme individuals and contemporary groups with high mean shear force values reduced residual variance, followed by a smaller reduction in additive genetic variance and little effect on heritability. Results show that edited data performed better at predicting progeny performance and reduced potential bias introduced in the genetic evaluation due to data quality. The effect of including post-slaughter covariates in the genetic analysis was tested by estimating different model predictability through regression of estimated breeding values against offspring performance, showing that the model including hot carcass weight performed better followed by the one including both carcass weight and C-site fat depth. Our results highlight that historic and current in-plant recording practices do not provide the capacity to account for non-genetic factors associated with abattoir environment that might be impacting the ability to accurately calculate shear force breeding values. In that sense, genetic evaluation can be improved by applying more rigorous data editing.

Analysis of Genetic and Non-genetic Factors Affecting Semen Traits in Baldi Black and New Zealand White Rabbits

Analysis of Genetic and Non-genetic Factors Affecting Semen Traits in Baldi Black and New Zealand White Rabbits

Case of familial interstitial lung disease attributedto ATP-binding cassette transporter 3 gene mutationin identical twins.

Mutations in ABCA3 can result in surfactant deficiency, leading to respiratory distress syndrome in term neonates, and interstitial lung disease (ILD) in children. Here, we report an extremely rare case of ILD in an identical twin with novel ABCA3 germline mutations. Interestingly, they showed mostly similar, but slightly different, clinical features. Our cases suggest that, in addition to genetic factors, non-genetic factors are involved in the severity of the disease and its clinical course. Studies of gene-environment interactions, especially with twins, are needed, as they may contribute to the understanding of the clinical heterogeneity of ILD and its association with various underlying conditions as well as rare variant mutations.

Investigating the Impact of Nutrition and Oxidative Stress on Attention Deficit Hyperactivity Disorder.

Background/Objectives: Attention deficit hyperactivity disorder (ADHD) is the most common childhood-onset neurodevelopmental disorder, characterized by difficulty maintaining attention, impulsivity, and hyperactivity. While the cause of this disorder is still unclear, recent studies have stated that heredity is important in the development of ADHD. This is linked to a few comorbidities, including depression, criminal behavior, and anxiety. Although genetic factors influence ADHD symptoms, there are also non-genetic factors, one of which is oxidative stress (OS), which plays a role in the pathogenesis and symptoms of ADHD. This review aims to explore the role of OS in ADHD and its connection to antioxidant enzyme levels, as well as the gut-brain axis (GBA), focusing on diet and its influence on ADHD symptoms, particularly in adults with comorbid conditions. Methods: The literature search included the main available databases (e.g., Science Direct, PubMed, and Google Scholar). Articles in the English language were taken into consideration and our screening was conducted based on several words such as "ADHD", "oxidative stress", "diet", "gut-brain axis", and "gut microbiota." The review focused on studies examining the link between oxidative stress and ADHD, the role of the gut-brain axis, and the potential impact of dietary interventions. Results: Oxidative stress plays a critical role in the development and manifestation of ADHD symptoms. Studies have shown that individuals with ADHD exhibit reduced levels of key antioxidant enzymes, including glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), as well as a diminished total antioxidant status (TOS) compared to healthy controls. Additionally, there is evidence of a close bidirectional interaction between the nervous system and gut microbiota, mediated by the gut-brain axis. This relationship suggests that dietary interventions targeting gut health may influence ADHD symptoms and related comorbidities. Conclusions: Oxidative stress and the gut-brain axis are key factors in the pathogenesis of ADHD, particularly in adults with comorbid conditions. A better understanding of these mechanisms could lead to more targeted treatments, including dietary interventions, to mitigate ADHD symptoms. Further research is required to explore the therapeutic potential of modulating oxidative stress and gut microbiota in the management of ADHD.

PSI-1 Genetic and non-genetic factors influencing beef cattle attractiveness to horn fly

Abstract Horn flies are the most common summer pests of cattle, leading to substantial economic losses due to impaired production and decreased animal welfare. Genetic and non-genetic factors have been reported to influence cattle susceptibility to horn flies. However, the wide range of heritability estimates, and few identified genomic regions associated with cattle resistance to horn fly may be due to subjective assessment in collecting the fly load phenotype and the small size of the population assessed. Here, beef calves from the UF purebred Brahman (BRA) and Multibreed Angus-Brahman (MAB) populations were video recorded at weaning using a GoPro camera mounted on the top of the chute. Fly infestation was determined as the average fly count obtained from five longitudinal images of each animal using ImageJ software. A total of 748 crossbred and 415 purebred calves born from 2021 to 2023 were evaluated during summer (August or September). Analysis of variance (ANOVA) was performed within herd by fitting linear models that included collection date, age, skin color, coat color, and pre-weaning average daily gain (ADG) as fixed effects, and residual as a random effect. For MAB calves, breed groups (BG) determined based on the percentage of Brahman breed, with BG1 ranging from 0 to 19%, BG2 from 20 to 39%, BG3 from 40 to 59%, BG4 from 60 to 79%, BG5 from 80 to 100%, were also fit in the model. Fly count was transformed to a natural log value (log[count +1]) ensuring normally distribute residuals. As expected, darker colors were significantly more attractive to horn flies, while animals with greaterr percentage of Brahman were less susceptible than animals with greater percentage of Angus breed. Considerable variability in fly load was observed within purebred Brahmans, indicating that additional genetic factors, other than breed, influence cattle resistance to flies. Positive estimates were observed between horn fly load and average daily gain in both herds, which can be due to the fly load below the previously reported economic injury level of 200 flies (BRA: 28.78 ± 38.20, MAB: 19.31 ± 26.72). Variance components were estimated within herds by fitting the same aforementioned effects and a genomic-based relationship matrix (G) constructed with genotypes from the GeneSeek Genomic Profiler F250 SNP chip. The moderate heritability estimate demonstrates the feasibility of selecting cattle resistant to horn flies. Overall, our findings have the potential to contribute to reducing losses and costs in beef cattle operations, while reducing the impact on the environment of overuse of insecticides.

Transcriptome-Wide Root Causal Inference.

Root causal genes correspond to the first gene expression levels perturbed during pathogenesis by genetic or non-genetic factors. Targeting root causal genes has the potential to alleviate disease entirely by eliminating pathology near its onset. No existing algorithm discovers root causal genes from observational data alone. We therefore propose the Transcriptome-Wide Root Causal Inference (TWRCI) algorithm that identifies root causal genes and their causal graph using a combination of genetic variant and unperturbed bulk RNA sequencing data. TWRCI uses a novel competitive regression procedure to annotate cis and trans-genetic variants to the gene expression levels they directly cause. The algorithm simultaneously recovers a causal ordering of the expression levels to pinpoint the underlying causal graph and estimate root causal effects. TWRCI outperforms alternative approaches across a diverse group of metrics by directly targeting root causal genes while accounting for distal relations, linkage disequilibrium, patient heterogeneity and widespread pleiotropy. We demonstrate the algorithm by uncovering the root causal mechanisms of two complex diseases, which we confirm by replication using independent genome-wide summary statistics.

The Impact of Genetic and Non-Genetic Factors on Lamb Loin Shear Force.

Shear force is commonly used to evaluate tenderness, one of the most crucial eating quality aspects of sheep meat. The effect size of various factors on tenderness is still unknown. Studies have suggested that both genetic and environmental factors contribute to the variation in meat tenderness, and there are possible interactions between these factors. An extensive data set (n = 23,696) was analyzed to examine genetic and non-genetic influences on the shear force at 5 days postmortem (SF5). SF5 was measured on lamb loins (Longissimus lumborum) taken from lambs reared over 12 years at eight sites across Australia. The results showed that all carcass traits had a significant (p < 0.001) impact on SF5, with the largest effect on SF5 associated with intramuscular fat (IMF %) (f = 1035). There was also a significant effect of sex, cold shortening at 18 °C, sire type and cohort on SF5 (p < 0.001), with a large variation observed between the minimum cohort at 15.9 ± 1.5 N and maximum at 51.2 ± 2.1 N. In conclusion, a complex matrix of production, processing and genetic factors impact lamb tenderness as measured by shear force. This experiment helps identify the size of the contribution of these factors towards lamb tenderness, enabling the sheep industry to enhance consumers' satisfaction.

Deciphering genetic and nongenetic factors underlying tumour dormancy: insights from multiomics analysis of two syngeneic MRD models of melanoma and leukemia

BackgroundTumour dormancy, a resistance mechanism employed by cancer cells, is a significant challenge in cancer treatment, contributing to minimal residual disease (MRD) and potential relapse. Despite its clinical importance, the mechanisms underlying tumour dormancy and MRD remain unclear. In this study, we employed two syngeneic murine models of myeloid leukemia and melanoma to investigate the genetic, epigenetic, transcriptomic and protein signatures associated with tumour dormancy. We used a multiomics approach to elucidate the molecular mechanisms driving MRD and identify potential therapeutic targets.ResultsWe conducted an in-depth omics analysis encompassing whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), transcriptome and proteome investigations. WES analysis revealed a modest overlap of gene mutations between melanoma and leukemia dormancy models, with a significant number of mutated genes found exclusively in dormant cells. These exclusive genetic signatures suggest selective pressure during MRD, potentially conferring resistance to the microenvironment or therapies. CNV, histone marks and transcriptomic gene expression signatures combined with Gene Ontology (GO) enrichment analysis highlighted the potential functional roles of the mutated genes, providing insights into the pathways associated with MRD. In addition, we compared “murine MRD genes” profiles to the corresponding human disease through public datasets and highlighted common features according to disease progression. Proteomic analysis combined with multi-omics genetic investigations, revealed a dysregulated proteins signature in dormant cells with minimal genetic mechanism involvement. Pathway enrichment analysis revealed the metabolic, differentiation and cytoskeletal remodeling processes involved in MRD. Finally, we identified 11 common proteins differentially expressed in dormant cells from both pathologies.ConclusionsOur study underscores the complexity of tumour dormancy, implicating both genetic and nongenetic factors. By comparing genomic, transcriptomic, proteomic, and epigenomic datasets, our study provides a comprehensive understanding of the molecular landscape of minimal residual disease. These results provide a robust foundation for forthcoming investigations and offer potential avenues for the advancement of targeted MRD therapies in leukemia and melanoma patients, emphasizing the importance of considering both genetic and nongenetic factors in treatment strategies.Graphical

Dynactin-1 mediates rescue of impaired axonal transport due to reduced mitochondrial bioenergetics in amyotrophic lateral sclerosis motor neurons.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. A key pathological signature of ALS is the cytoplasmic mislocalization and aggregation of TDP-43 in affected motor neurons, which is found in 97% of cases. Recent reports have shown that mitochondrial dysfunction plays a significant role in motor neuron degeneration in ALS, and TDP-43 modulates several mitochondrial transcripts. In this study, we used induced pluripotent stem cell-derived motor neurons from ALS patients with TDP-43 mutations and a transgenic TDP-43M337V mouse model to determine how TDP-43 mutations alter mitochondrial function and axonal transport. We detected significantly reduced mitochondrial respiration and ATP production in patient induced pluripotent stem cell-derived motor neurons, linked to an interaction between TDP-43M337V with ATPB and COX5A. A downstream reduction in speed of retrograde axonal transport in patient induced pluripotent stem cell-derived motor neurons was detected, which correlated with downregulation of the motor protein complex, DCTN1/dynein. Overexpression of DCTN1 in patient induced pluripotent stem cell-derived motor neurons significantly increased the percentage of retrograde travelling mitochondria and reduced the percentage of stationary mitochondria. This study shows that ALS induced pluripotent stem cell-derived motor neurons with mutations in TDP-43 have deficiencies in essential mitochondrial functions with downstream effects on retrograde axonal transport, which can be partially rescued by DCTN1 overexpression.

Influence of non-genetic factors on milk production traits of Gangatiri cattle in Varanasi district of Uttar Pradesh

Research was carried out to examine the influence of non-genetic factors on the milk production characteristics of Gangatiri cows. The study was analyzed from 1254 Gangatiri cows across three tehsils (Pindra, Rajatalab, and Sadar) in Varanasi, Uttar Pradesh. The objective was to ascertain the effects of a number of variables on lactation duration, daily milk production, and lactation milk production including the area, calving season, farmer's economic background, parity, and age at first calving. The overall average means for lactation milk production, daily production of milk, and lactation period were discovered to be 794.6413 kg, 3.956 kg, and 203.8327 days, respectively. The comparison of different parameters indicated that non-genetic factors had a significant impact on milk production. These factors include the region where the survey was conducted, the calving season, the financial context of the farmer, parity or lactation, and first calving age. By analyzing the mean of these parameters, we could determine their impact on milk yield potentials. Given the influence of external variables and differences in the qualities under investigation, the study indicates that significant improvements in the population of Gangatiri cattle can be accomplished by improved management.

Reconceptualizing and Defining Exposomics within Environmental Health: Expanding the Scope of Health Research.

Exposomics, the study of the exposome, is flourishing, but the field is not well defined. The term "exposome" refers to all environmental influences and associated biological responses throughout the lifespan. However, this definition is very similar to that of the term "environment"-the external elements and conditions that surround and affect the life and development of an organism. Consequently, the exposome seems to be nothing more than a synonym for the environment, and exposomics a synonym for environmental research. As a result, some have rebranded their "standard" environmental health research with the neologistic exposome term, whereas others ignore or seek to abandon the seemingly redundant concept of the exposome. We argue that exposomics needs to sharpen its mission focus to counteract this apparent redundancy. Exposomics should be defined as a research program in environmental health aimed at enabling a comprehensive and discovery-driven approach to identifying environmental determinants of human health. Similar to the aim of the Human Genome Project, exposomics aims to analyze the complete complexity of exposures and their corresponding biological responses. Exposomics' primary premise is that the existence of undiscovered, potentially interconnected, nongenetic (environmental) risk factors for health necessitates a comprehensive discovery-driven analysis approach. We argue that exposomics researchers should adopt our reconceptualization of exposomics and focus on the productiveness and integrity of their research program: its purpose and principles. We suggest that exposomics researchers should coordinate the writing of reviews that assess the program's productiveness and integrity, as well as provide a platform for exposomics researchers to define their vision for the field. https://doi.org/10.1289/EHP14509.