Influence Of Genetic Background Research Articles

Pyoverdine-antibiotic combination treatment: its efficacy and effects on resistance evolution in Escherichia coli

Abstract Antibiotic resistance is a growing concern for global health, demanding innovative and effective strategies to combat pathogenic bacteria. Pyoverdines, iron-chelating siderophores produced by environmental Pseudomonas spp., present a novel class of promising compounds to induce growth arrest in pathogens through iron starvation. While we previously demonstrated the efficacy of pyoverdines as antibacterials, our understanding of how these molecules interact with antibiotics and impact resistance evolution remains unknown. Here, we investigated the propensity of three Escherichia coli strains to evolve resistance against pyoverdine, the cephalosporin antibiotic ceftazidime, and their combination. We used a naive E. coli wildtype strain and two isogenic variants carrying the blaTEM-1 β-lactamase gene on either the chromosome or a costly multicopy plasmid to explore the influence of genetic background on selection for resistance. We found that strong resistance against ceftazidime and weak resistance against pyoverdine evolved in all E. coli variants under single treatment. Ceftazidime resistance was linked to mutations in outer membrane porin genes (envZ and ompF), whereas pyoverdine resistance was associated with mutations in the oligopeptide permease (opp) operon. In contrast, ceftazidime resistance phenotypes were attenuated under combination treatment, especially for the E. coli variant carrying blaTEM-1 on the multicopy plasmid. Altogether, our results show that ceftazidime and pyoverdine interact neutrally and that pyoverdine as an antibacterial is particularly potent against plasmid-carrying E. coli strains, presumably because iron starvation compromises both cellular metabolism and plasmid replication.

Validation and identification of new QTLs for plant and fruit developmental and composition traits in eggplant under low N conditions

Enhancing plant adaptation to low input conditions is a fundamental goal for implementing sustainable agriculture. In the present study, two eggplant (Solanum melongena) accessions (MEL1 and MEL5), two introgression lines (ILs) derived from eggplant wild relatives S. dasyphyllum (IL-M1-D1) and S. insanum (IL-M5-I9), and a heterozygous version of this last IL (ILHet-M5-I9), along with hybrids among them were evaluated under low N (LN) conditions. IL-M1-D1 carries an introgressed fragment of 4.9 Mb in homozygosis from S. dasyphyllum on chromosome 2, while IL-M5-I9 and ILHet-M5-I9 carry an introgression of 21.5 Mb on chromosome 9 in homozygosis and heterozygosis, respectively, from S. insanum. Multiple quantitative trait loci (QTLs) for several traits of interest were associated with both introgressions under LN conditions in a previous study with segregating advanced backcrosses. Here we evaluated the performance of these materials for 22 agronomic and developmental traits under low N fertilization (LN) conditions. Hybrids with the ILs enabled the study of genetic background effects on QTLs expression. The materials evaluated showed a significant phenotypic variation, particularly within hybrids segregating for the introgression from S. insanum in chromosome 9. Statistical analysis revealed no significant differences among hybrids carrying or not the introgression on chromosome 2 of S. dasyphyllum, and only slight differences were observed between the IL-M1-D1 and its recurrent parent S. melongena MEL1, suggesting a limited impact of this introgression on chromosome 2 on the phenotype variation. However, the differences observed between IL-M5-I9 and its recurrent parent S. melongena MEL5, together with the association between genotypic and phenotypic variation in hybrids segregating for this introgression, allowed the identification of 13 QTLs on chromosome 9. These results successfully validated the previously identified QTLs for flavonol content in leaves, nitrogen balanced index, fruit mean weight, and nitrogen content in leaves and, also revealed nine new QTLs associated with the introgressed genomic region in chromosome 9. This study emphasizes the influence of environmental conditions, genotypes, and genetic backgrounds on the phenotypic expression of eggplant QTLs introgressed from wild relatives and highlights the importance of QTL validation. These findings contribute valuable insights for developing new eggplant cultivars for a more sustainable agriculture, particularly with adaptation to LN conditions.

Abstract Mo009: Systems genetics approach identifies the genetic basis underlying anthracycline-induced cardiotoxicity

Background: Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated cancer patients. Effects of genetic variations to individual susceptibility to ACT is emerging. However, diverse lifestyle and environmental factors combined with small sample sizes in human cohorts remain as limitations to effectively clarify the genetic susceptibility to ACT. This study employed a murine genetic reference population (GRP) of BXD mice derived from crosses between DBA/2J and C57BL/6J strains for mapping of quantitative trait loci (QTLs) associated with doxorubicin (DOX)-induced traits using systems genetics methods. Methods: To model the variability in ACT to DOX, 56 BXD strains (N≥3 mice/sex, 3-4 month-old) were injected intraperitonially once with DOX (20 mg/kg). Survival and body weight (BW) were monitored daily for 10 Days (D). Echocardiography was performed before and on D5 after DOX. Genetic mapping was performed using WebQTL (www.genenetwork.org) and multi-criteria scoring was used for filtering candidate genes associated with DOX-induced traits. Results: Varied body weight loss, proportions and median survival rates were found among DOX-treated BXDs. Parental C57BL/6J strain had 100% survival, while 75% of DBA/2J mice survived on D10. Among BXDs tested, 47 strains had median survival of 6±1 D, with the lowest seen in BXD77 (4 D). Echocardiography revealed abnormal small heart and restrictive dysfunction in BXDs, resembling Grinch syndrome seen in ACT patients. A significant QTL (LRS = 17.11) at 86~94 Mb of Chromosome (Chr) 10 was identified (genome wide P < 0.05). Further filtering identified Gnptab , Slc25a3 , Uhrf1bp1l, and Chpt1 as top candidate genes associated with the survival of DOX-treated BXDs. Mapping of QTLs associated with echocardiography values and weight loss are in a progress. Conclusions: Survival, BW loss, and echocardiography parameters significantly varied among DOX-treated BXDs suggesting an influence of genetic background on expression of those traits. Gnptab , Slc25a3, Uhrf1bp1l, and Chpt1 (Chr 10) are associated with DOX-induced survival traits in BXDs of GRP, suggesting that these genes are involved in modulating ACT severity in humans and require further functional and biological validation.

Elimination of the extra chromosome of Dup15q syndrome iPSCs for cellular and molecular investigation

Chromosome 15q11.2–13.1 duplication (Dup15q) syndrome is one of the most common autism spectrum disorders (ASDs) associated with copy number variants (CNVs). For the analysis of CNV-relevant pathological cellular phenotypes, a CNV-corrected isogenic cell line is useful for excluding the influence of genetic background. Here, we devised a strategy to remove the isodicentric chromosome 15 by inserting a puro-ΔTK selection cassette into the extra chromosome using the CRISPR-Cas9 system, followed by a subsequent two-step drug selection. A series of assays, including qPCR-based copy number analysis and karyotype analysis, confirmed the elimination of the extra chromosome. Furthermore, cerebral organoids were generated from the parental Dup15q iPSCs and their isogenic iPSCs. scRNA-seq analysis revealed the alteration of expression levels in ion-channel-related genes and synapse-related genes in glutamatergic and GABAergic neurons in Dup15q organoids, respectively. The established isogenic cell line is a valuable resource for unraveling cellular and molecular alterations associated with Dup15q syndrome.

Impact of parental body mass index at diagnosis on obesity in survivors of pediatric craniopharyngioma.

It is well known that both genetic background and lifestyle influence the development of 'general' obesity. However, the role of parental body mass index (BMI) on the development of obesity in long-term survivors of childhood-onset craniopharyngioma (CP) is not well understood. This study analyzed the correlation of patients' BMI at diagnosis and last visit and parental BMI at CP diagnosis and further explored potential risk factors for obesity in CP patients. This is a registry-based retrospective cohort study. In total,291 CP patients and their parents recruited in the German KRANIOPHARYNGEOM studies were included. Correlations between patient's BMI SDS at CP diagnosis and last visit and parental BMI at CP diagnosis were analyzed. The associations between hypothalamic damage, maternal/paternal BMI and CP patients' obesity at last visit were analyzed by multivariable logistic regression. At follow-up, 52% of CP patients developed obesity (BMI > 3SDS). Patient's BMI SDS at last visit was moderately correlated with BMI-SDS at CP diagnosis (r = 0.48, 95% CI: 0.38-0.58, P < 0.001), and also with maternal BMI at diagnosis (r = 0.28, 95% CI: 0.17-0.38, P < 0.001) and paternal BMI at diagnosis (r = 0.3, 95% CI: 0.19-0.41, P < 0.001). However, the contributing role of parental BMI to the pathogenesis of obesity was small compared to the impact of hypothalamic damage. We conclude that besides hypothalamic damage, parental disposition for obesity is associated with the development of obesity in patients after CP. Our results indicate that also the family situation could have an influence on the development of obesity after CP and might be a therapeutic target. Survivors of childhood-onset craniopharyngioma are at risk of developing morbid obesity. So far, patients with posterior hypothalamic involvement and lesion were identified as a high risk group. With this study, the influence of parental body mass index on the risk of obesity was investigated. Patient's body-mass-index at last visit was correlated with maternal and paternal body mass index at diagnosis. With increasing maternal or paternal body mass index, the likelihood of obesity in individuals with CP increased. Nevertheless, the parents' weight had only a small effect on the development of patients' obesity compared to hypothalamic damage.

Regulatory Mechanisms of Aging Through the Nutritional and Metabolic Control of Amino Acid Signaling in Model Organisms

Life activities are supported by the intricate metabolic network that is fueled by nutrients. Nutritional and genetic studies in model organisms have determined that dietary restriction and certain mutations in the insulin signaling pathway lead to lifespan extension. Subsequently, the detailed mechanisms of aging as well as various nutrient signaling pathways and their relationships have been investigated in a wide range of organisms, from yeast to mammals. This review summarizes the roles of nutritional and metabolic signaling in aging and lifespan with a focus on amino acids, the building blocks of organisms. We discuss how lifespan is affected by the sensing, transduction, and metabolism of specific amino acids and consider the influences of life stage, sex, and genetic background on the nutritional control of aging. Our goal is to enhance our understanding of how nutrients affect aging and thus contribute to the biology of aging and lifespan.

Enhanced Novel Object Recognition and Spatial Memory in Rats Selectively Bred for High Nicotine Preference.

This study examined the influence of genetic background on cognitive performance in a selectively bred high nicotine-preferring (NP) rat line. Using the novel object recognition (NOR), novel location recognition (NLR), and Morris water maze (MWM) tests, we evaluated object memory, spatial memory, and spatial navigation in nicotine-naive NP rats compared to controls. Our results demonstrate that in the NOR test, both male and female NP rats spent more time exploring the novel object (higher discrimination index) compared to sex-matched controls. In the NLR, the discrimination index differed significantly from zero chance (no preference) in both NP males and females but not in controls, indicating enhanced spatial memory in the NP line. During MWM acquisition, the NP groups and control males took a shorter path to reach the platform compared to control females. On the probe trial, the distance traveled in the target quadrant was longer for NP males and females compared to their respective controls, suggesting enhanced spatial navigation and learning in the NP rats. The interesting preference for novel objects and locations displayed by NP rats may indicate a potential novelty-seeking phenotype in this line. These results highlight the complex interplay between genetic factors, cognitive function, and nicotine preference.

Attachment-like behavioral expressions to humans in puppies are related to oxytocin and cortisol: A comparative study of Akitas and Labrador Retrievers

This study investigated the relationship between urinary hormone concentrations and attachment-related behaviors in two dog breeds, the Akitas and Labrador Retrievers, to elucidate the hormonal and behavioral mechanisms underlying domestication and interspecies attachment to humans. By measuring cortisol and oxytocin concentrations, and conducting the Strange Situation Test (SST), we aimed to investigate breed differences in endocrine secretions associated with domestication and how these differences influence dog behavior toward humans. Our results showed significant breed differences in urinary cortisol concentrations, with Akitas exhibiting higher levels than Labrador Retrievers. This suggests a breed-specific stress response related to genetic proximity to wolves. However, oxytocin concentrations did not differ significantly, which suggests a complex interplay between factors influencing the domestication process and the formation of attachment behaviors. Behavioral observations during the SST revealed breed-specific patterns, with Labrador Retrievers showing more playful and attachment-like behaviors and Akitas showing more exploratory and passive behaviors. The study found correlations between hormones and behaviors within breeds, particularly in Labrador Retrievers, where oxytocin concentrations were associated with attachment-like behaviors, and cortisol concentrations reflected individual differences in physical activity rather than stress responses to social situations. These findings contribute to the understanding of the evolutionary and adaptive processes underlying the ability of domestic dogs to form close relationships with humans while highlighting the role of hormonal mechanisms in mediating attachment behaviors and the influence of breed-specific genetic backgrounds on these processes.

The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

Development and Characterization of a Novel FVB-PrkdcR2140C Mouse Model for Adriamycin-Induced Nephropathy.

The Adriamycin (ADR) nephropathy model, which induces podocyte injury, is limited to certain mouse strains due to genetic susceptibilities, such as the PrkdcR2140C polymorphism. The FVB/N strain without the R2140C mutation resists ADR nephropathy. Meanwhile, a detailed analysis of the progression of ADR nephropathy in the FVB/N strain has yet to be conducted. Our research aimed to create a novel mouse model, the FVB-PrkdcR2140C, by introducing PrkdcR2140C into the FVB/NJcl (FVB) strain. Our study showed that FVB-PrkdcR2140C mice developed severe renal damage when exposed to ADR, as evidenced by significant albuminuria and tubular injury, exceeding the levels observed in C57BL/6J (B6)-PrkdcR2140C. This indicates that the FVB/N genetic background, in combination with the R2140C mutation, strongly predisposes mice to ADR nephropathy, highlighting the influence of genetic background on disease susceptibility. Using RNA sequencing and subsequent analysis, we identified several genes whose expression is altered in response to ADR nephropathy. In particular, Mmp7, Mmp10, and Mmp12 were highlighted for their differential expression between strains and their potential role in influencing the severity of kidney damage. Further genetic analysis should lead to identifying ADR nephropathy modifier gene(s), aiding in early diagnosis and providing novel approaches to kidney disease treatment and prevention.

Influence of genetic background on the clinical picture of bipolar affective disorder in a population of children and adolescents

IntroductionBipolar disorder in children is characterized by a different course than in adults, which is a diagnostic difficulty. DAT-1 is a dopamine transporter gene that regulates dopaminergic neurotransmission through the mechanism of active reuptake of this neurotransmitter from the synapse. Polymorphisms within the described gene can result in changes in dopamine levels, which may have implications for the development of bipolar disorder.Objectives The aim of the project was to analyze the relationship between single nucleotide polymorphisms (SNPs) within the dopamine transporter gene DAT-1 and the risk of development of bipolar disorder in a population of children and adolescents.Methods21 healthy controls (12 females, 9 males) have been recruited into the study and 13 patients (9 girls, 4 boys) with bipolar disorder diagnosis from Department of Psychiatry and outpatient clinic, were recruited for the study group. Questionnaires such as the KSADS-PL were carried out and blood was taken for laboratory tests of four SNPs within the DAT-1 transporter. PQStat, Microsoft Excel 2013 and StatSoft STATISTICA were used to perform the statistical analysis.ResultsSNPs within the dopamine transporter gene and environmental risk factors influenced the risk of developing bipolar disorder in the population of children and adolescents.ConclusionsThe ambiguity in results emphasizes the necessity for further investigations into correlation between genetic factors in bipolar disorder etiology. Future research should involve more participants. The results of this project are likely to make a significant and valuable contribution to the current knowledge of bipolar disorder and to the development of innovative diagnostic methods, making a significant contribution to the advancement of science.Disclosure of InterestNone Declared

Host Genetic Background Influences BCG-Induced Antibodies Cross-Reactive to SARS-CoV-2 Spike Protein.

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) protects against childhood tuberculosis; and unlike most vaccines, BCG broadly impacts immunity to other pathogens and even some cancers. Early in the COVID-19 pandemic, epidemiological studies identified a protective association between BCG vaccination and outcomes of SARS-CoV-2, but the associations in later studies were inconsistent. We sought possible reasons and noticed the study populations often lived in the same country. Since individuals from the same regions can share common ancestors, we hypothesized that genetic background could influence associations between BCG and SARS-CoV-2. To explore this hypothesis in a controlled environment, we performed a pilot study using Diversity Outbred mice. First, we identified amino acid sequences shared by BCG and SARS-CoV-2 spike protein. Next, we tested for IgG reactive to spike protein from BCG-vaccinated mice. Sera from some, but not all, BCG-vaccinated Diversity Outbred mice contained higher levels of IgG cross-reactive to SARS-CoV-2 spike protein than sera from BCG-vaccinated C57BL/6J inbred mice and unvaccinated mice. Although larger experimental studies are needed to obtain mechanistic insight, these findings suggest that genetic background may be an important variable contributing to different associations observed in human randomized clinical trials evaluating BCG vaccination on SARS-CoV-2 and COVID-19.

Different patterns of inter-annual variability in mean vessel area and tree-ring widths of beech from provenance trials in Slovenia and Hungary

Key messageStudied beech provenances showed different patterns of inter-annual variability in mean vessel area and ring widths, indicating influence of intraspecific variability and diverse environment on hydraulic conductivity and carbon storage potential.International provenance trials of ecologically and economically important tree species are crucial to deciphering the influence of environmental factors and intraspecific variability on tree growth and performance under climate change to guide assisted gene flow and assisted migration of tree provenances and species. In this context, we compared inter-annual trends in tree-ring widths (carbon sequestration potential) and vessel characteristics (conductivity optimisation) of four beech provenances in two international provenance trials, one in Slovenia (Kamenski hrib, a core beech growing site) and one in Hungary (Bucsuta, a marginal beech site) in 2009–2019. We found different patterns of inter-annual variability in mean vessel area and tree-ring widths among provenances and sites, pointing to diverse genetic background and environmental influence on these two wood-anatomical traits. The average values of the vessel area varied less between provenances at Kamenski hrib than at Bucsuta. Weather conditions differently affected tree-ring width and mean vessel area. Furthermore, the length of the period of response of vessel area to the analysed weather conditions differed in summer and winter periods. The differences in the mean vessel area within the tree ring were more pronounced in the weather-wise extreme years, regardless of the provenance. Consistent with previous studies, we confirmed that site conditions affect the climate sensitivity of trees, which is more pronounced at marginal sites or in extreme years. The findings on how different environmental conditions affect the radial growth of young beech trees of different origin are very important for future forest management.

SARS-CoV-2 immune response and reinfection in vaccinated Maya and mestizo in Southeast of Mexico.

Immune response to pathogens, including coronaviruses, is influenced by HLA haplotypes. 1,2. Maya ethnic group is predominant in Yucatan peninsula, this Amerindian group present allele frequency HLA-G*01:01:02, HLA-G*01:01:01, HLA-G*01:04:01, HLA-A*68 not found in another Amerindians.3-5 Immune response to SARS-CoV-2 vaccination and reinfection particularly after Omicron variant appeared was explored in 118 vaccinated subjects with complete two shots immunization in Maya ascendant and mestizo no-Maya. 1172 epidemiological survey applied to university staff in Campeche, Mexico to evaluate reinfection, co-morbidities, variant virus, disease severity, aftermaths, clinical outcomes, age, sex, ethnicity, and vaccination shots. Multiple logistic regression, correspondence analysis, and association tests were used to analysis data. Sixteen percent of vaccinated subjects became seronegative after 11 months. We found that vaccinated Maya subjects respond with higher IgG immune response compared to no-Maya subjects, similarly women respond with higher IgG response than men (p<0.05). During an eleven-month period and after two vaccination shots, 7% of the vaccinated subjects reported a confirmed positive infection, and after the third vaccine shot a higher IgG immune response than two vaccination shots or natural infection was detected. However, we observed 23.7% reinfection in people after the third shot. This data represents almost three times the reinfection rate reported when compared to previous third vaccine shots. The increase of reinfection in vaccinated subjects was associated with circulation of Omicron variant by 71.5%. Others have reported reinfection of 40% and vaccine effectiveness of 60% during Omicron dominance.6 To understand COVID-19 severity after reinfection in vaccinated subjects and the associated variables, we carried out a multiple logistic regression, and found a strong association between less severe symptoms with Alfa and Omicron variants (B 5.3; Error 0.39; Wald 0.00; Significance 0.00; OR201). However, subjects with severe symptoms and or hospitalization correspondent to individuals with multiplex comorbidities and Gamma SARS-CoV-2 variants (B 5.06; Error 0.97; Wald 26.8; Significance 0.00; OR 158). A follow-up survey of COVID-19 recovered patients experienced diverse digestive, respiratory, cardiac, neurological, or joints involvement sequelae. We looked for SARS-CoV-2 variant and COVID-19 sequelae in a correspondence analysis. Our data suggest that Beta and Delta variants are associated with respiratory and digestive symptoms, whereas Omicron was more closely associated with joints and digestive symptoms, and finally the Gamma variant displayed wider and more diverse symptoms. Our results suggest that genetic background and gender influence IgG response to SARS-CoV-2 vaccine, and Maya ascendant has higher immune IgG response to vaccine than mestizos. Reinfection in our population studied fluctuate from 7% to 23.7% nevertheless is higher if Omicron variant is involved, but symptoms are less severe and more closely associated with joints and digestive symptoms.

Genetic background and thermal regime influence adaptation to novel environment in the seed beetle, Callosobruchus maculatus.

Climate change is associated with the increase in both the mean and variability of thermal conditions. Therefore, the use of more realistic fluctuating thermal regimes is the most appropriate laboratory method for predicting population responses to thermal heterogeneity. However, the long- and short-term implications of evolving under such conditions are not well understood. Here, we examined differences in key life-history traits among populations of seed beetles (Callosobruchus maculatus) that evolved under either constant control conditions or in an environment with fluctuating daily temperatures. Specifically, individuals from two distinct genetic backgrounds were kept for 19 generations at one of two temperatures, a constant temperature (T = 29 °C) or a fluctuating daily cycle (Tmean = 33 °C, Tmax = 40 °C, and Tmin = 26 °C), and were assayed either in their evolved environment or in the other environment. We found that beetles that evolved in fluctuating environments but were then switched to constant 29 °C conditions had far greater lifetime reproductive success compared with beetles that were kept in their evolved environments. This increase in reproductive success suggests that beetles raised in fluctuating environments may have evolved greater thermal breadth than control condition beetles. In addition, the degree of sexual dimorphism in body size and development varied as a function of genetic background, evolved thermal environment, and current temperature conditions. These results not only highlight the value of incorporating diel fluctuations into climate research but also suggest that populations that experience variability in temperature may be better able to respond to both short- and long-term changes in environmental conditions.

Genetic background influences arterial vasomotor function in male and female mice.

The purpose of this study was to assess the influence of genetic background and sex on nitric oxide (NO)-mediated vasomotor function in arteries from different vascular territories. Vasomotor function was assessed in thoracic aorta, abdominal aorta, carotid arteries, and femoral arteries from the following mouse strains: SJL/J, DBA/2J, NZW/LacJ, and C57BL/6J. Contractile responses were assessed using the α1-adrenergic receptor agonist phenylephrine (PE, 10-9 -10-5 M). Vasorelaxation responses were assessed by examining relaxation to an endothelium-dependent vasodilator acetylcholine (ACh, 10-9 -10-5 M) and an endothelium-independent vasodilator sodium nitroprusside (SNP, 10-9 -10-5 M). To evaluate the role of NO, relaxation responses to ACh and SNP were assessed in the absence or presence of a nitric oxide synthase inhibitor (N omega-nitro-l-arginine methyl ester hydrochloride: 10-4 M). Vasomotor responses to ACh and PE varied across strains and among the arteries tested with some strains exhibiting artery-specific impairment. Results indicated some concentration-response heterogeneity in response to ACh and SNP between vessels from females and males, but no significant differences in responses to PE. Collectively, these findings indicate that vasomotor responses vary by genetic background, sex, and artery type.

Exploring the interplay between metabolomics and genetics in Parkinson's disease: Insights from ongoing research and future avenues

Parkinson's disease (PD) is a widespread neurodegenerative disorder, whose complex aetiology remains under construction. While rare variants have been associated with the monogenic PD form, most PD cases are influenced by multiple genetic and environmental aspects. Nonetheless, the pathophysiological pathways and molecular networks involved in monogenic/idiopathic PD overlap, and genetic variants are decisive in elucidating the convergent underlying mechanisms of PD. In this scenario, metabolomics has furnished a dynamic and systematic picture of the synergy between the genetic background and environmental influences that impact PD, making it a valuable tool for investigating PD-related metabolic dysfunctions. In this review, we performed a brief overview of metabolomics current research in PD, focusing on significant metabolic alterations observed in idiopathic PD from different biofluids and strata and exploring how they relate to genetic factors associated with monogenic PD. Dysregulated amino acid metabolism, lipid metabolism, and oxidative stress are the critical metabolic pathways implicated in both genetic and idiopathic PD. By merging metabolomics and genetics data, it is possible to distinguish metabolic signatures of specific genetic backgrounds and to pinpoint subgroups of PD patients who could derive personalized therapeutic benefits. This approach holds great promise for advancing PD research and developing innovative, cost-effective treatments.

Genetic background modulates phenotypic expressivity in OPA1 mutated mice, relevance to DOA pathogenesis.

Dominant optic atrophy (DOA) is mainly caused by OPA1 mutations and is characterized by the degeneration of retinal ganglion cells (RGCs), whose axons form the optic nerve. The penetrance of DOA is incomplete and the disease is marked by highly variable expressivity, ranging from asymptomatic patients to some who are totally blind or who suffer from multisystemic effects. No clear genotype-phenotype correlation has been established to date. Taken together, these observations point toward the existence of modifying genetic and/or environmental factors that modulate disease severity. Here, we investigated the influence of genetic background on DOA expressivity by switching the previously described DOA mouse model bearing the c.1065 + 5G → A Opa1 mutation from mixed C3H; C57BL/6 J to a pure C57BL/6 J background. We no longer observed retinal and optic nerve abnormalities; the findings indicated no degeneration, but rather a sex-dependent negative effect on RGC connectivity. This highlights the fact that RGC synaptic alteration might precede neuronal death, as has been proposed in other neurodegenerative diseases, providing new clinical considerations for early diagnosis as well as a new therapeutic window for DOA. Furthermore, our results demonstrate the importance of secondary genetic factors in the variability of DOA expressivity and offer a model for screening for aggravating environmental and genetic factors.

Potential of bone morphogenetic protein-7 in treatment of lupus nephritis: addressing the hurdles to implementation.

Up to 50% of systemic lupus erythematosus (SLE) patients world-wide develop lupus nephritis (LN). In low to middle income countries and in particular in sub-Saharan Africa, where SLE is prevalent with a more aggressive course, LN and end stage renal disease is a major cause of mortality. While developed countries have the funding to invest in SLE and LN research, patients of African descent are often underrepresented in clinical trials. Thus, the complex influence of ethnicity and genetic background on outcome of LN and SLE as a whole, is not fully understood. Several pathophysiological mechanisms including major role players driving LN have been identified. A large body of literature suggest that prevention of fibrosis-which contributes to chronicity of LN-may significantly improve long-term prognosis. Bone morphogenetic protein-7 (BMP-7) was first identified as a therapeutic option in this context decades ago and evidence of its benefit in various conditions, including LN, is ever-increasing. Despite these facts, BMP-7 is not being implemented as therapy in the context of renal disease. With this review, we briefly summarise current understanding of LN pathology and discuss the evidence in support of therapeutic potential of BMP-7 in this context. Lastly, we address the obstacles that need to be overcome, before BMP-7 may become available as LN treatment.

Comparative Analysis of Structural Composition and Function of Intestinal Microbiota between Chinese Indigenous Laiwu Pigs and Commercial DLY Pigs.

Intestinal microbiota has an important impact on pig phenotypes. Previous studies mainly focused on the microbiota of feces and worldwide farmed commercial pigs, while research on the microbiota of various intestinal sections and indigenous pig breeds is very limited. This study aimed to characterize and compare the biogeography of intestinal microbiota in pigs of one Chinese indigenous breed and one commercial crossbred. In this study, we sequenced the microbiota of six intestinal segments in the grown-up pigs of a Chinese indigenous breed, Laiwu pigs, and the worldwide farmed crossbred Duroc × Landrace × Yorkshire (DLY) pigs by 16S rRNA sequencing, characterized the biogeography of intestinal microbiota, and compared the compositional and functional differences between the two breeds. The results showed that there were obvious differences in microbial structure and abundance between the small and large intestines. Laiwu pigs had higher large intestinal diversity than DLY pigs, while DLY pigs had higher small intestinal diversity than Laiwu pigs. Moreover, some specific bacterial taxa and Kyoto Encyclopedia of Genes and Genomes pathways were found to be related to the high fat deposition and good meat quality of Laiwu pigs and the high growth speed and lean meat rate of DLY pigs. This study provides an insight into the shifts in taxonomic composition, microbial diversity, and functional profile of intestinal microbiota in six intestinal segments of Laiwu and DLY pigs, which would be essential for exploring the potential influence of the host's genetic background on variation in microbiota composition and diversity.