Genetic Disposition Research Articles

The Influence of the Gut Microbiota on Host Health: A Focus on the Gut–Lung Axis and Therapeutic Approaches

The human gut microbiota is a complex ecosystem harboring thousands of microbial strains that play a crucial role in maintaining the overall well-being of its host. The composition of the gut microbiota varies with age from infancy to adulthood and is influenced by dietary habits, environment, and genetic disposition. Recent advances in culture-independent techniques and nucleic acid sequencing have improved our understanding of the diversity of the gut microbiota. The microbial species present in the gut release short-chain fatty acids (SCFAs), which have anti-inflammatory properties. The gut microbiota also plays a substantial role in modulating the host′s immune system, promoting immune tolerance, and maintaining homeostasis. The impact of the gut microbiota on the health of the host is quite evident, as gut dysbiosis has been linked to various diseases, including metabolic disorders, autoimmune diseases, allergies, and inflammatory bowel diseases. The gut microbiota has bidirectional communication with the respiratory system, creating the gut–lung axis, which has been associated with different respiratory diseases. Therapeutic approaches targeting the gut microbiota, such as probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation (FMT), aim to restore microbial balance and promote the growth of beneficial strains in the gut. Nonetheless, gaining knowledge of the complex interactions between the gut microbiota and the host is necessary to develop personalized medicine approaches and microbiota-based therapies for various conditions. This review summarizes studies related to the gut–lung axis with particular emphasis on the role of the microbiota. Future research directions are also discussed.

Prediabetes : Prevalence and Causes

Prediabetes is a condition where the blood glucose levels are high, but not enough to be diagnosed as diabetes. The HbA1C test can identify the prediabetes conditions as the blood glucose levels are between 5.7% to 6.4%. The fasting glucose level are said to be around 125 mg/dL and IGT levels are seen around 199 mg/dL. Prediabetes have a high burden of Cardiovascular Risk. Prediabetes is a multifactorial condition, the environmental risk factors include diet, lack of physical activity, increase age, obesity or overweight and the biological risk factors include insulin resistance, genetic disposition and beta cell dysfunction. According to research carried out in 2021, the global prevalence is said to be around 14%, combining the prevalence of IGT and IFG. Awareness of Prediabetes is very much needed because an affected individual, if not aware, may end up in a severe disease such as CVD.

Analysis of genetic variants for different horn phenotypes and their inheritance in Icelandic sheep

Abstract. Icelandic sheep are characterized by a great diversity in horn phenotypes. Within their breed, they show a variability in terms of this trait to an extent rarely observed elsewhere. Previously, several genetic variants were published as markers for horn status (in terms of absence or presence of horns, including scurs) and horn traits (e.g., oval horns, horn length and polyceraty). The aim of this study was to genotype, for the first time, five of these genetic variants in Icelandic sheep with different horn phenotypes, as well as to analyze their inheritance. Phenotypic and pedigree data, as well as DNA samples from two Icelandic sheep farms, were used. Genetic variants were genotyped by published PCR-based methods in all samples (n=94) or in subsets. As in other sheep breeds with variable horn status, the inheritance of the presence or absence of horns was shown to be complex in Icelandic sheep, especially when sheep carry anything other than regularly formed horns. The 1.78 kb sized RXFP2 insertion on ovine chromosome 10 previously described to be associated with polledness in several sheep breeds was also found to be present in Icelandic sheep and showed some association but not a perfect segregation with the individuals' horn statuses. Missing associations were especially seen in sheep with scurs and oval horns. Regarding horn shape, there was no agreement with the studied variants described in Chinese breeds having comparable horn traits. However, matching tendencies were seen for the horn size variant that was found in the same study. All sheep with four or more horns carried the already published 4 bp deletion in HOXD1, as previously described for three other sheep breeds. Interestingly, for the first time, the deletion was also detected in phenotypically polled animals originating from multi-horned families. According to the results from animals genotyped simultaneously for the RXFP2 and the HOXD1 variants, polledness in sheep with a genetic disposition for polyceraty seems not to be controlled by the RXFP2 insertion. However, this and all other findings in Icelandic sheep need to be confirmed by analyzing a higher number of well-phenotyped animals.

Cancer predisposing syndromes in childhood and adolescence pose several challenges necessitating interdisciplinary care in dedicated programs.

Genetic disposition is a major etiologic factor in childhood cancer. More than 100 cancer predisposing syndromes (CPS) are known. Surveillance protocols seek to mitigate morbidity and mortality. To implement recommendations in patient care and to ascertain that the constant gain of knowledge forces its way into practice specific pediatric CPS programs were established. We retrospectively analyzed data on children, adolescents, and young adults referred to our pediatric CPS program between October 1, 2021, and March 31, 2023. Follow-up ended on December 31, 2023. We identified 67 patients (30 male, 36 female, 1 non-binary, median age 9.5 years). Thirty-five patients were referred for CPS surveillance, 32 for features suspicious of a CPS including café-au-lait macules (n = 10), overgrowth (n = 9), other specific symptoms (n = 4), cancer suspicious of a CPS (n = 6), and rare neoplasms (n = 3). CPS was confirmed by clinical criteria in 6 patients and genetic testing in 7 (of 13). In addition, 6 clinically unaffected at-risk relatives were identified carrying a cancer predisposing pathogenic variant. A total of 48 patients were eventually diagnosed with CPS, surveillance recommendations were on record for 45. Of those, 8 patients did not keep their appointments for various reasons. Surveillance revealed neoplasms (n = 2) and metachronous tumors (n = 4) by clinical (n = 2), radiological examination (n = 2), and endoscopy (n = 2). Psychosocial counselling was utilized by 16 (of 45; 35.6%) families. The diverse pediatric CPSs pose several challenges necessitating interdisciplinary care in specified CPS programs. To ultimately improve outcome including psychosocial well-being joint clinical and research efforts are necessary.

Repeated Exposure of Vancomycin to Vancomycin-Susceptible Staphylococcus aureus(VSSA) Parent Emerged VISA and VRSA Strains with Enhanced Virulence Potentials.

The emergence of resistance against the last-resort antibiotic vancomycin in staphylococcal infections is a serious concern for human health. Although various drug-resistant pathogens of diverse genetic backgrounds show higher virulence potential, the underlying mechanism behind this is not yet clear due to variability in their genetic dispositions. In this study, we investigated the correlation between resistance and virulence in adaptively evolved isogenic strains. The vancomycin-susceptible Staphylococcus aureus USA300 was exposed to various concentrations of vancomycin repeatedly as a mimic of the clinical regimen to obtain mutation(s)-accrued-clonally-selected (MACS) strains. The phenotypic analyses followed by expression of the representative genes responsible for virulence and resistance of MACS strains were investigated. MACS strains obtained under 2 and 8µg/ml vancomycin, named Van2 and Van8, respectively; showed enhanced vancomycin minimal inhibitory concentrations (MIC) to 4 and 16µg/ml, respectively. The cell adhesion and invasion of MACS strains increased in proportion to their MICs. The correlation between resistance and virulence potential was partially explained by the differential expression of genes known to be involved in both virulence and resistance in MACS strains compared to parent S. aureus USA300. Repeated treatment of vancomycin against vancomycin-susceptible S. aureus (VSSA) leads to the emergence of vancomycin-resistant strains with variable levels of enhanced virulence potentials.

Oxidatively-induced DNA base damage and base excision repair abnormalities in siblings of individuals with bipolar disorder DNA damage and repair in bipolar disorder

Previous evidence suggests elevated levels of oxidatively-induced DNA damage, particularly 8-hydroxy-2’-deoxyguanosine (8-OH-dG), and abnormalities in the repair of 8-OH-dG by the base excision repair (BER) in bipolar disorder (BD). However, the genetic disposition of these abnormalities remains unknown. In this study, we aimed to investigate the levels of oxidatively-induced DNA damage and BER mechanisms in individuals with BD and their siblings, as compared to healthy controls (HCs). 46 individuals with BD, 41 siblings of individuals with BD, and 51 HCs were included in the study. Liquid chromatography-tandem mass spectrometry was employed to evaluate the levels of 8-OH-dG in urine, which were then normalized based on urine creatinine levels. The real-time-polymerase chain reaction was used to measure the expression levels of 8-oxoguanine DNA glycosylase 1 (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1), poly ADP-ribose polymerase 1 (PARP1), and DNA polymerase beta (POLβ). The levels of 8-OH-dG were found to be elevated in both individuals with BD and their siblings when compared to the HCs. The OGG1 and APE1 expressions were downregulated, while POLβ expressions were upregulated in both the patient and sibling groups compared to the HCs. Age, smoking status, and the number of depressive episodes had an impact on APE1 expression levels in the patient group while body mass index, smoking status, and past psychiatric history had an impact on 8-OH-dG levels in siblings. Both individuals with BD and unaffected siblings presented similar abnormalities regarding oxidatively-induced DNA damage and BER, suggesting a link between abnormalities in DNA damage/BER mechanisms and familial susceptibility to BD. Our findings suggest that targeting the oxidatively-induced DNA damage and BER pathway could offer promising therapeutic strategies for reducing the risk of age-related diseases and comorbidities in individuals with a genetic predisposition to BD.

The Representational Challenge for Designing and Managing 5P Medicine Ecosystems.

Health and social care systems around the globe currently undergo a transformation towards personalized, preventive, predictive, participative precision medicine (5PM), considering the individual health status, conditions, genetic and genomic dispositions, etc., in personal, social, occupational, environmental and behavioral context. This transformation is strongly supported by technologies such as micro- and nanotechnologies, advanced computing, artificial intelligence, edge computing, etc. For enabling communication and cooperation between actors from different domains using different methodologies, languages and ontologies based on different education, experiences, etc., we have to understand the transformed health ecosystems and all its components in structure, function and relationships in the necessary detail ranging from elementary particles up to the universe. That way, we advance design and management of the complex and highly dynamic ecosystem from data to knowledge level. The challenge is the consistent, correct and formalized representation of the transformed health ecosystem from the perspectives of all domains involved, representing and managing them based on related ontologies. The resulting business view of the real-world ecosystem must be interrelated using the ISO/IEC 21838 Top Level Ontologies standard. Thereafter, the outcome can be transformed into implementable solutions using the ISO/IEC 10746 Open Distributed Processing Reference Model. Model and framework for this system-oriented, architecture-centric, ontology-based, policy-driven approach have been developed by the first author and meanwhile standardized as ISO 23903 Interoperability and Integration Reference Architecture.

Role of Vitamin D in the Pathogenesis of Inflammatory Bowel Diseases: Literature Review

The pathogenesis of inflammatory bowel diseases still remains unclear nowadays. Genetic disposition, impaired immune regulation, disturbance in intestinal microbiota composition, exposure to environmental factors are associated with the development of inflammation in intestinal mucosa and increased epithelial penetrance that define disease's development and progression. There is a theory in scientific literature that vitamin D deficiency (among other environmental factors) increases the risk of inflammatory bowel disease. However, the role of vitamin D in the development of gastrointestinal tract diseases remains poorly studied. This article presents current data on the vitamin D effect on the intestinal mucosa barrier function, on the immune system and on the intestinal microbiota in the context of inflammatory bowel diseases pathogenesis.

Association between uncoupling protein 1-3826 A/G polymorphism and the effects of anaerobic exercises on serum oxidative stress

ObjectivesAerobic exercise promotes uncoupling protein-1 (UCP-1) induced white adipose tissue browning by increasing serum nitric oxide (NO), irisin and interleukin-6 (IL-6). However, oxidative stress (OS) occurring during anaerobic exercise downregulates UCP-1. Moreover, UCP-1-3826 A/G polymorphism (UCP1P) is associated with weight gain due to impaired thermogenesis which may be due to UCP1P induced modification in OS. Therefore, our purpose was to investigate the role of UCP1P on the effects of acute maximal exercise (AME) and chronic anaerobic exercise (CAT) on serum OS, UCP-1, NO, irisin and IL-6 levels. Equipments and methodsSport group (SG, n=43) was formed of anaerobic athletes, while control group (CG, n=43) comprised physically inactive men. Postprandial blood was taken from SG and CG before and after AME to determine serum UCP-1, irisin, IL-6, NO, and oxidative stress index (OSI=total oxidant/antioxidant status [TOS/TAS] ratio). To investigate the effects of CAT on serum parameters, SG and CG's results were compared. UCP1P was determined by restriction fragment length polymorphism analysis. ResultsAME significantly increased all parameters in SG and CG (P<0.05). However, CAT increased only OSI and IL-6 (P<0.05), decreased UCP-1 and TAS and did not affect TOS, NO and irisin. OSI of GG homozygous athletes were significantly higher than other genotype groups (P<0.05). Although significant negative correlations were found between UCP-1 and OS markers in GG and AA genotype groups before AME, significant positive correlations were found between UCP-1 and TAS in AA genotype group after AME. GG homozygous athletes may be more prone to higher OS. Decrease in UCP-1 due to CAT may be affected by GG genotype group's genetic disposition for OS.

Pouchitis: pathophysiology and management.

Pouchitis is an acute or chronic inflammatory disease of the ileal reservoir. It is common after restorative proctocolectomy with ileal pouch-anal anastomosis, and treatment of chronic antibiotic-refractory pouchitis has proven challenging. Most cases of acute pouchitis evolve into chronic pouchitis. The aetiology of acute pouchitis is likely to be partly related to the gut microbiota, whereas the pathophysiology of chronic pouchitis involves abnormal interactions between genetic disposition, faecal stasis, the gut microbiota, dysregulated host immunity, surgical techniques, ischaemia and mesentery-related factors. Pouchoscopy with biopsy is the most valuable modality for diagnosis, disease monitoring, assessment of treatment response, dysplasia surveillance and delivery of endoscopic therapy. Triggering or risk factors, such as Clostridioides difficile infection and use of non-steroidal anti-inflammatory drugs, should be modified or eradicated. In terms of treatment, acute pouchitis usually responds to oral antibiotics, whereas chronic antibiotic-refractory pouchitis often requires induction and maintenance therapy with integrin, interleukin or tumour necrosis factor inhibitors. Chronic pouchitis with ischaemic features, fistulae or abscesses can be treated with hyperbaric oxygen therapy.

Albino Wistar Rats: Advantages and Limitations in Biomedical Research

Abstract Albino Wistar rats refer to a strain of the Wistar rats which is part of the Norway rat species; it is a popular animal model in many areas of research specifically in neuroscience, pharmacology, and toxicology among others. These rats are particularly valuable due to their high level of genetic homogeneity, ease of handling, and reproducible results which have kept them in the list of requirements for researchers who want to minimize extraneous variables in their studies. One can bet on the fact that the Albino Wistar rats are inbred, and therefore, even their genetic disposition is normalized. Wistar rats originated from the United States of America in the 19th century. In several generations of breeding, this rat strain was used to establish desired characteristics, which resulted in greatly reduced genetic variability. Thus, throughout the whole process of the research, one can be sure that the results of the study will not have any relation to the genetic differences of the participants. In addition, Albino Wistar rats are a kind of animal that is inoffensive and takes well to experimental environment. This ensures that the animals do not have to be subdued or fought before getting a sample and the process does not have to stress the animals or the researcher. Furthermore, they have a shorter gestation period, approximately 21 days, and a short existence of approximately 2 years. Such features make Albino Wistar rats suitable to be used by researchers who would wish to get a fast result or those who have a small budget. It should also be pointed out, although, that there are some drawbacks in employing Albino Wistar rats as animal subjects as well. The following is the major drawback; they are prone to certain diseases for example infections and some types of tumors. It means that the studied population may have higher sensitivity to disease and its manifestations, which may influence the results of studies, when disease processes or potential treatments are examined. The other limitation is that Albino Wistar rat has a relatively shorter life span than any other strain of rats. Reduced life expectancy can also reduce the possibilities of research, especially in trials concerned with aging or late outcomes of interventions. Experimentalists must put these aspects into consideration when choosing their sample and the type of animals to use. Nevertheless, despite these drawbacks, Wistar rats still can be considered valuable source for the researchers taking into account all the mentioned advantages. Because of their high reproducibility, ease of handling, genetic uniformity, and ability to adapt to the laboratory conditions, they provide a perfect model for dissecting complex biological functions and generating new models for diseases affecting mankind. Due to the advancement in scientific knowledge and technology, the researchers may 1 day overcome the said-named limitations associated with the use of Albino Wistar rats as animal models.

A STUDY ON FINGERTIP DERMATOGLYPHIC PATTERN IN PATIENTS WITH MYOCARDIAL INFARCTION IN THE NORTH INDIAN POPULATION

Objectives: Myocardial infarction is one of the rising heart ailments causing mortality and morbidity around the world and especially in the north Indian population. In earlier studies, it has been found that dermatoglyphics and myocardial infarction have a correlation due to genetic disposition. The present study is based on the same hypothesis to find out such a relation and its uses as an economical diagnostic tool. Methods: The present study was conducted after taking informed consent forms from 150 patients with myocardial infarction as cases, whereas 150 normal health individuals were included in the study as controls. Fingerprints were taken using the method described by Cummin and Mildo. Result: The study found that the different fingerprints which are whorls, arches, and loops have a specific pattern that differs in myocardial infarction cases and control. In some cases, the loop and whorls have been increasing, whereas the arches were found to be decreasing as compared to controls. The mean total finger ridge count (TFRC) and absolute finger ridge count (AFRC) have been found to decrease in both males and females and the decrease was statistically significant. Conclusion: Dermatoglyphics and myocardial infarction have shown a close correlation due to genetic association. Thus, it can be used as one of the cost-effective diagnostic tools for myocardial infarction.

Unravelling the Crosstalk between Estrogen Deficiency and Gut-biotaDysbiosis in the Development of Diabetes Mellitus.

Estrogens are classically considered essential hormonal signals, but they exert profound effects in a number of physiological and pathological states, including glucose homeostasis and insulin resistance. Estrogen deficiency after menopause in most women leads to increased androgenicity and changes in body composition, and it is recommended to manipulate the β-cell function of the pancreas, insulin-induced glucose transport, and hepatic glucose output, hence, the increasing incidence of type 2 diabetes mellitus. Recently, studies have reported that gut biota alteration due to estrogen deficiency contributes to altered energy metabolism and, hence, accentuates the pathology of diabetes mellitus. Emerging research suggests estrogen deficiency via genetic disposition or failure of ovaries to function in old age modulates the insulin resistance and glucose secretion workload on pancreatic beta cells by decreasing the levels of good bacteria such as Akkermansia muciniphila, Bifidobacterium spp., Lactobacillus spp., Faecalibacterium prausnitzii, Roseburia spp., and Prevotella spp., and increasing the levels of bad bacteria's such as Bacteroides spp., Clostridium difficile, Escherichia coli, and Enterococcus spp. Alteration in these bacteria's concentrations in the gut further leads to the development of impaired glucose uptake by the muscles, increased gluconeogenesis in the liver, and increased lipolysis and inflammation in the adipose tissues. Thus, the present review paper aims to clarify the intricate interactions between estrogen deficiency, gut microbiota regulation, and the development of diabetes mellitus.

Temporal classification of short time series data

MotivationWithin the frame of their genetic capacity, organisms are able to modify their molecular state to cope with changing environmental conditions or induced genetic disposition. As high throughput methods are becoming increasingly affordable, time series analysis techniques are applied frequently to study the complex dynamic interplay between genes, proteins, and metabolites at the physiological and molecular level. Common analysis approaches fail to simultaneously include (i) information about the replicate variance and (ii) the limited number of responses/shapes that a biological system is typically able to take.ResultsWe present a novel approach to model and classify short time series signals, conceptually based on a classical time series analysis, where the dependency of the consecutive time points is exploited. Constrained spline regression with automated model selection separates between noise and signal under the assumption that highly frequent changes are less likely to occur, simultaneously preserving information about the detected variance. This enables a more precise representation of the measured information and improves temporal classification in order to identify biologically interpretable correlations among the data.Availability and implementationAn open source F# implementation of the presented method and documentation of its usage is freely available in the TempClass repository, https://github.com/CSBiology/TempClass [58].

Genetic Disposition: Susceptibility of Human Blood Groups and Abo Analysis to Malaria and Typhoid Infections

Genetic Disposition: Susceptibility of Human Blood Groups and Abo Analysis to Malaria and Typhoid Infections

Average phenotype but not plasticity in two metabolic hormones covary in wild female bonobos (Pan paniscus)

Each individual is equipped with a distinct genetic disposition and ontogenetic history and experiences environmental conditions in a unique way. As a result, individuals vary in terms of phenotypic differences regarding their responses to internal and external conditions. By modulating hormone secretion, an individual can react to changing conditions, thus maintaining homeostasis. Cortisol and triiodothyronine (T3) are involved in mediating energy homeostasis. The secretion of metabolic hormones enables individuals to respond flexibly to internal and external conditions. However, this flexibility may be constrained by tradeoffs between average hormone levels and the degree of hormonal plasticity and the impact of the HPA axis on T3 secretion and effects. Like many other species, bonobos (Pan paniscus) are confronted with rapid ecological and climatic perturbations, resulting in challenges to energetic homeostasis. Due to their limited genetic diversity, K-strategist and stenoecious species characteristics, they are predicted to have only limited potential for adaptation. Therefore, it is important to quantify individual cortisol and T3 reaction norms and examine their relationship with each other to understand the level of flexibility of metabolic hormone phenotypes. Using a multivariate random slope model, we found that diurnal urinary excretion patterns of cortisol and T3 in wild female bonobos have (i) no relationship between average phenotype and plasticity within the reaction norms of both hormones. (ii) We also found a negative correlation between the intercepts of the two metabolic hormones, but (iii) no relationship between their slopes. (iv) Standard deviations of cortisol and T3 intercepts and slopes between females indicate little variation among females. Our data show that plasticity within and between the two metabolic hormones is not related to overall low or high hormone levels, but there is a linear negative relationship between cortisol and T3 average phenotypes. Thus, individuals with high average cortisol levels, investing in restoring energy depots, have low average T3 levels, reducing energy expenditure, and vice versa. From this we conclude that the plasticity of diurnal hormone excretion is not affected by average metabolic hormone phenotypes. Evaluations of cortisol and T3 plasticity along ecological gradients can enhance our understanding of the adaptive potential of a given species to environmental changes.

Long Non-Coding RNA LINC00XPRR Is Upregulated in Newly Diagnosed Multiple Myeloma Promoting Poor Response to High-Dose Melphalan with Autologous Stem Cell Transplantation and Three-Drug Regimen

Abstract Multiple myeloma is an incurable malignant hematopoietic blood cancer. It develops from genetic disposition and abnormal plasma cells with over 30,000 new cases diagnosed in the United States every year. The 5-year relative survival rate for myeloma patients if diagnosed at early stage is 79.5%, however majority of patients are diagnosed once the cancer has already metastasized which decreases the 5-year relative survival rate to only 59%. The standard care for treating newly diagnosed multiple myeloma (NDMM) is three-drug induction therapy followed by high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT). While there is no cure for multiple myeloma, diagnosis and standard therapy leads to prolonged remission and improved quality of life. Identifying genetic predictors for positive treatment responses and survival represents an unmet medical need. Long non-coding RNAs (lncRNAs) play important regulatory roles in promoting cancer growth and metastasis and due to their tissue-specificity they are becoming important players for development of personalized therapies. In addition, lncRNA-protein interactions have shown to be vital for biological processes associated with cancer, but currently there is a lack in our understanding of their role in initiation or progression of myeloma. Further, the roles of lncRNAs as biomarkers or targets for myeloma therapies have not yet been defined. In order to address these issues, we performed transcriptome sequencing from NDMM patients which identified 244 differentially expressed lncRNAs in poor responders (indicated as &amp;lt;24 months progression free survival (PFS)) to three-drug regimen, HDM and ASCT (n=38) compared to standard responders (indicated as &amp;gt;24 months PFS) to three-drug regimen, HDM and ASCT (n=78). Our analysis revealed LINC00XPRR (lncRNA00Xpoor responder-related) as one of the top-most upregulated novel lncRNA associated with poor responders to standard myeloma care. We next validated LINC00XPRR high expression in single cell RNA-sequencing data in NDMM patient samples. Multiplexed fluorescent RNA in situ hybridization (mFISH) analysisshowed that LINC00XPRR expression increased in melphalan treated myeloma cell lines and is highly expressed in bone marrow aspirates from patient samples. We further determined higher levels of LINC00XPRR in the cytoplasmic compartment of the cells compared to nuclear localization through QuPath analysis. LINC00XPRR mechanistically and epigenetically modulates cytotoxic and apoptotic phenotypes in myeloma cell lines when overexpressed in U266B1 and MM1.S cells or using RPMI8226 CRISPR/Cas9 knockdown system and in appropriate multiple myeloma-associated mouse models. Additionally, we used RNA immunoprecipitation (RIP) combined with qPCR to determined that LINC00XPRR directly interacts with CELF2, RNA-binding protein. Lastly, using target specific LINC00XPRR designed locked-nucleic acid antisense oligonucleotides (LNA ASOs) to knockdown LINC00XPRR, we saw an increase in apoptotic phenotypes indicating clinical potential of LNA ASOs-mediated LINC00XPRR knockdown. Overall, we are the first to identify lncRNAs associated with poor response in NDMM patients to standard three-drug induction chemotherapy followed by HDM and ASCT and show that LINC00XPRR enhanced expression may be both an important biomarker and target for future therapeutic interventions. Our current studies focus on the biology of lncRNAs in myeloma and the mechanism by which increased expression of LINC00XPRR is associated with poor outcomes in patients with NDMM receiving standard induction therapy, HDM and ASCT. Topics: multiple myeloma, long non-coding RNAs, LNA ASOs, RNA therapeutics, treatment response, RNA sequencing, apoptosis

Sample‐based robust model reduction for non‐linear systems biology models

AbstractComplex non‐linear systems biology models comprise relevant knowledge on processes of pharmacological interest. They are, however, too complex to be used in inferential settings, for example, to allow for the estimation of patient‐specific parameters for individual dose optimisation. Thus, there is a need for simple models with interpretable components to infer the drug effect in a clinical setting. In particular, it is essential to accurately quantify and simulate the interindividual variability in the drug response in order to account for covariates like body weight, age and genetic disposition. To this end, non‐linear model order reduction and simplification methods can be used if they maintain model interpretability during reduction and consider an entire population rather than just a single reference individual. We present a sample‐based approach for robust model order reduction and propose two improvements for efficiency. In particular, we introduce a new sampling method to generate the virtual population based on transformed latin hypercube sampling. Thereby, the sample is stratified in the relevant parameter‐space directions, which are identified using empirical observability Gramians. We illustrate our approach in application to a blood coagulation pathway model, where we reduce the complexity from a 62‐dimensional highly non‐linear to a six‐dimensional and a nine‐dimensional system of ordinary differential equations for two scenarios, respectively.

Association of polygenic scores for depression and neuroticism with perceived stress in daily life during a long-lasting stress period.

Genetic factors contribute significantly to interindividual differences in the susceptibility to stress-related disorders. As stress can also be conceptualized as environmental exposure, controlled gene-environment interaction (GxE) studies with an in-depth phenotyping may help to unravel mechanisms underlying the interplay between genetic factors and stress. In a prospective-longitudinal quasi-experimental study, we investigated whether polygenic scores (PGS) for depression (DEP-PGS) and neuroticism (NEU-PGS), respectively, were associated with responses to chronic stress in daily life. We examined law students (n = 432) over 13 months. Participants in the stress group experienced a long-lasting stress phase, namely the preparation for the first state examination for law students. The control group consisted of law students without particular stress exposure. In the present manuscript, we analyzed perceived stress levels assessed at high frequency and in an ecologically valid manner by ambulatory assessments as well as depression symptoms and two parameters of the cortisol awakening response. The latter was only assessed in a subsample (n = 196). No associations between the DEP-PGS and stress-related variables were found. However, for the NEU-PGS we found a significant GxE effect. Only in individuals experiencing academic stress a higher PGS for neuroticism predicted stronger increases of perceived stress levels until the exam. At baseline, a higher NEU-PGS was associated with higher perceived stress levels in both groups. Despite the small sample size, we provide preliminary evidence that the genetic disposition for neuroticism is associated with stress level increases in daily life during a long-lasting stress period.

Genetic Variants in WNT16 and PKD2L1 Locus Affect Heel Ultrasound Bone Stiffness: Analyses from the General Population and Patients Evaluated for Osteoporosis.

Osteoporosis, a complex chronic disease with increasing prevalence, is characterised by reduced bone mineral density (BMD) and increased fracture risk. The high heritability of BMD suggests substantial impact of the individual genetic disposition on bone phenotypes and the development of osteoporosis. In the past years, genome-wide association studies (GWAS) identified hundreds of genetic variants associated with BMD or osteoporosis. Here, we analysed 1103 single nucleotide polymorphisms (SNPs), previously identified as associated with estimated BMD (eBMD) in the UK Biobank. We assessed whether these SNPs are related to heel stiffness index obtained by quantitative ultrasound in 5665 adult participants of the Study of Health in Pomerania (SHIP). We confirmed 45 significant associations after correction for multiple testing. Next, we analysed six selected SNPs in 631 patients evaluated for osteoporosis [rs2707518 (CPED1/WNT16), rs3779381 (WNT16), rs115242848 (LOC101927709/EN1), rs10239787 (JAZF1), rs603424 (PKD2L1) and rs6968704 (JAZF1)]. Differences in minor allele frequencies (MAF) of rs2707518 and rs3779381 between SHIP participants (higher MAF) and patients evaluated for osteoporosis (lower MAF) indicated a protective effect of the minor allele on bone integrity. In contrast, differences in MAF of rs603424 indicated a harmful effect. Co-localisation analyses indicated that the rs603424 effect may be mediated via stearoyl-CoA desaturase (SCD) expression, an enzyme highly expressed in adipose tissue with a crucial role in lipogenesis. Taken together, our results support the role of the WNT16 pathway in the regulation of bone properties and indicate a novel causal role of SCD expression in adipose tissue on bone integrity.