Genetically Research Articles

Full Genome Characterization of the First Oropouche Virus Isolate Imported in Europe from Cuba.

On 27 May 2024, the Cuban Ministry of Health reported the first outbreak of Oropouche fever on the island. The etiologic agent, Oropouche virus (OROV), is a poorly understood arbovirus that has been known since the 1960s and represents a public health burden in Latin America. We report the whole-genome characterization of the first European OROV isolate from a returning traveler from Cuba with Oropouche fever-like symptoms. The isolate was obtained from the patient's serum; whole-genome sequencing was performed by next-generation sequencing, followed by phylogenetic analysis and genetic variability studies. The analysis showed that the most closely related sequence was from the French Guiana 2020 outbreak. Interestingly, our isolate is a reassortant virus, included in a highly supported monophyletic clade containing recent OROV cases (Brazil 2015-Colombia 2021), separated from the other four previously known genotypes. More deeply, it was found to be included in a distinct branch containing the sequences of the Brazil 2022-2024 outbreak. The reassortment event involved the S and L segments, which have high similarity with sequences belonging to a new cluster (here defined as OROV_SCDC_2024), while the M segment shows high similarity with older sequences. These results likely describe the viral strain responsible for the current outbreak in Cuba, which may also reflect the ongoing outbreak in Latin America. Further studies are needed to understand how OROV evolves towards traits that facilitate its spread and adaptation outside its original basin, and to track its spread and evolution in the European continent.

Integrated Transcriptomics and Metabolomics Studies Reveal Steroid Biosynthesis Pathway and BCL2 Inhibitory Diazo-Progesterone of Drimia indica for Conservation and Sustainable Utilization.

This study is the first report on the sequence of the transcriptome of Drimia indica, a non-model plant with medicinal properties found in a forest tribal belt, using the Illumina NovaSeq platform. The primary objectives of this study were to elucidate the gene expression profiles in different tissues, identify key regulatory genes and pathways involved in secondary metabolite biosynthesis, and explore the plant's potential pharmacological properties. The study generated 670087 unigenes from both leaves and roots and identified putative homologs of annotated sequences against UniProt/Swiss-Prot and KEGG databases. The functional annotation of the identified unigenes revealed the secondary metabolite biosynthetic process as the most prominent pathway, with gene enrichment analysis predominantly accounting for secondary metabolite pathways, such as terpenoid, steroid, flavonoid, alkaloid, selenocompound, and cortisol synthesis. The study also identified regulatory genes NAC, Bhlh, WRKY, and C2H2 on the transcriptome dataset. The functionally annotated unigenes suggested phytocompounds in Drimia indica to have multi-potent properties, such as anti-cancer, anti-inflammatory, and anti-diabetic activities, which has been further validated by GC-MS-based metabolite profiling. Notably, we have identified two novel molecules, di-azo progesterone and 4H-pyran-4-one 2,3-dihydro-3,5-dihydroxy- 6-methyl, with potential BCL2 inhibitory anticancer properties, supported by stable binding interactions observed in molecular docking and dynamics simulations. Additionally, an abundance of mono-nucleotide SSR markers has been identified, useful for genetic diversity studies. This study provides a foundational understanding of the molecular mechanisms in Drimia indica, highlighting its potential as a source for novel therapeutic agents and contributing valuable insights for future pharmacological and agricultural applications. However, further in vivo studies are warranted to confirm these findings and validate their pharmacological efficacy and therapeutic potential. The SSR markers identified also offer valuable tools for molecular genetics, plant breeding, and sustainable drug development.

Genetic Associations of Persistent Opioid Use After Surgery Point to OPRM1 but Not Other Opioid-Related Loci as the Main Driver of Opioid Use Disorder.

Persistent opioid use after surgery is a common morbidity outcome associated with subsequent opioid use disorder, overdose, and death. While phenotypic associations have been described, genetic associations remain unidentified. Here, we conducted the largest genetic study of persistent opioid use after surgery, comprising ~40,000 non-Hispanic, European-ancestry Michigan Genomics Initiative participants (3198 cases and 36,321 surgically exposed controls). Our study primarily focused on the reproducibility and reliability of 72 genetic studies of opioid use disorder phenotypes. Nominal associations (p < 0.05) occurred at 12 of 80 unique (r2 < 0.8) signals from these studies. Six occurred in OPRM1 (most significant: rs79704991-T, OR = 1.17, p = 8.7 × 10-5), with two surviving multiple testing correction. Other associations were rs640561-LRRIQ3 (p = 0.015), rs4680-COMT (p = 0.016), rs9478495 (p = 0.017, intergenic), rs10886472-GRK5 (p = 0.028), rs9291211-SLC30A9/BEND4 (p = 0.043), and rs112068658-KCNN1 (p = 0.048). Two highly referenced genes, OPRD1 and DRD2/ANKK1, had no signals in MGI. Associations at previously identified OPRM1 variants suggest common biology between persistent opioid use and opioid use disorder, further demonstrating connections between opioid dependence and addiction phenotypes. Lack of significant associations at other variants challenges previous studies' reliability.

The first report of prion protein gene sequences in Dybowski’s frog and the American bullfrog: high amyloid propensity of the frog prion protein

Prion diseases are fatal infectious neurodegenerative diseases caused by the proteinase K-sensitive form of prion protein (PrPSc). The exact origin of prion seeding and the transition factor of PrPSc has not been elucidated. The main hosts of prion diseases are herbivores, so the feces and corpses of Amphibians can seed PrPSc through ecosystems. The frog is an excellent candidate for transmission studies for this reason, but genetic analyses of the prion protein gene (PRNP) in the context of prion-related characteristics of frog species are lacking. We amplified frog PRNP gene sequences in Dybowski’s frog and the American bullfrog by polymerase chain reaction (PCR) and amplicon sequencing. In addition, we carried out multiple sequencing alignments and annotated major PrP components including signal peptide, tandem repeat domain, and PrPC-PrPSc interaction region of frog PrPs by bioinformatics tools. We predicted secondary and tertiary structures and amyloid propensities of frog PrPs using AlphaFold2 and AMYCO, respectively. We obtained DNA sequences of the PRNP gene in Dybowski’s frog and the American bullfrog, as well as a partially conserved palindromic sequence (PrPC-PrPSc interaction region) and absence of tandem repeat region of PrP in seven frog species. We analyzed protein structure of among these frog species and found that the high Himalaya frog has high aggregation propensity and the western clawed frog does not have the N-terminal signal peptide. To the best of our knowledge, this was the first comparative genetic study regarding prion-related features of frog species.

Epigenetics and Asthma: A Systematic Review.

Asthma is a chronic respiratory condition characterized by the narrowing of the airways, causing difficulty in breathing. Its heritability has long been an area of research, and the study of genetics alone has not been sufficient in the explanation of both its heritability and susceptibility. The study of epigenetics, which is defined as "the study of heritable changes in gene expression that do not involve changes to the underlying DNA sequence," can be used to explain the heritability and susceptibility of asthma. These epigenetic alterations to our DNA are influenced by environmental factors which are already known as risk factors for asthma; these include factors such as diet, smoking, and air pollution. The epigenetic mechanisms work by altering gene transcription and therefore determine whether specific genes are expressed, such mechanisms include DNA methylation and histone acetylation.

Genetic inheritance studies in rice (Oryza sativa L.) for grain protein, quality and yield

The present study was undertaken to investigate the genetic parameters of yield component and quality traits of the F3 population from BPT 5204 and JAK-686 cross in rice. High heritability and high genetic advance as a percentage of the mean were recorded for productive tillers per plant, grains per panicle, panicle length and grain yield per plant indicating the effectiveness of direct phenotypic selection for improvement of these traits. For traits such as grains per panicle, 1000 grain weight, amylose content and grain protein content, the magnitude of additive (d) effects surpassed dominance (h) gene effects. This implies that phenotypic selection using methods like pureline selection, mass selection would be beneficial. Gel consistency exhibited complimentary gene interaction. Furthermore, duplicate gene interaction was prevalent in traits like days to 50% flowering, productive tillers per plant, plant height, panicle length, grain yield per plant, kernel length, kernel breadth, and kernel L/B ratio, making selection in later generations more effective. The inheritance studies highlighted the importance of selecting desired recombinants from the segregating population to enhance rice quality as well as grain yield. Keywords: Rice, Grain protein content, Quality, Variability, Heritability, Gene action

Association of Polygenic Risk Score With Lifetime Risk of Developing Multiple Sclerosis in a Population-Based Birth-Year Cohort.

More than 200 genetic variants have been associated with multiple sclerosis (MS) susceptibility. However, it is unclear to what extent genetic factors influence lifetime risk of MS. Using a population-based birth-year cohort, we investigate the effect of genetics on lifetime risk of MS. In the Project Y study, we tracked down almost all persons with MS (pwMS) from birth year 1966 in the Netherlands. As control participants, we included non-MS participants from the Project Y cohort (born 1965-1967 in the Netherlands) and non-MS participants from the Amsterdam Dementia Cohort born between 1963 and 1969. Genetic variants associated with MS were determined in pwMS and control participants using genotyping or imputation methods. Polygenic risk scores (PRSs) based on variants and weights from the largest genetic study in MS were calculated for each participant and assigned into deciles based on the PRS distribution in the control participants. We examined the lifetime risk for each decile and the association between PRS and MS disease variables, including age at onset and time to secondary progression. MS-PRS was calculated for 285 pwMS (mean age 53.0 ± 0.9 years, 72.3% female) and 267 control participants (mean age 51.8 ± 3.2 years, 58.1% female). Based on the lifetime risk estimation, we observed that 1:2,739 of the women with the lowest 30% genetic risk developed MS, whereas 1:92 of the women with the top 10% highest risk developed MS. For men, only 1:7,900 developed MS in the lowest 30% genetic risk group, compared with 1:293 men with the top 10% genetic risk. The PRS was not significantly associated with age at onset and time to secondary progression in both sexes. Our results show that the lifetime risk of MS is strongly influenced by genetic factors. Our findings have the potential to support diagnostic certainty in individuals with suspected MS: a high PRS could strengthen a diagnosis, but especially a PRS from the lowest tail of the PRS distribution should be considered a red flag and could prevent misdiagnosing conditions that mimic MS.

The Role of Generative Learning Strategy in Bridging the Gap between High and Low Achievers in Genetics Studies in Sefwi-Wiawso Municipality, Ghana

The study sought to investigate the use of the Generative Learning Strategy (GLS) in bridging the performance gap between high- and low-achieving students in genetics in Ghana's Western North region's capital, Sefwi-Wiawso Municipality. The study adopted an embedded research design involving the quasi-experimental pretest/posttest groups with a sample size of 106 SHS 3 Biology students. Two intact classes were randomly selected, treated as one group and exposed to the same treatment conditions. The Genetic Concepts Test and a semi-structured interview guide collected the quantitative and qualitative data, respectively. The GCT's internal consistency was 0.784, indicating a preferable internal consistency. The quantitative data was analyzed using the SPSS version 26, by employing descriptive and inferential statistics. The study found no significant performance difference between high and low achievers after using the GLS. The approach improved the lower achievers’ performance. The interview results revealed that Senior High School Biology students perceived that the Generative Learning Strategy improved the understanding, motivation, retention and self-directed learning of genetic concepts, thereby enhancing their learning outcomes. The study recommended that SHS Biology teachers employ the Generative Learning Strategy in teaching genetic concepts to bridge the performance gap between high and low achievers.

Impact of Genetic Testing on the Diagnosis, Management, and Prognosis of Hypertrophic Cardiomyopathy: A Systematic Review.

Hypertrophic cardiomyopathy (HCM) is a hereditary cardiovascular condition marked by heart muscle thickening, fibrosis, and myocardial disorders. It is often inherited in an autosomal dominant pattern. Symptoms include dyspnea, fatigue, palpitations, dizziness, syncope, and an increased risk of sudden cardiac death (SCD). Genetic studies have identified many asymptomatic carriers, indicating a higher prevalence of HCM. Advances in genetic testing (GT) and novel therapies, such as cardiac myosin inhibitors, have significantly impacted the diagnosis and management of HCM. This integrative review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and aimed to synthesize information regarding the impact of GT on the diagnosis and management of HCM patients. An electronic search was conducted on May 17, 2024, across PubMed, Embase, Scopus, Web of Science, and Cochrane databases, covering January 2020 to May 2024. Inclusion criteria were studies involving adult HCM patients who underwent GT and follow-up. Exclusion criteria included non-human studies, pediatric cases, non-HCM-related GT, non-peer-reviewed articles, systematic reviews, conference abstracts, and editorials. From 1,155 articles identified, 42 met the inclusion criteria after applying filters and removing duplicates. GT identified pathogenic variants in a significant proportion of HCM patients, enhancing diagnostic accuracy and management. Key mutations were found in myosin binding protein C3 and myosin heavy chain 7 genes. GT facilitated personalized management strategies, including risk stratification for SCD and family screening. Patients with identified mutations often required closer monitoring and tailored treatments. GT has revolutionized the diagnosis and management of HCM. The integration of genetic data has improved risk stratification, facilitated early intervention, and enhanced patient outcomes. Despite these advances, challenges remain in identifying genetic variants in some patients, emphasizing the need for continuous improvement in genetic panels and diagnostic methods. This review highlights the significant role of GT in optimizing HCM care through precise risk assessment and tailored treatment strategies.

Chromosome-scale genome assembly of acerola (Malpighia emarginata DC.).

Acerola (Malpighia emarginata DC.) is a tropical evergreen shrub that produces vitamin C-rich fruits. Increasing fruit nutrition is one of the main targets of acerola breeding programs. Genomic tools have been shown to accelerate plant breeding even in fruiting tree species, which generally have a long life cycle; however, the availability of genomic resources in acerola, so far, has been limited. In this study, as a first step toward developing an efficient breeding technology for acerola, we established a chromosome-scale genome assembly of acerola using high-fidelity long-read sequencing and genetic mapping. The resultant assembly comprises 10 chromosome-scale sequences that span a physical distance of 1,032.5Mb and contain 35,892 predicted genes. Phylogenetic analysis of genome-wide SNPs in 60 acerola breeding materials revealed three distinct genetic groups. Overall, the genomic resource of acerola developed in this study, including its genome and gene sequences, genetic map, and phylogenetic relationship among breeding materials, will not only be useful for acerola breeding but will also facilitate genomic and genetic studies on acerola and related species.

Genetic family studies and prospective evaluation for multisystem involvement are needed in LHON patients.

Genetic family studies and prospective evaluation for multisystem involvement are needed in LHON patients.

The Jan Sjödin faba bean mutant collection: morphological and molecular characterization.

Plant mutagenesis creates novel alleles, thereby increasing genetic and phenotypic diversity. The availability of the faba bean (Vicia faba L.) reference genome and a growing set of additional genomic resources has increased the scientific and practical value of mutant collections. We aimed to genotype and morphologically phenotype a historical faba bean mutant collection developed and characterized by Jan Sjödin (1934-2023) over half a century ago in order to increase its value to researchers. The collection was genotyped using high-throughput single-primer enrichment technology (SPET) assays. We used 11,073 informative single nucleotide polymorphism (SNP) markers spanning the faba bean genome to genotype 52 mutant lines along with the background line, cv. Primus. A range of flower, seed, leaf, and stipule mutations were observed. The analysis of population structure revealed a shallow structure with no major subpopulations. Principal component and cluster analyses revealed, to a minor extent, that the mutants clustered by their phenotype. The mutants' phenotypic variation and shallow structure indicate that the Sjödin faba bean collection has the potential to play a significant role in faba bean breeding and in genetic and functional studies.

Assessing the population structure and genetic diversity of wheat germplasm with the iPBS-retrotransposons marker system

Context Wheat (Triticum aestivum L.) is an important crop that provides food to millions of people all over the world. Currently, wheat production is limited due to various biotic and abiotic stresses resulting from uneven patterns of climate change. Therefore, it is very important to develop climate-resilient wheat cultivars. Crop genetic diversity allows the scientific community to identify genetic variations that can be utilised in the development of improved cultivars. Aims This study planned to characterise the wheat germplasm with the iPBS-retrotransposons marker system. Methods A total of 30 iPBS-retrotransposons markers were screened and among these, the 12 most polymorphic markers were selected for further analysis. Key results Molecular characterisation yielded a total of 170 bands, of which 143 were polymorphic. A substantial level of genetic diversity was observed (mean effective number of alleles: 1.37, Shannon’s information index: 0.23, gene diversity: 0.35). Maximum genetic distance was observed in G9 and G60 genotypes. Analysis of molecular variance revealed that most genetic variation (95%) occurred within the populations. The model-based structure algorithm divided the studied germplasm into three populations based on their collection regions. Similarly, the neighbour-joining analysis also divided 70 tested wheat genotypes into three populations, whereas principal coordinate analysis divided the evaluated germplasm into four populations. Conclusions This study confirms the iPBS-retrotransposons as an ideal marker for the genetic diversity assessment studies for any crop, especially for wheat. Implications The results presented here will be helpful for the scientific community in the marker-assisted breeding of wheat.

Striatal cell-type-specific molecular signatures reveal therapeutic targets in a model of dystonia.

Striatal dysfunction is implicated in many forms of dystonia, including idiopathic, inherited and iatrogenic dystonias. The striatum is comprised largely of GABAergic spiny projection neurons (SPNs) that are defined by their long-range efferents. Direct SPNs (dSPNs) project to the internal globus pallidus/substantia nigra reticulata whereas indirect pathway SPNs (iSPNs) project to the external pallidum; the concerted activity of both SPN subtypes modulates movement. Convergent results from genetic, imaging and physiological studies in patients suggest that abnormalities of both dSPNs and iSPNs contribute to the expression of dystonia, but the molecular adaptations underlying these abnormalities are not known. Here we provide a comprehensive analysis of SPN cell-type-specific molecular signatures in a model of DOPA-responsive dystonia (DRD mice), which is caused by gene defects that reduce dopamine neurotransmission, resulting in dystonia that is specifically associated with striatal dysfunction. Individually profiling the translatome of dSPNs and iSPNs using translating ribosome affinity purification with RNA-seq revealed hundreds of differentially translating mRNAs in each SPN subtype in DRD mice, yet there was little overlap between the dysregulated genes in dSPNs and iSPNs. Despite the paucity of shared adaptations, a disruption in glutamatergic signaling was predicted for both dSPNs and iSPNs. Indeed, we found that both AMPA and NMDA receptor-mediated currents were enhanced in dSPNs but diminished in iSPNs in DRD mice. The pattern of mRNA dysregulation was specific to dystonia as the adaptations in DRD mice were distinct from those in parkinsonian mice where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. We leveraged the unique molecular signatures of dSPNs and iSPNs in DRD mice to identify biochemical mechanisms that may be targets for therapeutics, including LRRK2 inhibition. Administration of the LRRK2 inhibitor MLi-2 ameliorated the dystonia in DRD mice suggesting a novel target for therapeutics and demonstrating that the delineation of cell-type-specific molecular signatures provides a powerful approach to revealing both CNS dysfunction and therapeutic targets in dystonia.

Identification of false smut – resistant donors in Rice (Oryza sativa L.) and analysis of their morpho-molecular diversity for resistance breeding

False smut disease of rice caused by the pathogen Ustilaginoidea virens is a growing threat to the rice farmers as it affects both quality and quantity. Development of resistant variety becomes difficult, since very few resistant donors were available for false smut resistant breeding programme. Therefore, to identify potential donors for resistance breeding a total of 60 genotypes were screened at hotspot location (Gudalur) during kharif 2023 which led to identification of 12 highly resistant genotypes and the notable ones are Koolavalai, Periya chandikar, Kapikar selection and Earapalli. Genetic variability studies indicated the presence of additive gene action for all the agronomic and disease related traits. Principal component analysis revealed the first 5 principal components collectively contributing 78.79 % of the total variance with disease-related traits contributing significantly to divergence. Ten clusters were delineated using Mahalanobis D2 statistics with clusters IX and V showing higher inter cluster distance (3453.64). Forty-one polymorphic markers were used to analyse the genotypes and The Unweighted Pair Group method with Arithmetic Mean (UPGMA) clustering by Jaccard distance formed 6 clusters. The Bayesian clustering classified the entire population into 2 subpopulations. False smut linked marker RM336 and RM218 were found to be the most informative marker with high Polymorphism Information Content (0.71, 0.69) and Heterozygosity Index (0.76, 0.73). The resistant genotypes such as IG71, Thulasi vasanai sambha, Arupatham vellai, Kaltikar and Chinna aduku nel can be used in the future breeding programmes to develop the resistant cultivar and to identify the candidate genes governing resistance.

Chromosome-scale genome assembly of the hunt bumble bee, Bombus huntii Greene, 1860, a species of agricultural interest.

The Hunt bumble bee, Bombus huntii, is a widely distributed pollinator in western North America. The species produces large colony sizes in captive rearing conditions, experiences low parasite and pathogen loads, and has been demonstrated to be an effective pollinator of tomatoes grown in controlled environment agriculture systems. These desirable traits have galvanized producer efforts to develop commercial Bombus huntii colonies for growers to deliver pollination services to crops. To better understand Bombus huntii biology and support population genetic studies and breeding decisions, we sequenced and assembled the Bombus huntii genome from a single haploid male. High-fidelity sequencing of the entire genome using PacBio, along with HiC sequencing, led to a comprehensive contig assembly of high continuity. This assembly was further organized into a chromosomal arrangement, successfully identifying 18 chromosomes spread across the 317.4 Mb assembly with a BUSCO score indicating 97.6% completeness. Synteny analysis demonstrates shared chromosome number (n = 18) with Bombus terrestris, a species belonging to a different subgenus, matching the expectation that presence of 18 haploid chromosomes is an ancestral trait at least between the subgenera Pyrobombus and Bombus sensu stricto. In conclusion, the assembly outcome, alongside the minimal tissue sampled destructively, showcases efficient techniques for producing a comprehensive, highly contiguous genome.

DETERMINANT OF UNDERGRADUATE STUDENTS’ INTEREST AND ENGAGEMENTS IN THE STUDY OF GENETICS AT THE UNIVERSITY OF EDUCATION, WINNEBA

Genetics is a fundamental aspect of biological education, crucial for understanding heredity, variation, and molecular mechanisms in life. Despite its importance, student engagement in genetics courses at the University of Education, Winneba (UEW) varies widely. This study investigates the factors influencing undergraduate students' interest and engagement in the study of genetics, focusing on the perceived relevance of genetics, pedagogical approaches, challenges faced by students, and misconceptions. A descriptive survey design was used, with data collected from 150 undergraduate students enrolled in the Biology and Integrated Science Education programs. Results indicate that the perceived relevance of genetics to students’ lives, including its application in health and global issues like food security, is the most significant predictor of interest and engagement (R² = 0.56). Pedagogical approaches, particularly hands-on activities and interactive learning methods were also found to enhance engagement. However, students faced moderate challenges in understanding genetic concepts, which reduced their overall engagement. Misconceptions about genetics were less impactful but still contributed to shaping students’ attitudes. The findings suggest that aligning teaching strategies with real-life applications and addressing student misconceptions can improve student engagement in genetics education.&lt;p&gt; &lt;/p&gt;&lt;p&gt;&lt;strong&gt; Article visualizations:&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;img src="/-counters-/soc/0115/a.php" alt="Hit counter" /&gt;&lt;/p&gt;

7576 A Rare and Atypical Presentation of Bladder Paraganglioma in a Patient on Long-Term Left Ventricular Assist Device

Abstract Disclosure: S.D. Leungsuwan: None. S.J. Lee: None. S.D. Lim: None. L. Loh: None. Background: Paragangliomas (PGLs) are rare neuroendocrine tumors arising from chromaffin cells. Capable of producing catecholamines, functional PGLs often cause a myriad of autonomic symptoms and complications, including cardiomyopathy. We report a case of bladder PGL in a patient on Left Ventricular Assist Device (LVAD). Clinical Case: A 64-year-old Chinese Female with a history of non-ischaemic cardiomyopathy on long-term continuous LVAD and Cardiac Resynchronisation Therapy Defibrillator (CRT-D) was admitted for recurrent low LVAD flow &amp;lt;2 Litres per minute and labile mean arterial pressure (MAP) 57-151mmHg. She has been on long-term Nebivolol, Entresto, Hydralazine, and Sildenafil without recent dose adjustment. Workup for acute illnesses was non-contributory. 24-hour urine metanephrine and normetanephrine (NM) were 939nmol/d [normal 400-1500nmol/d] and 33883nmol/d [normal 600-1900nmol/d] respectively. Plasma free metanephrine and NM were 0.37nmol/L [normal &amp;lt;0.33nmol/L] and &amp;gt;10.00nmol/L [normal &amp;lt;0.99nmol/L] accordingly. A review of previous ultrasonography and Computed Tomography (CT) imaging revealed a right adnexal mass indenting the bladder which the patient formerly declined further assessment; adrenal glands were normal. FDG-PET CT was done and showed an isolated focus of increased tracer uptake corresponding with the right pelvic mass. An impression of likely bladder PGL was made. A multidisciplinary team including Cardiology, Anaesthesiology, Interventional Radiology (IR), Urology, Gynaecology, and Endocrinology was convened; the patient was recommended surgical resection of the tumor. Preoperatively, she was started on phenoxybenzamine 10mg BD and advised judicious fluid and salt intake. Nebivolol was continued while hydralazine was stopped. This achieved targets of i) MAP 70-80mmHg, ii) approximately 10mmHg MAP postural fluctuation, iii) sitting and standing heart rates 60-70 beats-per-minute (BPM) and 70-80BPM, and iv) no more than 1 PVC every 5 minutes. Two weeks later, she underwent IR-guided angioembolisation and tumor resection uneventfully. Intraoperatively, the patient had haemodynamic fluctuations requiring dynamic administrations of phentolamine, norepinephrine, epinephrine, vasopressin, glyceryl trinitrate, and sodium nitroprusside. Histopathology was consistent with PGL with intact SDH-A and SDH-B expression. Postoperatively, phenoxybenzamine was discontinued and no recurrent LVAD low flow was noted. Subsequent plans for repeat plasma metanephrines and genetic studies were made. Discussion: This case is the first to report an atypical presentation of PGL with LVAD low flow and labile blood pressure. The significant elevations of urine NM (17.8x upper normal limit) and plasma NM (&amp;gt;10.1x upper normal limit) also underline the concept of fold-elevations and post-test probability of PGL. Presentation: 6/3/2024

Runx2 silencing sensitized human renal cell carcinoma cells to ABT-737 apoptosis

The prognostic value of Runt-related transcription factor 2 (Runx2) and its involvement in cell growth and motility have been reported in patients diagnosed with renal cell carcinoma (RCC). Since Runx2 may have the potential to be a target for the purpose of antitumor intervention, there is an urgent need to gain insight into its oncogenic properties. Using human 786-O, Caki-1 and ACHN RCC cells as models, the silencing of cellular Runx2 expression brought about a reduction in cyclin D1 and β-catenin expression, cell growth and migration without any significant cell death. Runx2-silenced cells turned into apoptosis vulnerable in the presence of ABT-737, a BH3 mimetic Bcl-2 inhibitor. Data from biochemical and molecular studies have revealed a positive correlation between Runx2 expression and Akt phosphorylation, Mcl-1 expression, and fibronectin expression. Results of genetic silencing studies have indicated the potential involvement of Mcl-1 and fibronectin in the decision of RCC cell ABT-737 resistance and sensitivity. The regulatory roles of the PI3K/Akt axis in the expression of Mcl-1 and fibronectin were suggested by means of the results taken from experiments involving pharmacological study of the PI3K/Akt. Since overexpression and prognostic roles of Runx2, activated Akt, Mcl-1, fibronectin, cyclin D1, and β-catenin have been revealed in RCC, it is important to explore the precise mechanisms underlying Runx2 oncogenic effects. Although the linking details between Runx2 and PI3K/Akt have yet to be identified, our findings suggest that Mcl-1 and fibronectin are downstream effectors of Runx2 via a regulatory axis of the PI3K/Akt and their promotion of cell growth, migration, and ABT-737 resistance in RCC cells.

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 &amp;lt;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