bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutational biases promote neutral increases in the complexity of protein interaction networks following gene duplication
Authors: Cisneros Angel F. , Nielly-Thibault Lou , Mallik Saurav , Levy Emmanuel D. , Landry Christian R. 
Published: November 2023

AbstractBiological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.
NEUTROPHILS ARE INDISPENSABLE FOR ADVERSE CARDIAC REMODELING IN HEART FAILURE
Authors: Antipenko Sergey , Mayfield Nicolas , Jinno Miki , Gunzer Matthias , Ismahil Mohamed Ameen , Hamid Tariq , Prabhu Sumanth D. , Rokosh Gregg 
Published: November 2023

ABSTRACTPersistent immune activation contributes significantly to left ventricular (LV) dysfunction and adverse remodeling in heart failure (HF). In contrast to their well-known essential role in acute myocardial infarction (MI) as first responders that clear dead cells and facilitate subsequent reparative macrophage polarization, the role of neutrophils in the pathobiology of chronic ischemic HF is poorly defined. To determine the importance of neutrophils in the progression of ischemic cardiomyopathy, we measured their production, levels, and activation in a mouse model chronic HF 8 weeks after permanent coronary artery ligation and large MI. In HF mice, neutrophils were expanded both locally in failing myocardium (more in the border zone) and systemically in the blood, spleen and bone marrow, together with increased BM granulopoiesis. There were heightened stimuli for neutrophil recruitment and trafficking in HF, with increased myocardial expression of the neutrophil chemoattract chemokines CXCL1 and CXCL5, and increased neutrophil chemotactic factors in the circulation. HF neutrophil NETotic activity was increased in vitro with coordinate increases in circulating neutrophil extracellular traps (NETs) in vivo. Neutrophil depletion with either antibody-based or genetic approaches abrogated the progression of LV remodeling and fibrosis at both intermediate and late stages of HF. Moreover, analogous to murine HF, the plasma milieu in human acute decompensated HF strongly promoted neutrophil trafficking. Collectively, these results support a key tissue-injurious role for neutrophils and their associated cytotoxic products in ischemic cardiomyopathy and suggest that neutrophils are potential targets for therapeutic immunomodulation in this disease.
Genomic hypomethylation in cell-free DNA predicts responses to checkpoint blockade in lung and breast cancer
Authors: Kim Kyeonghui , Kim Hyemin , Shin Inkyung , Noh Seung-Jae , Kim Jeong Yeon , Suh Koung Jin , Kim Yoo-Na , Lee Jung-Yun , Cho Dae-Yeon , Kim Se Hyun , Kim Jee Hyun , Lee Se-Hoon , Choi Jung Kyoon 
Published: November 2023

AbstractGenomic hypomethylation has recently been identified as a determinant of therapeutic responses to immune checkpoint blockade (ICB). However, tumor tissue is often unattainable, and tissue-based methylation profiling suffers from low tumor purity. In this study, we developed an assay named iMethyl to estimate the genomic hypomethylation status from cell-free DNA (cfDNA) as well as tissue by deep targeted sequencing of young LINE-1 elements with > 400,000 reads per sample. iMethyl was applied to a total of 653 ICB samples encompassing lung cancer (cfDNA n=167; tissue n=137; cfDNA early during treatment n=40), breast cancer (cfDNA n=91; tissue n=50; PBMC n=50; cfDNA at progression n=44), and ovarian cancer (tissue n=74). iMethyl-tissue had better predictive power than tumor mutation burden and PD-L1 expression. Furthermore, iMethyl-liquid predicted ICB responses accurately regardless of the tumor purity of tissue samples. iMethyl-liquid was also able to monitor therapeutic responses early during treatment (3 or 6 weeks after initiation of ICB) and detect progressive hypomethylation accompanying tumor progression. In conclusion, our method allows for reliable noninvasive prediction, early evaluation, and monitoring of clinical responses to ICB therapy.
Maternal sucrose consumption alters steroid levels in the mother, placenta, and fetus
Authors: Seib Désirée R. , Jung Minseon M. , Soma Kiran K. 
Published: November 2023

ABSTRACTMaternal diet has long-term effects on offspring brain development and behavior. Sucrose (table sugar) intakes are high in modern diets, but it is not clear how a maternal high-sucrose diet (HSD) affects the offspring. In rats, a maternal HSD (26% of calories from sucrose, which is human-relevant) alters maternal metabolism and brain and also alters adult offspring endocrinology and behavior in a sex-specific manner. Maternal sucrose intake increases corticosterone levels in adult female offspring and increases motivation for a sugar reward in adult male offspring. Here, to identify possible underlying mechanisms, we examined how a maternal HSD affects steroids in the dam, placenta, and fetus at embryonic day 19.5 using liquid chromatography tandem mass spectrometry. Maternal sucrose intake increased glucocorticoids (11-deoxycorticosterone and 11-dehydrocorticosterone) and tended to increase the mineralocorticoid aldosterone in maternal serum. In the placenta, maternal sucrose intake decreased androstenedione and testosterone. Maternal HSD increased aldosterone in the fetal blood. Similarly, in the fetal brain, maternal high-sucrose intake increased aldosterone in the medial prefrontal cortex and nucleus accumbens, decreased testosterone in the nucleus accumbens, and decreased corticosterone in the orbital cortex. In addition, the 11-dehydrocorticosterone/corticosterone and aldosterone/corticosterone ratios were increased in most examined brain regions. Lastly, maternal HSD increased 11-dehydrocorticosterone and aldosterone in the amniotic fluid. In summary, we found dramatic and widespread changes in maternal, placental, and fetal steroids that might mediate the long-term effects of maternal sucrose consumption on adult offspring neuroendocrinology and behavior.
Trained dogs can detect the odour of Parkinson’s Disease
Authors: Rooney Nicola , Trivedi Drupad K , Sinclair Eleanor , Walton Doyle Caitlin , Silverdale Monty , Barran Perdita , Kunath Tilo , Morant Steve , Somerville Mark , Smith Jayde , Jones-Diette Julie , Corish Jenny , Milne Joy , Guest Claire 
Published: November 2023

AbstractA definitive diagnostic test for PD remains elusive, so identification of potential biomarkers may shed light on methods for diagnosis and facilitate early intervention. Excess sebum secretion and skin pathology are recognised symptoms of early PD. It is likely these result in a unique signature of volatile organic compounds that could be used to identify early stages of disease. Numerous medical conditions produce distinctive odours, and dogs have been trained to detect many of these. A single previous study, suggested that dogs can also be trained to detect Parkinson’s Disease. In this study, two dogs were trained to distinguish sebum swabs obtained from drug naïve, and medicated Parkinson’s patients from swabs from control participants. After 38-53 weeks of training on 205 samples (90 target and 115 control), the dogs were tested in a double-blind trial using 60 control and 40 target samples from drug-naïve patients. The dogs both showed high sensitivity (proportion of target samples found 70% and 80%) and specificity (proportion of control samples not alerted to 90% and 98%) of alerting response. This trial supports previous findings that dogs can be trained to reliably detect the odour of PD. We suggest there is a potential for dogs to achieve even higher accuracy with increased exposure and refined training methods and to detect early-stage PD, even prior to diagnosis, as well as hard to diagnose PD cases. Further exploration of the factors which affect dogs’ sensitivity and specificity and sample features which affect accuracy of discrimination are now required.
Atrial Fibrillation in Middle-Aged Athletes: Impact on Left Atrial, Ventricular and Exercise Performance
Authors: Vecchiarelli E , Bentley R.F , Connelly KA , Dorian P , Yan A , Mak S , Sasson Z , Goodman J.M 
Published: November 2023

AbstractHigh volume endurance training may increase the risk of paroxsysmal atrial fibrillation (AF) in middle-aged athletes. Limited data are available describing the cardiovascular phenotype of middle-aged endurance athletes, or the impact of AF on atrial function and exercise performance performed in sinus rhythm. The purpose of this study was to characterize LA phasic function at rest and during exercise in athletes with paroxysmal AF, and to determine its impact on exercise performance. Fifteen endurance trained males (EA) (56 ± 5 years) without AF and 14 endurance trained males with paroxysmal AF (EA-AF) (55 ± 8 years) underwent echocardiography during cycle-ergometry at light and moderate intensities. Resting LA maximal volumes were similar between EA and EA-AF (30 ± 4 vs. 29 ± 8 ml/m2, p=0.50), and there were no differences in AEMD. During moderate intensity exercise, EA-AF had reduced LA conduit (30 ± 6 vs. 40 ± 5 ml/m2, p=0.002) LA booster volumes (17 ± 5 vs. 21 ± 4 ml/m2, p=0.021), and reduced LV stroke volumes (100 ± 12 vs. 117 ± 16 ml, p=0.007). These results demonstrate that exercise testing in athletes with AF unmasks evidence of adverse functional cardiac remodelling that may contribute to impaired exercise performance. It is unclear whether these functional alterations are the consequence of AF. Reductions in LA conduit volume, LA booster volume, and LV stroke volume during exercise may be helpful in clinical management and distinguishing pathologic from physiologic remodelling.
ENO1 as a biomarker of breast cancer progression and metastasis – a bioinformatic approach
Authors: Giannoudis Athina , Heath Alistair , Sharma Vijay 
Published: November 2023

AbstractBackgroundMetabolic reprogramming is one of the hallmarks of cancer cells and many key metabolic enzymes are dysregulated. In breast cancer (BC), the commonest malignancy of women, several metabolic enzymes are overexpressed and/or overactivated. One of these is Enolase 1 (ENO1) an enzyme that catalyses glycolysis but is also involved in the regulation of multiple signalling pathways. ENO1 overexpression in BC has been linked to worse tumour prognosis and metastasis, rendering it a promising biomarker of disease progression and a potential therapeutic target.MethodsUtilising available online platforms such as the KM-plotter, the ROC-plotter, the cBioPortal, the G-2-O, the MethSurvand, we performed a bioinformatic analysis to establish the prognostic and predictive effects related to ENO1 expression in breast cancer. A Network analysis was also performed using the Oncomine platform and signalling and epigenetic pathways including immune regulation constituting the hallmarks of cancer were explored. The relationship between ENO1 and the immune response was also obtained from the TISIDB portal and Spearman’s rho (r) was used to determine their correlation.ResultsENO1 is overexpressed in all the analysed Oncomine, epigenetic and immune pathways in triple-negative, but not in hormone receptor-positive BCs. In HER2-positive BCs, ENO1 expression showed a mixed profile. Similarly, analysis on disease progression and histological types showed ENO1 overexpression in ductalin situand invasive carcinoma, high grade tumours followed by advanced and/or metastasis and was linked to worse survival (death by 5 years). High ENO1 expression was also associated with relapse-free (RFS), distant metastasis-free (DMFS) and overall survival (OS) as analysed by the KM-plot software, irrespectively of treatment and was also related to basal subtype and to a lesser extend to HER2 and luminal B subtypes. ENO1 was underexpressed in the less invasive and with better prognosis subtypes.ConclusionsOverexpression of ENO1 largely confers a worse prognosis in breast cancer and recruits a range of signalling pathways during disease progression. ENO1 expression can be utilised as a biomarker of disease progression and as a potential therapeutic target, particularly in triple-negative and invasive breast carcinomas (NST).
Leveraging large-scale multi-omics to identify therapeutic targets from genome-wide association studies
Authors: Lessard Samuel , Chao Michael , Reis Kadri ,   FinnGen, Estonian Biobank Research Team, Beauvais Mathieu , Rajpal Deepak K. , Shankara Srinivas , Sloane Jennifer , Palta Priit , Klinger Katherine , de Rinaldis Emanuele , Khader Shameer , Chatelain Clément 
Published: November 2023

ABSTRACTBACKGROUND: Therapeutic targets supported by genetic evidence from genome-wide association studies (GWAS) show higher probability of success in clinical trials. GWAS is a powerful approach to identify links between genetic variants and phenotypic variation; however, identifying the genes driving associations identified in GWAS remains challenging. Integration of molecular quantitative trait loci (molQTL) such as expression QTL (eQTL) using mendelian randomization (MR) and colocalization analyses can help with the identification of causal genes. Careful interpretation remains warranted because eQTL can affect the expression of multiple genes within the same locus.METHODS: We used a combination of genomic features that include variant annotation, activity-by-contact maps, MR, and colocalization with molQTL to prioritize causal genes across 4,611 disease GWAS and meta-analyses from biobank studies, namely FinnGen, Estonian Biobank and UK Biobank.RESULTS: Genes identified using this approach are enriched for gold standard causal genes and capture known biological links between disease genetics and biology. In addition, we find that eQTLs colocalizing with GWAS are statistically enriched for corresponding disease-relevant tissues. We show that predicted directionality from MR is generally consistent with matched drug mechanism of actions (>78% for approved drugs). Compared to the nearest gene mapping method our approach also shows a higher enrichment in approved therapeutic targets (risk ratio 1.38 vs 2.06). Finally, using this approach, we detected a novel association between the IL6 receptor signal transduction gene IL6ST and polymyalgia rheumatica, an indication for which sarilumab, a monoclonal antibody against IL-6, has been recently approved.CONCLUSIONS: Combining variant annotation and activity-by-contact maps to molQTL increases performance to identify causal genes, while informing on directionality which can be translated to successful target identification and drug development.
Evaluating the impact of modeling choices on the performance of integrated genetic and clinical models
Authors: Morley Theodore J. , Willimitis Drew , Ripperger Michael , Lee Hyunjoon , Han Lide , Zhou Yu , Kang Jooeun , Davis Lea K. , Smoller Jordan W. , Choi Karmel W. , Walsh Colin G. , Ruderfer Douglas M. 
Published: November 2023

AbstractThe value of genetic information for improving the performance of clinical risk prediction models has yielded variable conclusions. Many methodological decisions have the potential to contribute to differential results across studies. Here, we performed multiple modeling experiments integrating clinical and demographic data from electronic health records (EHR) and genetic data to understand which decision points may affect performance. Clinical data in the form of structured diagnostic codes, medications, procedural codes, and demographics were extracted from two large independent health systems and polygenic risk scores (PRS) were generated across all patients with genetic data in the corresponding biobanks. Crohn’s disease was used as the model phenotype based on its substantial genetic component, established EHR-based definition, and sufficient prevalence for model training and testing. We investigated the impact of PRS integration method, as well as choices regarding training sample, model complexity, and performance metrics. Overall, our results show that including PRS resulted in higher performance by some metrics but the gain in performance was only robust when combined with demographic data alone. Improvements were inconsistent or negligible after including additional clinical information. The impact of genetic information on performance also varied by PRS integration method, with a small improvement in some cases from combining PRS with the output of a clinical model (late-fusion) compared to its inclusion an additional feature (early-fusion). The effects of other modeling decisions varied between institutions though performance increased with more compute-intensive models such as random forest. This work highlights the importance of considering methodological decision points in interpreting the impact on prediction performance when including PRS information in clinical models.
Evaluating the Multimodal Capabilities of Generative AI in Complex Clinical Diagnostics
Authors: Schubert Marc Cicero , Lasotta Maximilian , Sahm Felix , Wick Wolfgang , Venkataramani Varun 
Published: November 2023

AbstractIn the rapidly evolving landscape of artificial intelligence (AI) in healthcare, the study explores the diagnostic capabilities of Generative Pre-trained Transformer 4 Vision (GPT-4V) in complex clinical scenarios involving both medical imaging and textual patient data. Conducted over a week in October 2023, the study employed 93 cases from the New England Journal of Medicine’s image challenges. These cases were categorized into four types based on the nature of the imaging data, ranging from radiological scans to pathological slides. GPT-4V’s diagnostic performance was evaluated using multimodal inputs (text and image), text-only, and image-only prompts. The results indicate that GPT-4V’s diagnostic accuracy was highest when provided with multimodal inputs, aligning with the confirmed diagnoses in 80.6% of cases. In contrast, text-only and image-only inputs yielded lower accuracies of 66.7% and 45.2%, respectively (after correcting for random guessing: multimodal: 70.5 %, text only: 54.3 %, image only: 29.3 %). No significant variation was observed in the model’s performance across different types of images or medical specialties. The study substantiates the utility of multimodal AI models like GPT-4V as potential aids in clinical diagnostics. However, the proprietary nature of the model’s training data and architecture warrants further investigation to uncover biases and limitations. Future research should aim to corroborate these findings with real-world clinical data while considering ethical and privacy concerns.
Effectiveness of resting transthoracic echocardiography at detecting significant coronary artery disease in adults
Authors: Woods Michael D. , Hatfield Jess , Hammonds Kendall , Pham Alex , Exaire Jose , Mixon Timothy , Nguyen Vinh , Chiles Christopher , Widmer Robert J. 
Published: November 2023

Structured AbstractBackground:Detection of regional wall motion abnormalities (RWMA) on TTE is a commonly used to correlate for coronary artery disease (CAD) and often prompts a further workup, including cardiac computed tomography (CT) or cardiac catheterization. However, RWMAs do not consistently predict obstructive CAD. This study investigates the accuracy and reliability of the presence of RWMA on TTE at detecting significant CAD (≥ 70 % vessel stenosis).Methods:A retrospective chart review was conducted of adults seen by the Baylor Scott & White Temple echocardiography laboratory who received a resting TTE followed by cardiac catheterization within 30 days over a 4-year period. Exclusion criteria included catheterization without coronary angiography and prior history of CAD, percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG). We analyzed RWMA on TTE and atherosclerotic CAD on cardiac catheterization to assess for correlation.Results:435 patients were included in the study and 198 patients received ultrasound enhancing agent (UEA). The sensitivity and specificity of RWMA on TTE for detecting CAD in adults was 49.5 % and 78.8%, respectively. The positive and negative likelihood ratios were 2.33 and 0.641, respectively. The use of UEA made no significant difference in the sensitivity or specificity.Discussion:Our results show that the presence of RWMA on TTE has a high ability to rule in CAD but the absence of RWMA displays a much lower ability to rule out CAD than previously reported. Our results also show UEA did not enhance or detract this relationship. Clinicians should be aware that the presence of RWMA on resting TTE has a high association with obstructive CAD but the absence of RWMA does not sufficiently exclude CAD.Clinical PerspectiveCurrent guidelines support the use of resting TTE in suspected occlusive coronary artery disease when ECG, biomarkers, and patient history are insufficient to warrant cardiac catheterization. Our study demonstrated the presence of RWMA on resting TTE has a high association with obstructive CAD but the absence of RWMA does not sufficiently exclude CAD. While a positive TTE provides good evidence for additional workup of CAD, practicing clinicians should carefully weigh their plan in the event of a negative TTE prior to ordering the test to determine if the test is a necessary diagnostic step for their patient. If the clinician would decide to continue with a workup for CAD despite a negative resting TTE, the clinician may consider skipping the TTE and moving straight to their further workup to increase the economic value of care provided.