bluuebunny/crossref_metadata_2025 huggingface dataset:
Towards robust and generalizable representations of extracellular data using contrastive learning
Authors: Vishnubhotla Ankit , Loh Charlotte , Paninski Liam , Srivastava Akash , Hurwitz Cole
Published: November 2023

Contrastive learning is quickly becoming an essential tool in neuroscience for extracting robust and meaningful representations of neural activity. Despite numerous applications to neuronal population data, there has been little exploration of how these methods can be adapted to key primary data analysis tasks such as spike sorting or cell-type classification. In this work, we propose a novel contrastive learning framework,CEED(ContrastiveEmbeddings forExtracellularData), for high-density extracellular recordings. We demonstrate that through careful design of the network architecture and data augmentations, it is possible to generically extract representations that far outperform current specialized approaches. We validate our method across multiple high-density extracellular recordings. All code used to run CEED can be found athttps://github.com/ankitvishnu23/CEED.
Intrinsic p53 Activation Restricts Gammaherpesvirus-Driven Germinal Center B Cell Expansion during Latency Establishment
Authors: Owens Shana M. , Sifford Jeffrey M. , Li Gang , Murdock Steven J. , Salinas Eduardo , Manzano Mark , Ghosh Debopam , Stumhofer Jason S. , Forrest J. Craig
Published: November 2023

Gammaherpesviruses (GHV) are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68), this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center (GC) B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of GHV pathogenesis, we demonstratein vivothat tumor suppressor p53 is activated specifically in B cells that are latently infected by MHV68. In the absence of p53, the early expansion of MHV68 latency was greatly increased, especially in GC B cells, a cell-type whose proliferation was conversely restricted by p53. We identify the B cell-specific latency gene M2, a viral promoter of GC B cell differentiation, as a viral protein sufficient to elicit a p53-dependent anti-proliferative response caused by Src-family kinase activation. We further demonstrate that EBV-encoded latent membrane protein 1 (LMP1) similarly triggers a p53 response in primary B cells. Our data highlight a model in which GHV latency gene-expression programs that promote B cell proliferation and differentiation to facilitate viral colonization of the host trigger aberrant cellular proliferation that is controlled by p53.

IMPORTANCE

Gammaherpesviruses cause lifelong infections of their hosts, commonly referred to as latency, that can lead to cancer. Latency establishment benefits from the functions of viral proteins that augment and amplify B cell activation, proliferation, and differentiation signals. In uninfected cells, off-schedule cellular differentiation would typically trigger anti-proliferative responses by effector proteins known as tumor suppressors. However, tumor suppressor responses to gammaherpesvirus manipulation of cellular processes remain understudied, especially those that occur during latency establishment in a living organism. Here we identify p53, a tumor suppressor commonly mutated in cancer, as a host factor that limits virus-driven B cell proliferation and differentiation, and thus, viral colonization of a host. We demonstrate that p53 activation occurs in response to viral latency proteins that induce B cell activation. This work informs a gap in our understanding of intrinsic cellular defense mechanisms that restrict lifelong GHV infection.
Small but significant genetic differentiation among populations ofPhyllachora maydisin the midwestern United States revealed by microsatellite (SSR) markers
Authors: Ross Tiffanna. J. , Jumbam Blaise , Bonkowski John , Chaky Jennifer L. , Chilvers Martin I. , Goodwin Stephen B. , Kleczewski Nathan. M. , Mueller Daren. S. , Robertson Alison. E. , Smith Damon. L. , Telenko Darcy. E. P.
Published: November 2023

Phyllachora maydisMaubl, the causal pathogen of tar spot of corn (Zea maysL.), has emerged recently in the United States and Canada. Studies related to its genetic diversity and population structure are limited and are necessary to improve our understanding of this pathogen’s biology, ecology, epidemiology, and evolutionary potential within this region. This study developed and used 13 microsatellites (SSR markers) to assess the genetic population structure, diversity, gene flow and reproductive mode of 181P. maydissamples across five states in the Midwest U.S. The polymorphic information content (PIC) of loci ranged from 0.32 to 0.72 per locus, indicating their high utility for assessing the dynamics ofP. maydispopulations. Analysis of molecular variance (AMOVA) detected a significantly low, but statistically significant genetic differentiation (FST= 0.15) among populations, where 85% of the variance resided within populations.P. maydispopulations were highly diverse (He = 0.55), with moderate gene flow (Nm = 2.80), and showed evidence of sexual recombination (r̄d;p = > 0.001). Structure analysis showed the samples were not geographically structured but rather grouped into two genetic clusters (k =2) of severe genetic admixture suggesting possible long-distance dispersal of aerial spores or infected corn materials among the five Midwest states. Both principal coordinate analysis (PCoA) and discriminate analysis of principal component (DAPC) supported the STRUCTURE analysis of the two clusters. These 13 highly polymorphic molecular markers could be used for future investigations of this pathogen’s population dynamics within the U.S., and possibly populations outside.
Hierarchical encoding of reward, effort and choice across the cortex and basal ganglia during cost-benefit decision making
Authors: Härmson Oliver , Grennan Isaac , Perry Brook , Toth Robert , McNamara Colin G. , Denison Timothy , Cagnan Hayriye , Manohar Sanjay G. , Walton Mark E. , Sharott Andrew
Published: November 2023

Adaptive value-guided decision-making requires weighing up the costs and benefits of pursuing an available opportunity. Though neurons across frontal cortical-basal ganglia circuits have been repeatedly shown to represent decision-related parameters, it is unclear whether and how this information is coordinated. To address this question, we performed large-scale single unit recordings simultaneously across 5 medial/orbital frontal and basal ganglia regions as rats decided whether to pursue varying reward payoffs available at different effort costs. We found that single neurons encoding combinations of the canonical decision variables (reward, effort and choice) were represented within all recorded brain regions. Co-active cell assemblies - ensembles of neurons that repeatedly co-activated within short time windows (<25ms) within and across structures - were able to provide representations of the same decision variables through the synchronisation of individual neurons with different coding properties. Together, these findings demonstrate a hierarchical encoding structure for cost-benefit computations, where individual neurons with diverse encoding properties are coordinated into larger, low-dimensional spaces within and across brain regions that can signal decision parameters on the millisecond timescale.
Kidney single-cell transcriptomes uncover SGLT2i-induced metabolic reprogramming via restoring glycolysis and fatty acid oxidation
Authors: Shi Ying , Bhalla Vivek
Published: November 2023

Approximately 40% of individuals with chronic kidney disease have type 2 diabetes mellitus, and diabetic kidney disease is the leading cause of end-stage kidney disease worldwide. Inhibitors of sodium-glucose cotransporter 2 (SGLT2) have been demonstrated to be effective in glucose control, improving cardiovascular outcomes and the progression of kidney disease. However, the protective role of SGLT2 inhibition on kidney metabolism is not fully understood. To explore these mechanisms further, we conducted analysis of publicly available single-cell RNA sequencing data of db/db mice treated with an SGLT2 inhibitor(dapagliflozin) and accompanying controls. We found that proximal tubule cells exhibited impaired glycolysis and high fatty acid oxidation in diabetes compared with control mice. SGLT2 inhibition reversed this metabolic dysfunction by reducing glycolysis and its substrate accumulation. SGLT2 inhibition also upregulates high fatty oxidation without increasing the uptake of fatty acids and elongation, along with low lipotoxicity. Surprisingly, both SGLT2(+) and SGLT2(-) cells show gene consistent changes in expression of metabolic genes, consistent with a non-cell autonomous effect of dapagliflozin treatment. This study demonstrates the protective role of SGLT2 inhibition via restoring metabolic dysfunction.
CryoSTAR: Leveraging Structural Prior and Constraints for Cryo-EM Heterogeneous Reconstruction
Authors: Li Yilai , Zhou Yi , Yuan Jing , Ye Fei , Gu Quanquan
Published: November 2023

Resolving conformational heterogeneity in cryo-electron microscopy (cryo-EM) datasets remains a significant challenge in structural biology. Previous methods have often been restricted to working exclusively on volumetric densities, neglecting the potential of incorporating any pre-existing structural knowledge as prior or constraints. In this paper, we present a novel methodology, cryoSTAR, that harnesses atomic model information as structural regularization to elucidate such heterogeneity. Our method uniquely outputs both coarse-grained models and density maps, showcasing the molecular conformational changes at different levels. Validated against four diverse experimental datasets, spanning large complexes, a membrane protein, and a small single-chain protein, our results consistently demonstrate an efficient and effective solution to conformational heterogeneity with minimal human bias. By integrating atomic model insights with cryo-EM data, cryoSTAR represents a meaningful step forward, paving the way for a deeper understanding of dynamic biological processes.1
Early Steps of Protein Disaggregation by Hsp70 Chaperone and Class B J-Domain Proteins are Shaped by Hsp110
Authors: Sztangierska Wiktoria , Wyszkowski Hubert , Pokornowska Maria , Kochanowicz Klaudia , Rychłowski Michał , Liberek Krzysztof , Kłosowska Agnieszka
Published: November 2023

Hsp70 is a key cellular system counteracting protein misfolding and aggregation, associated with stress, ageing and disease. Hsp70 solubilizes aggregates and aids protein refolding through substrate binding and release cycles regulated by co-chaperones: J-domain proteins (JDPs) and Nucleotide Exchange Factors (NEFs). Here, we elucidate the collaborative impact of Hsp110 NEFs and different JDP classes throughout Hsp70-dependent aggregate processing. We show that Hsp110 plays a major role at initial stages of disaggregation, determining its final efficacy. The NEF catalyses the recruitment of thick Hsp70 assemblies onto aggregate surface, which modifies aggregates into smaller species more readily processed by chaperones. Hsp70 stimulation by Hsp110 is much stronger with Class B than Class A JDPs and requires the auxiliary interaction between Class B JDP and the Hsp70 EEVD motif. Furthermore, we demonstrate for the first time that Hsp110 disrupts the JDP-Hsp70 interaction. Such destabilisation of chaperone complexes at the aggregate surface might improve disaggregation, but also lead to the inhibition above the substoichiometric Hsp110 optimum. Thus, balanced interplay between the co-chaperones and Hsp70 is critical to unlock its disaggregating potential.
Cryo-EM structure of the Spo11 core complex bound to DNA
Authors: Yu You , Wang Juncheng , Liu Kaixian , Zheng Zhi , Arter Meret , Bouuaert Corentin Claeys , Pu Stephen , Patel Dinshaw J. , Keeney Scott
Published: November 2023

The DNA double-strand breaks that initiate meiotic recombination are formed by topoisomerase relative Spo11, supported by conserved auxiliary factors. Because high-resolution structural data are lacking, many questions remain about the architecture of Spo11 and its partners and how they engage with DNA. We report cryo-EM structures at up to 3.3 Å resolution of DNA-bound core complexes ofSaccharomyces cerevisiaeSpo11 with Rec102, Rec104, and Ski8. In these structures, monomeric core complexes make extensive contacts with the DNA backbone and with the recessed 3’-OH and first 5’ overhanging nucleotide, definitively establishing the molecular determinants of DNA end-binding specificity and providing insight into DNA cleavage preferences in vivo. The structures of individual subunits and their interfaces, supported by functional data in yeast, provide insight into the role of metal ions in DNA binding and uncover unexpected structural variation in homologs of the Top6BL component of the core complex.
Genome evolution and introgression in the New Zealand mud snailsPotamopyrgus estuarinusandPotamopyrgus kaitunuparaoa
Authors: Fields Peter D. , Jalinsky Joseph R. , Bankers Laura , McElroy Kyle E. , Sharbrough Joel , Higgins Chelsea , Morgan-Richards Mary , Boore Jeffrey L. , Neiman Maurine , Logsdon John M.
Published: November 2023

We have sequenced, assembled, and analyzed the nuclear and mitochondrial genomes and transcriptomes ofPotamopyrgus estuarinusandPotamopyrgus kaitunuparaoa, two prosobranch snail species native to New Zealand that together span the continuum from estuary to freshwater. These two species are the closest known relatives of the freshwater speciesP. antipodarum—a model for studying the evolution of sex, host-parasite coevolution, and biological invasiveness—and thus provide key evolutionary context for understanding its unusual biology. TheP. estuarinusandP. kaitunuparaoagenomes are very similar in size and overall gene content. Comparative analyses of genome content indicate that these two species harbor a near-identical set of genes involved in meiosis and sperm functions, including seven genes with meiosis-specific functions. These results are consistent with obligate sexual reproduction in these two species and provide a framework for future analyses ofP. antipodarum—a species comprising both obligately sexual and obligately asexual lineages, each separately derived from a sexual ancestor. Genome-wide multigene phylogenetic analyses indicate thatP. kaitunuparaoais likely the closest relative toP. antipodarum.We nevertheless show that there has been considerable introgression betweenP. estuarinusandP. kaitunuparaoa.That introgression does not extend to the mitochondrial genome, which appears to serve as a barrier to hybridization betweenP. estuarinusandP. kaitunuparaoa.Nuclear-encoded genes whose products function in joint mitochondrial-nuclear enzyme complexes exhibit similar patterns of non-introgression, indicating that incompatibilities between the mitochondrial and the nuclear genome may have prevented more extensive gene flow between these two species.

Significance Statement

No whole-nuclear genome sequences are currently available for snails of the genusPotamopyrgus, best known forPotamopyrgus antipodarum, an invasive species of rivers and lakes worldwide, and a famous model for the study of the evolution of sex. We have sequenced and analyzed the genome of sexualP. estuarinusandP. kaitunuparaoa, the closest known relatives ofP. antipodarum. We show that 1) the genomes are very similar in gene content and size, 2)P. kaitunuparaoais the closest relative toP. antipodarum, 3) significant introgression has occurred betweenP. estuarinusandP. kaitunuparaoa; these genomes set the stage for powerful direct analyses of the genomic features,e.g., sex to asexual transitions and invasive success, that makeP. antipodarumunique.
Resting state global brain activity induces bias in fMRI motion estimates
Authors: Mao Yixiang , Chen Conan , Nguyen Truong , Liu Thomas
Published: November 2023

Head motion is a significant source of artifacts in resting-state fMRI (rsfMRI) studies and has been shown to affect resting-state functional connectivity (rsFC) measurements. In many rsfMRI studies, motion parameters estimated from volume registration are used to characterize head motion and to mitigate motion artifacts in rsfMRI data. While prior task-based fMRI studies have shown that task-evoked brain activations may induce temporally correlated bias in the motion estimates, resulting in artificial activations after registration, relatively little is known about neural-related bias in rsfMRI motion parameters. In this study, we demonstrate that neural-related bias exists in rsfMRI motion estimates and characterize the potential effects of the bias on rsFC estimates. Using a public multi-echo rsfMRI dataset, we use the differences between motion estimates from the first echo and second echo data as a measure of neural-induced bias. We show that the resting-state global activity of the brain, as characterized with the global signal (GS), induces bias in the motion estimates in the y- and z-translational axes. Furthermore, we demonstrate that the GS-related bias reflects superior-inferior and anterior-posterior asymmetries in the GS beta coefficient map. Finally, we demonstrate that regression with biased motion estimates can negatively bias rsFC estimates and reduce rsFC differences between young and old subjects.
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

Biological 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

Persistent 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

Genomic 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

Maternal 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

A 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

High 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

Background

Metabolic 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.

Methods

Utilising 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.

Results

ENO1 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.

Conclusions

Overexpression 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

BACKGROUND: 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

The 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

In 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 Abstract

Background: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 Perspective

Current 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.
Pyrimidine salvage inToxoplasma gondiias a target for new treatment
Authors: Elati Hamza A. A. , Goerner Amber L. , Di Genova Bruno Martorelli , Sheiner Lilach , de Koning Harry P.
Published: November 2023

Toxoplasmosis is a common protozoan infection that can have severe outcomes in the immunocompromised and during pregnancy, but treatment options are limited. Recently, nucleotide metabolism has received much attention as a target for new antiprotozoal agents and here we focus on pyrimidine salvage byToxoplasma gondiias a drug target. Whereas uptake of [3H]-cytidine and particularly [3H]-thymidine was at most marginal, [3H]-uracil and [3H]-uridine were readily taken up. Kinetic analysis of uridine uptake was consistent with a single transporter with a Kmof 3.3 ± 0.8 µM, which was inhibited by uracil with high affinity (Ki= 1.15 ± 0.07 µM) but not by thymidine or 5-methyluridine, showing that the 5-Me group is incompatible with uptake byT. gondii. Conversely, [3H]-uracil transport displayed a Kmof 2.05 ± 0.40 µM, not significantly different from the uracil Kion uridine transport, and was inhibited by uridine with a Ki2.44 ± 0.59 µM, also not significantly different from the experimental uridine Km. The reciprocal, complete inhibition, displaying Hill slopes of approximately ∼1, strongly suggest that uridine and uracil share a single transporter with similarly high affinity for both, and we designate it uridine/uracil transporter 1 (TgUUT1). While TgUUT1 excludes 5-methyl substitutions, the smaller 5F substitution was tolerated as 5F-uracil inhibited uptake of [3H]-uracil with a Kiof 6.80 ± 2.12 µM (P> 0.05 compared to uracil Km). Indeed, we found that 5F-Uridine, 5F-uracil and 5F,2’-deoxyuridine were all potent antimetabolites againstT. gondiiwith EC50values well below that of the current first line treatment, sulfadiazine.In vivoevaluation also showed that 5F-uracil and 5F,2’-deoxyuridine were similarly effective as sulfadiazine against acute toxoplasmosis. Our preliminary conclusion is that TgUUT1 mediates potential new anti-toxoplasmosis drugs with activity superior to the current treatment.
My host’s enemy is my enemy: plasmids carrying CRISPR-Cas as a defence against phages
Authors: Siedentop Berit , Rüegg Dario , Bonhoeffer Sebastian , Chabas Hélène
Published: November 2023

Bacteria are infected by mobile genetic elements like plasmids and virulent phages, and those infections significantly impact bacterial ecology and evolution. Recent discoveries reveal that some plasmids carry anti-phage immune systems like CRISPR-Cas, suggesting that plasmids may participate in the coevolutionary arms-race between virulent phages and bacteria. Intuitively, this seems reasonable as virulent phages kill the plasmid’s obligate host. However, the efficiency of CRISPR-Cas systems carried by plasmids can be expected to be lower than those carried by the chromosome due to continuous segregation loss, creating susceptible cells for phage amplification. To evaluate the anti-phage protection efficiency of CRISPR-Cas on plasmids, we develop a stochastic model describing the dynamics of a virulent phage infection against which a conjugative plasmid defends using CRISPR-Cas. We show that CRISPR-Cas on plasmids provides robust protection, except in limited parameter-sets. In these cases, high segregation favours phage outbreaks by generating a population of defenceless cells on which the phage can evolve and escape CRISPR-Cas immunity. We show that the phage’s ability to exploit segregation loss depends strongly on the evolvability of both CRISPR-Cas and the phage itself.
The DEAD-box ATPase Dbp10/DDX54 initiates peptidyl transferase center formation during 60S ribosome biogenesis
Authors: Cruz Victor E. , Weirich Christine S. , Peddada Nagesh , Erzberger Jan P.
Published: November 2023

DEAD-box ATPases play crucial roles in guiding rRNA restructuring events during the biogenesis of large (60S) ribosomal subunits, but their precise molecular functions are currently unknown. In this study, we present cryo-EM reconstructions of nucleolar pre-60S intermediates that reveal an unexpected, alternate secondary structure within the nascent peptidyl-transferase-center (PTC). Our analysis of three sequential nucleolar pre-60S intermediates reveals that the DEAD-box ATPase Dbp10/DDX54 remodels this alternate base pairing and enables the formation of the rRNA junction that anchors the mature form of the universally conserved PTC A-loop. Post-catalysis, Dbp10 captures rRNA helix H61, initiating the concerted exchange of biogenesis factors during late nucleolar 60S maturation. Our findings show that Dbp10 activity is essential for the formation of the ribosome active site and reveal how this function is integrated with subsequent assembly steps to drive the biogenesis of the large ribosomal subunit.
Determinants of an effective digital transformation in construction organisations: a qualitative investigation
Authors: Zulu Sambo Lyson , Saad Ali , Ajayi Saheed , Unuigbe Maria
Published: November 2023

Purpose

Digital uptake amongst construction organisations is described as slow and ineffective, undermining a fundamental transformation and limiting construction firms from exploiting the digital benefits. In this space, meaningful research that utilises a qualitative approach in pursuit for employees' insights towards digital transformation is lacking. Such limited focus from previous efforts presents an opportunity to illuminate the determinants of an effective digital transformation that are, arguably, responsible for the status quo of low digital uptake in the construction sector. This paper aims to discuss the aforementioned idea.

Design/methodology/approach

This study adopts a qualitative approach to address the literature's digital discreetness in construction. The qualitative approach captures employees' perspectives through its unbounded characteristic of encouraging illustration and discussion.

Findings

This paper captures 35 digital transformation determinants under three clusters, namely, organisation related, i.e. hierarchy, size and management, people related, i.e. team orientation, training and knowledge and leadership related, i.e. awareness, attitude, approach and leaders' characteristics. Findings suggest a new set of arguments in relation to understudied factors and their influence on the digital uptake in construction organisations.

Originality/value

This paper offers empirical indication of the determinants believed to influence an effective digital transformation in construction organisations. Such conceptualisation is crucial and is depicted as perceived by construction employees and practitioners, which is a less biased approach than that of comparable studies that argue the viewpoints of industry leaders in isolation of other members of the hierarchy.
How technology, organization and environment affected open government data during COVID-19: the moderating role of pandemic severity
Authors: Ma Xubu , Xiang Yafan , Qin Chunxiu , Liang Huigang , Liu Dongsu
Published: November 2023

Purpose

With the worldwide open government data (OGD) movement and frequent public health emergencies in recent years, academic research on OGD for public health emergencies has been growing. However, it is not fully understood how to promote OGD on public health emergencies. Therefore, this paper aims to explore the factors that influence OGD on public health emergencies.

Design/methodology/approach

The technology–organization–environment framework is applied to explore factors that influence OGD during COVID-19. It is argued that the effects of four key factors – technical capacity, organizational readiness, social attention and top-down pressure – are contingent on the severity of the pandemic. A unique data set was created by combining multiple data sources which include archival government data, a survey of 1,034 Chinese respondents during the COVID-19 outbreak and official COVID-19 reports.

Findings

The data analysis indicates that the four factors positively affect OGD, and pandemic severity strengthens the effects of technical capacity, organizational readiness and social attention on OGD.

Originality/value

This study provides theoretical insights regarding how to improve OGD during public health emergencies, which can guide government efforts in sharing data with the public when dealing with outbreak in the future.