bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional and phenotypic heterogeneity underpinning venetoclax resistance in AML
Authors: Mohanty Vakul , Baran Natalia , Huang Yuefan , Ramage Cassandra L , Cooper Laurie M , He Shan , Iqbal Ramiz , Daher May ,   CTD2 Research Network, Tyner Jeffrey W. , Mills Gordon B. , Konopleva Marina , Chen Ken 
Published: January 2024

AbstractThe venetoclax BCL2 inhibitor in combination with hypomethylating agents represents a cornerstone of induction therapy for older AML patients, unfit for intensive chemotherapy. Like other targeted therapies, venetoclax-based therapies suffer from innate and acquired resistance. While several mechanisms of resistance have been identified, the heterogeneity of resistance mechanism across patient populations is poorly understood. Here we utilized integrative analysis of transcriptomic andex-vivodrug response data in AML patients to identify four transcriptionally distinct VEN resistant clusters (VR_C1-4), with distinct phenotypic, genetic and drug response patterns. VR_C1 was characterized by enrichment for differentiated monocytic- and cDC-like blasts, transcriptional activation of PI3K-AKT-mTOR signaling axis, and energy metabolism pathways. They showed sensitivity to mTOR and CDK inhibition. VR_C2 was enriched forNRASmutations and associated with distinctive transcriptional suppression ofHOXexpression. VR_C3 was characterized by enrichment forTP53mutations and higher infiltration by cytotoxic T cells. This cluster showed transcriptional expression of erythroid markers, suggesting tumor cells mimicking erythroid differentiation, activation of JAK-STAT signaling, and sensitivity to JAK inhibition, which in a subset of cases synergized with venetoclax. VR_C4 shared transcriptional similarities with venetoclax-sensitive patients, with modest over-expression of interferon signaling. They were also characterized by high rates ofDNMT3Amutations. Finally, we projected venetoclax-resistance states onto single cells profiled from a patient who relapsed under venetoclax therapy capturing multiple resistance states in the tumor and shifts in their abundance under venetoclax selection, suggesting that single tumors may consist of cells mimicking multiple VR_Cs contributing to intra-tumor heterogeneity. Taken together, our results provide a strategy to evaluate inter- and intra-tumor heterogeneity of venetoclax resistance mechanisms and provide insights into approaches to navigate further management of patients who failed therapy with BCL2 inhibitors.
Approximate Nearest Neighbor Graph Provides Fast and Efficient Embedding with Applications in Large-scale Biological Data
Authors: Zhao Jianshu , Pierre-Both Jean , Konstantinidis Konstantinos T. 
Published: January 2024

AbstractDimension reduction (or embedding), as a popular way to visualize data, has been a fundamental technique in many applications. Non-linear dimension reduction such as t-SNE and UMAP has been widely used in visualizing single cell RNA sequencing data and metagenomic binning and thus receive many attentions in bioinformatics and computational biology. Here in this paper, we further improve UMAP-like non-linear dimension reduction algorithms by updating the graph- based nearest neighbor search algorithm (e.g. we use Hierarchical Navigable Small World Graph, or HNSW instead of K-graph) and combine several aspects of t-SNE and UMAP to create a new non-linear dimension reduction algorithm. We also provide several additional features including computation of LID (Local Intrinsic Dimension) and hubness, which can reflect structures and properties of the underlying data that strongly affect nearest neighbor search algorithm in traditional UMAP-like algorithms and thus the quality of embeddings. We also combined the improved non-linear dimension reduction algorithm with probabilistic data structures such as MinHash-likes ones (e.g., ProbMinHash et.al.) for large-scale biological sequence data visualization. Our library is called annembed and it was implemented and fully parallelized in Rust. We benchmark it against popular tools mentioned above using standard testing datasets and it showed competitive accuracy. Additionally, we apply our library in three real-world problems: visualizing large-scale microbial genomic database, visualizing single cell RNA sequencing data and metagenomic binning, to showcase the performance, scalability and efficiency of the library when distance computation is expensive or when the number of data points is large (e.g. millions or billions). Annembed can be found here:https://github.com/jean-pierreBoth/annembed
Sustaining healthy long-term host-microbiome interactions in a physiologically relevant dynamic gingival tissue model
Authors: Adelfio M. , Callen G. E. , Diaz A. R. , Paster B J. , He X. , Hasturk H. , Ghezzi C. E. 
Published: January 2024

AbstractHost-oral microbiome interactions are known to be critical in maintaining local and systemic health of the human body, although they are difficult to study in both clinical andin vitroapplications. Despite efforts, recapitulation of gingival architecture and physiological characteristics of the periodontal niche cannot be achieved by traditional tissue engineering strategies. Here, we advanced our humanized three-dimensional gingival model by co-culturing it with a healthy patient-derived microbiomes for seven days within an oral bioreactor that mimics native salivary dynamics. Our results indicated long-term host and microbiome viability, host barrier integrity and physiological response, and preservation of healthy microbial populations and interbacterial dialogues. The model has proven useful in successfully mimicking tissue homeostasis at the interface of the periodontal niche and suitable for the introduction of immune cells. Future studies will focus on using the model as a comparator of periodontal inflammation and identifying biomarkers associated with eubiotic/dysbiotic profiles.Graphical AbstractCreated partially in biorender.com.
Crossover Interference Mediates Multiscale Patterning Along Meiotic Chromosomes
Authors: White Martin A. , Weiner Beth , Chu Lingluo , Lim Gyubum , Kleckner Nancy E. 
Published: January 2024

AbstractThe classical phenomenon of crossover interference is a one-dimensional spatial patterning process that produces evenly spaced crossovers during meiosis. Quantitative analysis of diagnostic molecules along budding yeast chromosomes reveals that this process also sets up a second, interdigitated pattern of related but longer periodicity, in a “two-tiered” patterning process. The second tier corresponds to a previously mysterious minority set of crossovers. Thus,in toto, the two tiers account for all detected crossover events. Both tiers of patterning set up spatially clustered assemblies of three types of molecules (“triads”) representing the three major components of meiotic chromosomes (crossover recombination complexes and chromosome axis and synaptonemal complex components), and give focal and domainal signals, respectively. Roles are suggested. All observed effects are economically and synthetically explained if crossover patterning is mediated by mechanical forces along prophase chromosomes. Intensity levels of domainal triad components are further modulated, dynamically, by the conserved protein remodeler Pch2/TRIP13.
Unravelling the ageing-reversal potency of stem cell-derived extracellular vesicles in a rat model of premature cardiac senescence
Authors: Gómez-Cid L , Campo-Fonseca A , Cervera-Negueruela M , Ocampo A , Pinto A , Gil-Jaurena JM , Suárez-Sancho S , Fernández-Avilés F , Bermejo J , Grigorian-Shamagian L 
Published: January 2024

AbstractCardiosphere-derived cells (CDCs) and the extracellular vesicles they release (CDC-EVs) have demonstrated to induce rejuvenation and to improve cardiac structure and function, but their efficacy may vary among donors and there is still a lack of adequate potency assays. We aimed to identify parameters that could easily predict the ageing-reversal potency of CDC-EVs. CDCs derived from cardiac tissue of 34 human donors (age range: 3-months to 81-years old) were characterized in terms of their phenotypical and biological properties. The anti-senescent activity of the CDC-EVs was assessedin vitrousing a predesigned matrix assay with several ageing-related markers. We found that while CDC-donor’s chronological age was not determinant, the degree of CDC senescence in culture showed a strong correlation to most CDĆs bioactive properties. However, CDC senescence alone was insufficient to predict CDC-EVin vitropotency. Thus, we scored the potency of the CDC-EVs based on their performance in the newly designedin vitromatrix assay and classified them as more-(P-EVs) and less-potent (NP-EVs). We then tested P- and NP-EVs in a rat model of premature cardiac ageing and found that only the P-EVs reduced senescence-associatedGLB1gene expression in the heart and tended to protect it from hypertrophy development and fibrosis. On the contrary, NP-EVs failed to induce any improvements and negatively affected cardiac hypertrophy, fibrosis, and perfusion. In conclusion, despite CDC-EV anti-ageing potency cannot be predicted by the chronological age of the donors or CDC senescence as surrogate markers, we propose anin vitropotency assay that could be used to evaluate allogenic EV suitability before its use in the treatment of cardiac ageing.
Familial risk of myocardial infarction with non-obstructive and obstructive coronary arteries-A nation-wide cohort study
Authors: Hakansson Felicia HK , Svensson Per , Pettersson Hans J , Ehrenborg Ewa , Spaak Jonas , Nordenskjold Anna M , Eggers Kai M , Tornvall Per 
Published: January 2024

ABSTRACTBackgroundThe familial risk among patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) is unknown. Previous studies of family history in myocardial infarction (MI), have not made a distinction between MINOCA and MI due to coronary artery disease (MI-CAD), based on angiographic findings.ObjectivesTo investigate familial risk of MI without and with obstructive coronary arteries.MethodsA register-based cohort study with a total of 15,462 MINOCA cases, 204,424 MI-CAD cases, 38,220 control subjects without MI and with non-obstructive coronary arteries. First-degree relatives were identified 1995-2020. Cox proportional hazard regression models were used to compare familial risk in MINOCA and MI-CAD with control subjects.ResultsDuring a mean follow-up of 8.1 ± 4.2 years, MINOCA occurred in 1.0% of first-degree relatives with MINOCA whereas MI-CAD occurred in 9.7% of first-degree relatives of MINOCA. The age- and sex-adjusted hazard ratio (HR) for a MINOCA-relative experiencing MINOCA and MI-CAD, compared to control subjects, was 0.99 (95% confidence interval [CI] 0.80-1.23) and 1.10 (95% CI 1.03-1.18), respectively. During a mean follow-up of 8.5 ±4.8 years, MI-CAD occurred in 12.2% of first-degree relatives with MI-CAD with age- and sex-adjusted HR 1.43 (95% CI 1.37-1.49).ConclusionsNo increased familial risk of MINOCA was observed for MINOCA-patients whereas there was an increased familial risk for MI-CAD when compared to control subjects. These results may indicate that genetic factors and shared environmental factors within a family leading to CAD are important also for MINOCA, thus MI-CAD and MINOCA could share underlying mechanisms.Condensed AbstractIn this register-based nation-wide cohort study including 15,462 MINOCA cases, 204,424 MI-CAD cases, and 38,220 control subjects, studied between 1995-2020, we show that there is an increased familial risk for MINOCA having a first-degree relative with MI-CAD, without an increased familial risk of MINOCA having a first-degree relative with MINOCA compared to controls. Age- and sex-adjusted hazard ratio (HR) for MICAD was 1.10 (95% confidence interval 1.03-1.18), and for MINOCA 0.99 (95% confidence interval 0.80-1.23). These results may indicate that genetic factors and shared environmental factors within a family leading to CAD are important also for MINOCA.
Sex Disparity in Referral for Catheter Ablation for Atrial Fibrillation at a Single Integrated Health System
Authors: Gangadharan Arati A. , Muhammad Lutfiyya N. , Song Jing , Knight Bradley , Passman Rod 
Published: January 2024

AbstractBackgroundCatheter ablation for atrial fibrillation (AFCA) is indicated for select patients with atrial fibrillation (AF) and has been shown to reduce AF burden and improve quality of life. Earlier studies demonstrated that women are less likely to undergo AFCA despite having more AF symptoms. We investigated whether an association exists between referral patterns and this sex disparity.Methods and ResultsA retrospective cohort study was conducted of outpatients with newly diagnosed AF using the electronic medical record at Northwestern. Of 5,445 patients analyzed, 2,108 were women, and 3,337 were men. Characteristics including race, insurance status, comorbidities, and prior AF treatment were compared by sex. Logistic regression models adjusted for socioeconomic and clinical factors were constructed to determine associations between sex and binary dependent variables including referrals to and visits with general cardiology and electrophysiology (EP) and utilization of AFCA. There were no significant differences in odds of referral to (aOR, 1.17 [0.92-1.48], P=0.20) or visits with (aOR, 1.03 [0.82-1.30], P=0.79) general cardiologists between women and men. There were no significant differences in odds of referral to (aOR, 0.83 [0.68-1.01], P=0.06) or visits with (aOR, 0.87 [0.72-1.05], P=0.15) electrophysiologists between women and men. Finally, no significant difference was found in likelihood to undergo AFCA between women and men (aOR, 1.08 [0.83-1.40], P=0.56).ConclusionsOur study demonstrates no significant differences in referral patterns to specialists or rates of AFCA between women and men. Encouraging equitable referral to specialists and access to AFCA is essential in ensuring appropriate care for all patients.
Development and Validation of a Bedside Scale for Assessing Upper Limb Function Following Stroke: A Methodological Study. [version 1; peer review: awaiting peer review]
Authors: Pawani Dhaval , Joshua Abraham M. , Nayak Akshatha , Palaniswamy Vijayakumar , Mithra Prasanna , Prabhakar Ashish John , Amaravadi Sampath Kumar 
Published: January 2024

AbstractBackgroundNumerous tools are available for evaluation of upper limb (UL) functions among stroke survivors. Despite the excellent psychometric properties, many require considerable amount of time, are resource-intensive, and often impractical for bedside evaluation.ObjectivesTo develop and concurrently validate a simple, resource-efficient, and time-efficient bedside tool for evaluating UL function in stroke survivors.MethodsRelevant literature review was carried out to conceptualize and define the theoretical framework of day-to-day UL movement tasks. Subsequently, an item pool of 18 UL movements was developed. A mini-Delphi method was employed to verify content validity. During the iterative rounds, 18-items were revised and refined to a 12-items scale. The final bedside upper limb evaluation tool (BUFET) scale underwent concurrent validation by correlating the scores with Wolf Motor Function Test (WMFT) scores using Spearman’s correlation coefficient. Internal consistency was evaluated through Cronbach’s alpha.ResultsConcurrent validity and internal consistency of the scale were supported by a high correlation coefficient (r = 0.937; p<0.001) with WMFT and high Cronbach’s alpha (0.948).ConclusionsNewly developed BUFET was found to be a valid and reliable bedside tool in the evaluation of upper limb functions and can be administered in a resource and time-efficient manner.
Slow running benefits: Boosts in mood and facilitation of prefrontal cognition even at very light intensity
Authors: Damrongthai Chorphaka , Kuwamizu Ryuta , Yamazaki Yudai , Aoike Naoki , Lee Dongmin , Byun Kyeongho , Torma Ferenc , Churdchomjan Worachat , Yassa Michal A. , Adachi Kazutaka , Soya Hideaki 
Published: January 2024

ABSTRACTAlthough running upright has been reported to have positive effects on both physical and mental health, the minimum running intensity/speed that would benefit mood and prefrontal cognition is not yet clear. For this reason, we aimed to investigate the acute effect of very slow running, which is classified as a very light intensity exercise, on mood, executive function (EF), and their neural substrates in the prefrontal cortex (PFC). Twenty-four healthy participants completed a 10-minute very slow running session on a treadmill at 35%and a resting control session in randomized order. EF was measured using the Stroop task and the mood state was measured using the Two-Dimensional Mood Scale (TDMS) before and after both sessions. Cortical hemodynamic changes while performing the task were monitored using functional near-infrared spectroscopy (fNIRS). The results show that ten minutes of very slow running significantly enhanced mood, reduced Stroop interference time (i.e., enhanced EF), and elicited left lateral PFC activation. Moreover, head acceleration, the magnitude of up-and-down oscillations, was measured during running, and a significant positive correlation with pleasant mood was found. Head acceleration is a remarkable characteristic of running and may be one of the factors related to a pleasant mood induced by very slow running. In conclusion, the current study reveals that a single bout of running, even at very slow speed, elicits a pleasant mood and improved executive function with enhancing activation in prefrontal subregions. This shed light on the slow running benefits to brain health.
Postharvest partial dehydration of blueberries enhanced blueberry wine aroma via upregulating phenylalanine metabolism and terpene biosynthesis
Authors: Wang Yu , Zhang Qi , Yang Qin , Bian Chen , Huang Shu-Qin , Zhao Lu-Lu , Huang Ya-Qiong , Shen Shan-Shan , Chen Qi , Zhang Hai-Wei , Gao Xue-Ling 
Published: January 2024

AbstractPostharvest partial dehydration of blueberries can enhance blueberry wine aroma, while the underlying mechanisms remain unclear. In this study, the key odor-active volatiles in blueberry wines fermented from dehydrated blueberries (30% weight loss) were identified via aroma extract dilution analysis. Results showed that increased levels of phenylalanine-derived compounds such as phenylethanol, and terpenes such as linalool and geraniol, primarily led to the enhancement of sweet, floral and fruity aromas of blueberry wines. Postharvest partial dehydration increased the contents of these compounds, which could be linked to the upregulation ofVcGOT2andVcPARinvolved in phenylalanine metabolism, and the upregulation ofVcDXS,VcHDRandVcTPSinvolved in terpene biosynthesis. Notably, the upregulatedVcTPSencoded a monoterpene synthase responsible for producing linalool. These findings provided insight into the impact of postharvest dehydration on phenylalanine and terpene metabolism in blueberries, offering a reference for improving blueberry wine aroma through postharvest partial dehydration techniques.
Intolerance of uncertainty does not significantly predict decisions about delayed, probabilistic rewards
Authors: Cobos Pedro L. , Quintero María J. , López Francisco J. , Luque David , Ciria Luis F. , Morís y Joaquín 
Published: January 2024

AbstractIntolerance of Uncertainty (IU) is thought to lead to maladaptive behaviours and dysfunctional decision making, both in the clinical and healthy population. The seminal study reported by Luhmann and collaborators in 2011 showed that IU was negatively associated with choosing a delayed, but more certain and valuable, reward over choosing an immediate, but less certain and valuable, reward. These findings have been widely disseminated across the field of personality and individual differences because of their relevance to understand the role of IU in maladaptive behaviours in anxiety-related disorders. We conducted a study to replicate and extend Luhmann et al.’s results with a sample of 313 participants, which exceeded the size necessary (N = 266) to largely improve the statistical power of the original study by using thesmall telescopes approach. The results of our well powered study strongly suggest that the relationship between IU and the tendency to prefer an immediate, but less certain and less valuable reward is virtually negligible. Consequently, although this relationship cannot be definitely discarded, we conclude that it cannot be detected with Luhmann et al.’s (2011) decision-making task.
Spike N354 glycosylation augments SARS-CoV-2 fitness for human adaptation through multiple mechanisms
Authors: Liu Pan , Yue Can , Meng Bo , Xiao Tianhe , Yang Sijie , Liu Shuo , Jian Fanchong , Zhu Qianhui , Yu Yuanling , Ren Yanyan , Wang Peng , Li Yixin , Wang Jinyue , Mao Xin , Shao Fei , Wang Youchun , Gupta Ravindra Kumar , Cao Yunlong , Wang Xiangxi 
Published: January 2024

SUMMARYSelective pressures have given rise to a number of SARS-CoV-2 variants during the prolonged course of the COVID-19 pandemic. Recently evolved variants differ from ancestors in additional glycosylation within the spike protein receptor-binding domain (RBD). Details of how the acquisition of glycosylation impacts viral fitness and human adaptation are not clearly understood. Here, we dissected the role of N354-linked glycosylation, acquired by BA.2.86 sub-lineages, as a RBD conformational control element in attenuating viral infectivity. The reduced infectivity could be recovered in the presence of heparin sulfate, which targets the “N354 pocket” to ease restrictions of conformational transition resulting in a “RBD-up” state, thereby conferring an adjustable infectivity. Furthermore, N354 glycosylation improved spike cleavage and cell-cell fusion, and in particular escaped one subset of ADCC antibodies. Together with reduced immunogenicity in hybrid immunity background, these indicate a single spike amino acid glycosylation event provides selective advantage in humans through multiple mechanisms.HIGHLIGHTSN354 glycosylation acts as a conformational control element to modulate infectivity Reduced infectivity could be recovered by altered binding mode of heparin sulfate N354 glycosylation improved fusogenicity and conferred escape from ADCC antibodies N354 glycosylation reduced immunogenicity and conferred immune evasion
Imaging Aβ aggregation by liquid-phase transmission electron microscopy
Authors: Ing Gabriel , Acosta-Gutiérrez Silvia , Vendruscolo Michele , Battaglia Giuseppe , Ruiz-Pérez Lorena 
Published: January 2024

AbstractThe amyloid beta peptide (Aβ) readily aggregates into amyloid fibrils. This process has been the subject of intense investigations since it is associated with Alzheimer’s disease. However, it has been highly challenging to observe the microscopic steps in the aggregation reaction directly and to characterize the oligomeric assemblies formed as intermediates. To achieve this goal, we apply liquid-phase transmission electron microscopy (LTEM) in combination with all-atom molecular dynamics simulations. Our results offer an initial visualization of the dynamics of Aβ oligomers, the formation of Aβ protofibrils, and the presence of Aβ oligomers on the surface of Aβ fibrils. This work illustrates how the application of LTEM to the study of protein aggregation in solution enables the imaging of key molecular events in the aggregation process of Aβ.