bluuebunny/crossref_metadata_2025_split huggingface dataset:
RNA Pol II antagonises mitotic chromatin folding and chromosome segregation by condensin
Authors: Lebreton Jeremy , Colin Léonard , Chatre Elodie , Bernard Pascal 
Published: August 2023

AbstractCondensin shapes mitotic chromosomes by folding chromatin into loops but whether it does so by DNA-loop extrusion remains speculative. While loop-extruding cohesin is stalled by transcription, no conclusive evidence has been provided regarding the impact of transcription on condensin despite its conserved enrichment at highly expressed genes. Using degrons of Rpb1 or the torpedo nuclease Dhp1XRN2, we depleted or displaced RNAP2 on chromatin in fission yeast metaphase cells. We show that RNAP2 does not load condensin on DNA but instead retains condensin and hinders its ability to fold mitotic chromatin and to support chromosome segregation, consistent with the stalling of a loop-extruder. Transcription termination by Dhp1 limits such a hindrance. Our results shed a new light on the integrated functioning of condensin and we argue that a tight control of transcription underlies mitotic chromosome assembly by loop-extruding condensin.
Pathogenic soluble tau peptide disrupts endothelial calcium signaling and vasodilation in the brain microvasculature
Authors: Freeman Kalev , Sackheim Adrian M , Mughal Amreen , Koide Masayo , Bonson Grace , Ebner Grace , Hennig Grant , Lockette Warren , Nelson Mark T 
Published: August 2023

ABSTRACTThe accumulation of the microtubule-associated tau protein in and around blood vessels contributes to brain microvascular dysfunction through mechanisms that are incompletely understood. Delivery of nutrients to active neurons in the brain relies on capillary inositol 1,4,5-triphosphate receptor (IP3R)–mediated calcium (Ca2+) signals to direct blood flow. The initiation and amplification of endothelial cell IP3R-mediated Ca2+signals requires an intact microtubule cytoskeleton. Since tau accumulation in endothelial cells disrupts native microtubule stability, we reasoned that tau-induced microtubule destabilization would impair endothelial IP3-evoked Ca2+signaling. We tested the hypothesis that tau disrupts the regulation of local cerebral blood flow by reducing endothelial cell Ca2+signals and endothelial-dependent vasodilation. We used a pathogenic soluble tau peptide (T-peptide) model of tau aggregation and mice with genetically encoded endothelial Ca2+sensors to measure cerebrovascular endothelial responses to tau exposure. T-peptide significantly attenuated endothelial Ca2+activity and cortical capillary blood flowin vivowithin 120 seconds. Further, T-peptide application constricted pressurized cerebral arteries and inhibited endothelium-dependent vasodilation. This study demonstrates that pathogenic tau alters cerebrovascular function through direct attenuation of endothelial Ca2+signaling and endothelium-dependent vasodilation.
The discovery of mixed colonies inTemnothoraxants supports the territoriality hypothesis of dulotic social parasite evolution in myrmicine ants
Authors: Bengston Sarah , Dornhaus Anna , Rabeling Christian 
Published: August 2023

AbstractSocial parasitism, where one social species parasitically depends on the other for survival and reproduction, is a highly successful life history strategy, especially in the eusocial Hymenoptera. In ants alone, more 400 species of socially parasitic species exist and multiple forms of social parasitism evolved independently and convergently. Yet disentangling the evolutionary history of obligate social parasitism is challenging. Identifying species that inform the transition from eusocial toward socially parasitic behavior is crucial for understanding the underlying co-evolutionary processes. Here, we report the first case of mixed colonies involving four predominantly free-livingTemnothoraxant species from the western United States. ThreeTemnothoraxspecies supplement their worker force with brood from the nests of their four congeners. We suggest, based on these observations and other published evidence, that this facultative dulotic behavior may have resulted from territorial contests due to limited nest sites. Socially parasitic behavior is not present in all populations across the species distribution ranges, however in populations where this behavior was observed, it is also associated with significant increases in interspecific aggression. These four species of Western USTemnothoraxants represent a particularly interesting case of social parasitism, because the presence of between-population behavioral variation provides a powerful system to test hypotheses about the ecological and behavioral conditions underlying the evolutionary transition from eusocial to socially parasitic behavior.
Aptamer-antibody chimera sensors for sensitive, rapid and reversible molecular detection in complex samples
Authors: Kong Dehui , Maganzini Nicolo , Thompson Ian A.P. , Eisenstein Michael , Soh H. Tom 
Published: August 2023

AbstractThe development of receptors suitable for the continuous detection of analytes in complex, interferent-rich samples remains challenging. Antibodies are highly sensitive but difficult to engineer in order to introduce signaling functionality, while aptamer switches are easy to construct but often yield only modest target sensitivity. We present here the programmable antibody and DNA aptamer switch (PANDAS), which combines the best features of both systems by using a nucleic acid tether to link an analyte-specific antibody to an internal strand-displacement (ISD)-based aptamer switch that recognizes the same target. The monoclonal antibody mediates initial analyte binding due to its higher affinity; the resulting increase in local analyte concentration then leads to cooperative binding and signaling by the ISD switch. We developed a PANDAS sensor for the clotting protein thrombin and show that this design achieves 100-fold enhanced sensitivity compared to using an aptamer alone. This design also exhibits reversible binding, enabling repeated measurements with temporal resolution of ∼10 minutes, and retains excellent sensitivity even in interferent-rich samples. With future development, this PANDAS approach could enable the adaptation of existing protein-binding aptamers with modest affinity into sensors that deliver excellent sensitivity and minute-scale resolution in minimally prepared biological specimens.
Generalization of procedural motor sequence learning after a single practice trial
Authors: Johnson B.P. , Iturrate I. , Fakhreddine R.Y. , Bönstrup M. , Buch E.R. , Robertson E.M. , Cohen L.G. 
Published: August 2023

AbstractWhen humans begin learning new motor skills, they typically display early rapid performance improvements. It is not well understood how knowledge acquired during this early skill learning period generalizes to new, related skills. Here, we addressed this question by investigating factors influencing generalization of early learning from a skill A to a different, but related skill B. Early skill generalization was tested over four experiments (N = 2,095). Subjects successively learned two related motor sequence skills (skills A and B) over different practice schedules. Skill A and B sequences shared ordinal (i.e. – matching keypress locations), transitional (i.e. – ordered keypress pairs), parsing rule (i.e., distinct sequence events like repeated keypresses that can be used as a breakpoint for segmenting the sequence into smaller units) structures, or possessed no structure similarities. Results showed generalization for shared parsing rule structure between skills A and B after only a single 10-second practice trial of skill A. Manipulating the initial practice exposure to skill A (1 to 12 trials) and inter-practice rest interval (0 to 30s) between skills A and B had no impact on parsing rule structure generalization. Furthermore, this generalization was not explained by stronger sensorimotor mapping between individual keypress actions and their symbolic representations. In contrast, learning from skill A did not generalize to skill B during early learning when the sequences shared only ordinal or transitional structure features. These results document sequence structure that can be very rapidly generalized during initial learning to facilitate generalization of skill.
Interferon response and epigenetic modulation bySMARCA4mutations drive ovarian tumor immunogenicity
Authors: Brodeur Melica Nourmoussavi , Dopeso Higinio , Zhu Yingjie , Longhini Ana Leda F. , Gazzo Andrea , Sun Siyu , Koche Richard , Qu Rui , Hamard Pierre-Jacques , Bykov Yonina , Green Hunter , Chiappinelli Katherine B. , Ozsoy Melih Arda , Basili Thais , Gardner Rui , Walderich Sven , DeStanchina Elisa , Greenbaum Benjamin , Gönen Mithat , Weigelt Britta , Zamarin Dmitriy 
Published: August 2023

AbstractCell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. The presence of damaging mutations in the SWI/SNF chromatin remodeling complex, such as theSMARCA4(BRG1) catalytic subunit, has been associated with improved response to ICB, however the mechanism by which this occurs is unclear. The aim of this current study was to examine the alterations in tumor cell-intrinsic and extrinsic immune signaling caused bySMARCA4loss. Using OC models with loss-of-function mutations inSMARCA4, we found thatSMARCA4loss resulted in increased cancer cell-intrinsic immunogenicity, characterized by upregulation of long-terminal RNA repeats such as endogenous retroviruses, increased expression of interferon-stimulated genes, and upregulation of antigen presentation machinery. Notably, this response was dependent on IRF3 signaling, but was independent of the type I interferon receptor. Mice inoculated with cancer cells bearingSMARCA4loss demonstrated increased activation of cytotoxic T cells and NK cells in the tumor microenvironment as well as increased infiltration with activated dendritic cells. These results were recapitulated when animals bearingSMARCA4-proficient tumors were treated with a BRG1 inhibitor, suggesting that modulation of chromatin remodeling through targetingSMARCA4may serve as a strategy to reverse immune evasion in OC.
Parvalbumin and somatostatin: biomarkers for two parallel tectothalamic pathways in the auditory midbrain
Authors: Liu Mengting , Gao Yixiao , Xin Fengyuan , Hu Ying , Wang Tao , Xie Fenghua , Li Tianyu , Wang Ningyu , Yuan Kexin 
Published: August 2023

AbstractThe inferior colliculus (IC) represents a crucial relay station in the auditory pathway, located in the midbrain’s tectum and primarily projecting to the thalamus. Despite the identification of distinct cell types based on various biomarkers in the IC, their specific contributions to the organization of auditory tectothalamic pathways have remained poorly understood. In this study, we demonstrate that IC neurons expressing parvalbumin (ICPV+) or somatostatin (ICSOM+) represent major, non-overlapping cell types throughout the three IC subdivisions. Strikingly, regardless of their location within the IC, these neurons predominantly project to the primary and secondary auditory thalamic nuclei, respectively. Retrograde tracing data specific to cell types indicate that ICPV+neurons primarily receive auditory inputs, whereas ICSOM+neurons integrate polymodal inputs that hold behavioral significance. Furthermore, ICPV+neurons exhibit significant heterogeneity in both intrinsic electrophysiological properties and presynaptic terminal size compared to ICSOM+neurons. Notably, approximately one quarter of ICPV+neurons are inhibitory neurons, whereas all ICSOM+neurons are excitatory neurons. Collectively, our findings suggest that parvalbumin and somatostatin expression in the IC can serve as biomarkers for two functionally distinct, parallel tectothalamic pathways. This discovery challenges the conventional IC subdivision-based definition of tectothalamic pathways and calls for a reassessment of their functional roles.
COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors
Authors: Ferreira Lucas G. A. , Kizys Marina M. L. , Gama Gabriel A. C. , Pachernegg Svenja , Robevska Gorjana , Sinclair Andrew H. , Ayers Katie L. , da Silva Magnus R. Dias 
Published: August 2023

AbstractThe absence of expression of the Y-chromosome linked testis-determining geneSRYin early supporting gonadal cells (ESGC) of bipotential gonads leads to ovarian development. However, genetic variants inNR2F2/COUP-TFII represent a novel cause ofSRY-negative 46,XX testicular/ovotesticular differences of sex development (T/OT-DSD). Thus, we hy-pothesized that COUP-TFII is part of the ovarian developmental network. We examinedNR2F2/COUP-TFII expression and the genetic network under its regulation in human gonadal cells by analyzing single cell RNA-sequencing datasets of fetal gonads, differentiating induced pluripotent stem cells into bipotential gonad-like cellsin vitro, and generating aNR2F2knockout (KO) in the human granulosa-like cell line COV434.NR2F2expression is highly upregulated during the bipotential gonad development, being detected in ESGCs. We identified thatNR2F2ablation in COV434 cells downregulated markers of ESGC and pre-granulosa cells, suggesting that COUP-TFII has a role in maintaining a multipotent state necessary for commitment to the ovarian development. We propose that impairment of COUP-TFII function may disrupt the transcriptional plasticity of ESGCs and instead drive them into commitment to the testicular pathway.
Characteristics and Attitudes of Wearable Device Users and Non-Users in a Large Healthcare System
Authors: Venn Rachael A. , Khurshid Shaan , Grayson Mia , Ashburner Jeffrey M. , Al-Alusi Mostafa A. , Chang Yuchiao , Foulkes Andrea , Ellinor Patrick T. , McManus David D. , Singer Daniel E. , Atlas Steven J. , Lubitz Steven A. 
Published: August 2023

ABSTRACTIntroductionConsumer wearable devices with health and wellness features are increasingly common and may enhance prevention and management of cardiovascular disease. However, the characteristics and attitudes of wearable device users versus non-users are poorly understood.MethodsWearable Activity Tracking for Comprehensive Healthcare-Integrated Technology (WATCH-IT) was a prospective study of adults aged ≥18 years receiving longitudinal primary or ambulatory cardiovascular care at one of eleven hospitals within the Mass General Brigham multi-institutional healthcare system between January 2010-July 2021. We invited patients, including wearable users and non-users, to participate via an electronic patient portal. Participants were asked to complete a 20-question survey regarding perceptions and use of consumer wearable devices. Responses were linked to electronic health record data. Multivariable logistic regression was used to identify factors associated with device use.ResultsAmong 280,834 individuals receiving longitudinal primary or cardiovascular care, 65,842 did not have an active electronic portal or opted out of research contact. Of the 214,992 individuals sent a survey link, 11,121 responded (5.2%), comprising the WATCH-IT patient sample. Most respondents (55.8%) reported current use of a wearable device, and most non-users (95.3%) reported they would use a wearable device if provided at no cost. Although most users (70.2%) had not shared device data with their doctor previously, the majority believed it would be very (20.4%) or moderately (34.4%) important to share device-related health information with providers. In multivariable models, older age (odds ratio [OR] 0.80 per 10-year increase, 95% CI 0.77-0.82), male sex (0.87, 95% CI 0.80-0.95), and heart failure (0.75, 95% CI 0.63-0.89) were associated with lower odds of wearable device use, whereas higher median zip code income (1.08 per 1-quartile increase, 95% CI 1.04-1.12) and care in a cardiovascular medicine clinic (1.17, 95% CI 1.05-1.30) were associated with greater odds of device use. Nearly all respondents (98%) stated they would share device data with researchers studying health outcomes.ConclusionsWithin an electronically assembled cohort of patients in primary and cardiovascular medicine clinics with linkage to detailed health records, wearable device use is common. Most users perceive value in wearable data. Our platform may enable future study of the relationships between wearable technology and resource utilization, clinical outcomes, and health disparities.
Deviation from Personalized Blood Pressure Targets Correlates with Worse Outcome after Successful Recanalization
Authors: Zhang Zhe , Pu Yuehua , Yu Lei , Bai Haiwei , Duan Wanying , Liu Xin , Liu Jingyi , Zheng Lina , Hu Xiao , Leng Xinyi , Pan Yuesong , Petersen Nils H. , Liu Liping 
Published: August 2023

AbstractBackgroundPersonalized blood pressure (BP) management for acute ischemic stroke patients after successful recanalization lacks evidence. Our study aimed to investigate whether the deviation of BP from cerebral autoregulation (CA) limits, either in duration or burden, is associated with worse outcomes.MethodsWe prospectively enrolled patients with acute large anterior circulation artery occlusive stroke who had achieved successful recanalization (mTICI 2b-3). CA was determined by measuring mean velocity index (Mx) using transcranial Doppler sonography (TCD). We calculated the percent time and the burden (defined as the time-BP area) with BP outside the CA limits of each subject within 48 hours after recanalization. The outcomes included unfavorable functional outcome (mRS scored 3-6) at 90 days, early neurological deterioration (END), infarct volume growth at 7 days, and symptomatic intracranial hemorrhage (sICH) within 48 hours.ResultsA total of 91 patients were enrolled. Entire failure of autoregulation was found in 31.9% (29 / 91) of patients. The burden with BP outside the CA limits was associated with poor functional outcome at 90 days (aORper 100 h·mmHg 1.29 [95% CI, 1.05 – 1.59]P=0.018). Both the percent time and the burden with BP out of the CA limits was correlated with END (aORper 10% time 1.38 [95% CI, 1.05 – 1.83]P=0.022, aORper 100h·mmHg 1.22 [95% CI, 1.01 – 1.48]P=0.039). The burden of BP that decreased below the CA lower limit was associated with infarct volume growth (adjustedβper 100 h·mmHg 5.47 [95% CI, 0.13 – 10.80]P=0.045). The percent time that BP exceeded the CA upper limit was associated with sICH (aORper 10% time 1.45 [95% CI, 1.01 – 2.07]P=0.043).ConclusionsBoth the percent time and burden of BP that deviates from the autoregulation-preserved range correlate with worse outcomes after successful recanalization. Further randomized control trials are warranted to examine the effectiveness of autoregulation-guided BP targets.
Comparative Immunogenicity, Safety and Efficacy Profiles of four COVID-19 Vaccine types in healthy adults: Systematic Review cum Meta-analysis of Clinical Trial data
Authors: Yoong Si Qi , Bhowmik Priyanka , Dutta Debprasad 
Published: August 2023

AbstractFour principal types of authorised COVID-19 vaccines include inactivated whole-virus vaccines, protein subunit vaccines, viral-vector vaccines and nucleic acid (mRNA and DNA) vaccines. Despite numerous Randomised Controlled Trials (RCTs), comprehensive systematic review and comparative meta-analysis have not been performed to validate the immunogenicity, safety and efficacy of COVID-19 vaccines in the healthy adult population. We aim to fulfil this unmet void. We searched for peer-reviewed articles about RCTs of the COVID-19 vaccines on healthy adults (18-64 years) available in eight major bibliographic databases (PubMed, EMBASE, Web of Science, Cochrane Library, Scopus, ScienceDirect, POPLINE, HINARI) till August 28, 2022. The Risk of Bias (RoB) was assessed using the Cochrane RoB-2. Random effects meta-analysis was conducted by pooling dichotomous outcomes using risk ratios (safety outcomes) and continuous outcomes using standardised mean differences (immunogenicity outcomes). Efficacy outcomes were summarised narratively. Moderate to high-quality evidence suggests that those receiving COVID-19 vaccines had significantly higher immune responses compared to placebo. Serious adverse events were rare, confirming that COVID-19 vaccines were safe and immunogenic for the healthy adult population. Remarkably, adverse events were the least common in inactivated vaccines, and nucleic acid vaccines were the most immunogenic. The efficacies of COVID-19 vaccines ranged from 21.9% to 95.9% in preventing COVID-19. We endorse all four types of COVID-19 vaccines for public health policy implementing taskforces. Yet, meta-analyses based on individual patient data are warranted for more extensive measurement of differential impacts of COVID-19 vaccines on different genders, ethnicities, comorbidities and types of vaccine jabbed.
Computational inference of eIF4F complex function and structure in human cancers
Authors: Wu Su , Wagner Gerhard 
Published: August 2023

AbstractThe canonical eukaryotic initiation factor 4F (eIF4F) complex, composed of eIF4G1, eIF4A1, and the cap-binding protein eIF4E, plays a crucial role in cap-dependent translation initiation in eukaryotic cells (1). However, cap-independent initiation can occur through internal ribosomal entry sites (IRESs), involving only eIF4G1 and eIF4A1 present, which is considered to be a complementary process to cap-dependent initiation in tumors under stress conditions (2). The selection and molecular mechanism of specific translation initiation in human cancers remains poorly understood. Thus, we analyzed gene copy number variations (CNVs) in TCGA tumor samples and found frequent amplification of genes involved in translation initiation. Copy number gains inEIF4G1andEIF3Efrequently co-occur across human cancers. Additionally,EIF4G1expression strongly correlates with genes from cancer cell survival pathways including cell cycle and lipogenesis, in tumors withEIF4G1amplification or duplication. Furthermore, we revealed that eIF4G1 and eIF4A1 protein levels strongly co-regulate with ribosomal subunits, eIF2, and eIF3 complexes, while eIF4E co-regulates with 4E-BP1, ubiquitination, and ESCRT proteins. Using Alphafold predictions, we modeled the eIF4F structure with and without eIF4G1-eIF4E binding. The modeling for cap-dependent initiation suggests that eIF4G1 interacts with eIF4E through its N-terminal eIF4E-binding domain, bringing eIF4E near the eIF4A1 mRNA binding cavity and closing the cavity with both eIF4G1 HEAT-2 domain and eIF4E. In the cap-independent mechanism, α-helix5of eIF4G1 HEAT-2 domain instead directly interacts with the eIF4A1 N-terminal domain to close the mRNA binding cavity without eIF4E involvement, resulting in a stronger interaction between eIF4G1 and eIF4A1.Significance StatementTranslation initiation is primarily governed by eIF4F, employing a “cap-dependent” mechanism, but eIF4F dysregulation may lead to a “cap-independent” mechanism in stressed cancer cells. We found frequent amplification of translation initiation genes, and co-occurring copy number gains ofEIF4G1andEIF3Egenes in human cancers.EIF4G1amplification or duplication may be positively selected for its beneficial impact on the overexpression of cancer survival genes. The co-regulation of eIF4G1 and eIF4A1, distinctly from eIF4E, reveals eIF4F dysregulation favoring cap-independent initiation. Alphafold predicts changes in the eIF4F complex assembly to accommodate both initiation mechanisms. These findings have significant implications for evaluating cancer cell vulnerability to eIF4F inhibition and developing treatments that target cancer cells with dependency on the translation initiation mechanism.