bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancer RNA transcriptome-wide association study reveals an atlas of pan-cancer susceptibility eRNAs
Authors: Chen Wenyan , Wang Zeyang , Lin Jianxiang , Chen Shuxin , Chen Hui , Ma Xuelian , Zou Xudong , Li Xing , Wang Yinuo , Qin Yangmei , Ma Xixian , Qiao Yunbo , Li Lei 
Published: March 2024

SummaryMany cancer risk variants are located within enhancer regions and lack sufficient molecular interpretation. Here, we constructed the first comprehensive atlas of enhancer RNA (eRNA)- mediated genetic effects from 28,033 RNA sequencing samples across 11,606 individuals, identifying 11,757 eRNA quantitative trait loci (eRNA-QTLs) significantly associated with eRNA expression. Mechanistically, eRNA-QTLs frequently altered binding motifs of transcription factors. In addition, 28.48% of cancer risk variants were strongly colocalized with eRNA-QTLs. We further performed an eRNA-based transcriptome-wide association study and identified 626 cancer susceptibility eRNAs across 23 cancer types. 54.9% of the eRNA target genes were overlooked by traditional gene expression studies, and most are essential for cancer cell proliferation. To substantiate our findings, we confirmed the enhancer functionality of two newly identified susceptibility eRNAs,CCND1eandSNAPC1e, through CRISPR-based inhibition, resulting in a marked decrease in the expression of their respective target genes, consequently suppressing the proliferation of prostate cancer cells. Our study underscores the essential role of eRNA in unveiling new cancer susceptibility genes and establishes a strong framework for enhancing our understanding of human cancer etiology.
TEMPORAL SPATIALIZATION AS A STRATEGY FOR URBAN MANAGEMENT IN CONTROLLING DISEASES TRANSMITTED BY MOSQUITOES
Authors: de Almeida Márlon Luiz , Souza Fábio Teodoro de , Pontes Alzair Eduardo , Nogueira Rodrigo Sant’Ana , Baldini Raquel Ribeiro de Medeiros 
Published: March 2024

AbstractDue to their ecophysiological ability to adapt to new environments, combined with climate change, mosquitoes that vector dengue fever and other arboviruses are increasingly expanding their areas of infestation. Dengue fever has shown growth across the planet, reaching countries and regions that were previously free of this disease. And urban management must find tools that help minimize or eradicate arbovirus vectors. This research aims to demonstrate how the temporal spatialization of diseases transmitted by mosquitoes can contribute to urban management in controlling these types of illnesses in small cities. Through a case study in a small town in the interior of Brazil, it was possible to accurately detect, through temporal spatialization, which neighborhoods were most prone to the disease from 2010 to 2020. Thus, urban management can develop public policies in these neighborhoods and improve their performance against the disease.
CZ ID: a cloud-based, no-code platform enabling advanced long read metagenomic analysis
Authors: Simmonds Sara E. , Ly Lynn , Beaulaurier John , Lim Ryan , Morse Todd , Thakku Sri Gowtham , Rosario Karyna , Perez Juan Caballero , Puschnik Andreas , Mwakibete Lusajo , Hickey Scott , Tato Cristina M. , Team CZ ID , Kalantar Katrina 
Published: March 2024

ABSTRACTMetagenomics has enabled the rapid, unbiased detection of microbes across diverse sample types, leading to exciting discoveries in infectious disease, microbiome, and viral research. However, the analysis of metagenomic data is often complex and computationally resource-intensive. CZ ID is a free, cloud-based genomic analysis platform that enables researchers to detect microbes using metagenomic data, identify antimicrobial resistance genes, and generate viral consensus genomes. With CZ ID, researchers can upload raw sequencing data, find matches in NCBI databases, get per-sample taxon metrics, and perform a variety of analyses and data visualizations. The intuitive interface and interactive visualizations make exploring and interpreting results simple. Here, we describe the expansion of CZ ID with a new long read mNGS pipeline that accepts Oxford Nanopore generated data (czid.org). We report benchmarking of a standard mock microbial community dataset against Kraken2, a widely used tool for metagenomic analysis. We evaluated the ability of this new pipeline to detect divergent viruses using simulated datasets. We also assessed the detection limit of a spiked-in virus to a cell line as a proxy for clinical samples. Lastly, we detected known and novel viruses in previously characterized disease vector (mosquitoes) samples.
Learning probability distributions of sensory inputs with Monte Carlo Predictive Coding
Authors: Oliviers Gaspard , Bogacz Rafal , Meulemans Alexander 
Published: March 2024

AbstractIt has been suggested that the brain employs probabilistic generative models to optimally interpret sensory information. This hypothesis has been formalised in distinct frameworks, focusing on explaining separate phenomena. On one hand, predictive coding theory proposed how the probabilistic models can be learned by networks of neurons employing local synaptic plasticity. On the other hand, neural sampling theories have demonstrated how stochastic dynamics enable neural circuits to represent the posterior distributions of latent states of the environment. Here, we bring together these two lines of theoretic work by introducing Monte Carlo predictive coding (MCPC). We demonstrate that the integration of predictive coding with neural sampling results in a neural network that learns precise generative models using local computation and plasticity. The neural dynamics of MCPC infer the posterior distributions of the latent states in the presence of sensory inputs, and can generate likely inputs in their absence. Furthermore, MCPC captures the experimental observations on the variability of neural activity during perceptual tasks. By combining predictive coding and neural sampling, MCPC offers a unifying theory of cortical computation which can account for both sets of neural data that previously had been explained by these individual frameworks.
Variables affecting acquisition and maintenance of operant ethanol self-administration in male and female Long-Evans rats
Authors: Wheeler Shannon R , Pitock Joseph R , Ayala Arleen Perez , Hou Shikun , Soto Nathaly M Arce , Glover Elizabeth J 
Published: March 2024

AbstractAimsThe goal of the present study was to determine the effect of prior experience with ethanol drinking and changes in session duration on the acquisition and maintenance of operant ethanol self-administration.MethodsAdult male and female Long-Evans rats were trained to operantly self-administer ethanol. A subset of male rats underwent intermittent-access two-bottle choice drinking in the home cage prior to operant training. Controls were given access to two bottles of water. Once fully trained in 30-min operant sessions, session duration was reduced to 15 min for all male and female rats. Differences between 30- and 15-min sessions were also assessed in a separate group of male and female rats trained to self-administer sucrose.ResultsNo differences were observed in acquisition rates, the magnitude of responding for ethanol, or total ethanol consumed between male rats allowed to drink ethanol in the home cage and those that remained ethanol naïve prior to operant training. A significant decrease in appetitive and consummatory behaviors was observed in males trained to lever press for either ethanol or sucrose. Females exhibited a similar decrease in operant performance for sucrose, but their behavior was largely unchanged in response to changes in session duration when ethanol was the reinforcer.ConclusionsThese data suggest that the use of prior home cage ethanol drinking as an initiation procedure offers little advantage over no initiation procedure at all. Moreover, reducing operant session duration from 30-min to 15-min has the potential to decrease, rather than increase, levels of ethanol intake.Short summaryIntermittent-access two-bottle choice ethanol drinking offers no advantage as an initiation procedure for operant ethanol self-administration over animals that are ethanol-naïve prior to training. In addition, shortening the operant session duration does not increase overall intake or promote binge-like patterns of intake for either ethanol or sucrose reinforcer.
Nanogap Solid-State Single-Molecule Detection at Mars, Europa, and Microgravity Conditions
Authors: Ramírez-Colón José L. , Johnson Emma , Duzdevich Daniel , Lee Sam , Soderblom Jason , Zuber Maria T. , Taniguchi Masateru , Ohshiro Takahito , Komoto Yuki , Carr Christopher E. 
Published: March 2024

AbstractSolid-state nanogap systems are an emerging technology forin-situlife detection due to their single-molecule resolution of a wide range of biomolecules, including amino acids and informational polymers, at the parts per billion to trillion level. By targeting the abundance distributions of organic molecules, this technology is a candidate for detecting ancient and extant life and discriminating between biotic and abiotic organics on future planetary missions to Mars and icy moons such as Enceladus and Europa. A benchtop system developed at Osaka University has a proven ability to detect and discriminate among single amino acids, RNA, and DNA using nanogap chips. The Electronic Life-detection Instrument for Enceladus/Europa (ELIE) prototype was subsequently developed to make this technology viable for space instrumentation through the simplification of electronics, reduction of size and weight, and automation of gap formation. Initial ground testing using a manually formed nanogap with the first ELIE prototype detected the amino acid L-proline. However, this manual adjustment approach posed limitations in maintaining a consistent gap size. To address this challenge, we integrated an automated piezo actuator to enable real-time gap control, permitting single-molecule identification of a target amino acid, L-proline, under reduced gravity (g), including Mars (g= 0.378), Europa or Lunar (g= 0.166), and microgravity conditions (g= 0.03-0.06), as validated through parabolic flight testing. Power supply noise and experimental constraints of the experiment design limited data collection to short segments of good-quality data. Nevertheless, the subsequent analysis of detected events within these segments revealed a consistent system performance and a controlled gap size across the different accelerations. This finding highlights the system’s resilience to physical vibrations. Future goals are to progress the instrument towards technology readiness level 4 with further reductions of size and mass, lower noise, and additional system automation. With further development, ELIE has the potential to be an autonomous and sensitive single-molecule detection instrument for deployment throughout the solar system.
Arid5a uses disordered extensions of its core ARID domain for distinct DNA- and RNA-recognition and gene regulation
Authors: von Ehr Julian , Oberstrass Lasse , Yazgan Ege , Schnaubelt Lara Ina , Blümel Nicole , McNicoll Francois , Weigand Julia E. , Zarnack Kathi , Müller-McNicoll Michaela , Korn Sophie Marianne , Schlundt Andreas 
Published: March 2024

AbstractAT-rich interacting domain (ARID)-containing proteins, Arids, are a heterogeneous DNA-binding protein family involved in transcription regulation and chromatin processing. For the member Arid5a, no exact DNA-binding preference has been experimentally defined so far. Additionally, the protein binds to mRNA motifs for transcript stabilization, supposedly through the DNA-binding ARID domain. To date, however, no unbiased RNA motif definition and clear dissection of nucleic acid-binding through the ARID domain have been undertaken. Using NMR-centered biochemistry, we here define the Arid5a DNA preference. Further, high-throughput in vitro binding (RBNS) reveals a consensus RNA-binding motif engaged by the core ARID domain. Finally, transcriptome-wide binding (iCLIP2) reveals that Arid5a has a weak preference for (A)U-rich regions in pre-mRNA transcripts of factors related to RNA processing. We find that the intrinsically disordered regions (IDR) flanking the ARID domain modulate the specificity and affinity of DNA-binding, while they appear crucial for RNA interactions. Ultimately, our data suggest that Arid5a uses its extended ARID domain for bi-functional gene regulation and that the involvement of IDR extensions is a more general feature of Arids in interacting with different nucleic acids at the chromatin-mRNA interface.
Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer
Authors: He Tongchen , Cheng Caleb , Qiao Yuanyuan , Cho Hanbyul , Young Eleanor , Mannan Rahul , Mahapatra Somnath , Miner Stephanie J. , Zheng Yang , Kim NamHoon , Zeng Victoria Z. , Wisniewski Jasmine P. , Hou Siyu , Jackson Bailey , Cao Xuhong , Su Fengyun , Wang Rui , Chang Yu , Kuila Bilash , Mukherjee Subhendu , Dukare Sandeep , Aithal Kiran B. , D.S. Samiulla , Abbineni Chandrasekhar , Lyssiotis Costas A. , Parolia Abhijit , Xiao Lanbo , Chinnaiyan Arul M. 
Published: March 2024

AbstractMammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 (BRD4) and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.Significance StatementThe mSWI/SNF complex is a promising therapeutic target for enhancer-driven cancers. PROTACs, which enable the targeting of “undruggable” proteins, often face the challenge of achieving oral bioavailability. Here, we present AU-24118, a first-in-class, orally bioavailable mSWI/SNF ATPase dual degrader with remarkable efficacy inin vitroandin vivomodels. Additionally, our study describes two distinct mechanisms of resistance to PROTAC degraders, providing crucial insights into potential challenges facing their clinical application. These findings are critical for advancing PROTAC-based therapies to clinical settings as targeted therapies for cancers.
The transcriptional regulator Lrp activates the expression of genes involved in tilivalline enterotoxin biosynthesis inKlebsiella oxytoca
Authors: De la Cruz Miguel A. , Valdez-Salazar Hilda A. , Robles-Leyva Nayely , Siqueiros-Cendón Tania , Rascón-Cruz Quintín , Rodríguez-Valverde Diana , León-Montes Nancy , Soria-Bustos Jorge , Rosales-Reyes Roberto , Cedillo María L. , Yañez-Santos Jorge A. , Ibarra J. Antonio , Torres Javier , Girón Jorge A. , Fox James G. , Ares Miguel A. 
Published: March 2024

ABSTRACTThe toxigenicKlebsiella oxytocastrains secret the tilivalline enterotoxin, which causes antibiotic-associated hemorrhagic colitis. The tilivalline is a non-ribosomal peptide synthesized by enzymes encoded in two divergent operons clustered in a pathogenicity island. The transcriptional regulator Lrp (leucine-responsiveregulatoryprotein) controls the expression of several bacterial genes involved in virulence. In this work, we determined the transcriptional expression ofaroXandnpsA, the first genes of each tilivalline biosynthetic operon inK. oxytocaMIT 09-7231 wild-type and its derivatives Δlrpmutant and complemented strains. The results show that Lrp directly activates the transcription of botharoXandnpsAgenes by binding to the intergenic regulatory region in a leucine-dependent manner. Furthermore, the lack of Lrp significantly diminished the cytotoxicity ofK. oxytocaon HeLa cells due to tilivalline reduced production. Altogether, our data highlight Lrp as a new regulator by which cytotoxin-producingK. oxytocastrains control the expression of genes involved in the biosynthesis of their main virulence factor.IMPORTANCETilivalline is an enterotoxin that is a hallmark for the cytotoxin-producingK. oxytocastrains, which cause antibiotic-associated hemorrhagic colitis. The biosynthesis of tilivalline is driven by enzymes encoded by thearoX- and NRPS-operons. In this study, we discovered that the transcriptional regulator Lrp directly activates expression of thearoX- and NRPS-operons and, in turn, tilivalline biosynthesis. Our results underscore a molecular mechanism by which tilivalline production by toxigenicK. oxytocastrains is regulated and shed further light on developing strategies to prevent the intestinal illness caused by this enteric pathogen.
RIPK3 coordinates RHIM domain-dependent inflammatory transcription in neurons
Authors: Kofman Sigal B. , Chu Lan H. , Ames Joshua M. , Chavarria Suny Dayane , Lichauco Katrina , Daniels Brian P. , Oberst Andrew 
Published: March 2024

AbstractNeurons are post-mitotic, non-regenerative cells that have evolved fine-tuned immunological responses to maintain life-long cellular integrity; this includes resistance to common programmed cell death (PCD) pathways, including apoptosis and necroptosis. We have previously demonstrated a necroptosis-independent role for the key necroptotic kinase RIPK3 in host defense against neurotropic flavivirus infection. While this work showed that neuronal RIPK3 expression is essential for chemokine production and recruitment of peripheral immune cells to the infected CNS, the full RIPK3-dependent transcriptional signature, and the molecular mechanism underlying RIPK3-dependent transcription in neurons are incompletely understood. It also remains unclear what factors govern differential RIPK3 effector functions in different cell types. Here, we show that RIPK3 activation has distinct outcomes in primary cortical neurons when compared to mouse embryonic fibroblasts (MEFs) during Zika virus (ZIKV) infection or following sterile activation. We found that RIPK3 activation does not induce death in neurons; in these cells, RIPK3 is the dominant driver of antiviral gene transcription following ZIKV infection. While RIPK3 activation in MEF cells induces cell death, ablation of downstream cell death effectors unveils a RIPK3-dependent transcriptional program which largely overlaps with that observed in ZIKV-infected neurons. Using death resistant MEFs as a model to study RIPK3 signaling revealed that RIPK3 transcription relied on interactions with the RHIM domain-containing proteins RIPK1 and TRIF, effects mirrored in the RIPK3-dependent antiviral transcriptional signature observed in ZIKV-infected neurons. These findings suggest the pleotropic functions of RIPK3 are largely context dependent and that in cells that are resistant to cell death, RIPK3 acts as a mediator of inflammatory transcription.One Sentence SummaryRHIM-domain containing proteins form a conserved signaling network capable of mediating inflammatory transcription and cell death.
Personalized Brain-Computer Interface-based Intervention for Mindful Anxiety Regulation in Young Adults: A Randomized Clinical Trial
Authors: Tan Wan Jie , Ding Yi , Lin Xiangting Bernice , Robinson Neethu , Zeng Qiuhao , Zhang Su , Wai Aung Aung Phyo , Lee Tih-Shih , Guan Cuntai 
Published: March 2024

AbstractImportanceBrain-computer interface-(BCI-) based interventions are promising means for self-administered anxiety treatment due to their non-invasiveness and portability. However, few studies have explored their viability in the home setting.ObjectiveTo evaluate the feasibility and preliminary efficacy of a novel, personalized, BCI-based intervention integrating mindfulness principles for anxiety regulation in the home setting.DesignAn open-label, two-arm randomized clinical trial was conducted from January 2021 to December 2021.SettingThe study was conducted at Duke-NUS Medical School, Singapore.ParticipantsThirty young adults from the community aged 21-35 with at least moderate anxiety were randomized 1:1 to either the intervention or waitlist-control group.InterventionThe intervention was self-administered by the participants and involved eight 30-minute sessions held at home over 2 weeks.Main Outcomes and MeasuresThe primary outcomes were safety, acceptability, and anxiety (Beck Anxiety Inventory II, State-Trait Anxiety Inventory [Form Y], and electroencephalography [EEG] data). Secondary outcomes were quality of sleep (Insomnia Severity Index), emotion regulation (Difficulties in Emotion Regulation Scale), mindful awareness (Mindfulness Awareness Attention Scale), and depression and stress subscales in the Depression Anxiety Stress Scale-21.ResultsThe intervention was safe and acceptable. No severe adverse events were reported. The attrition rate was 40%, predominantly due to technical issues. Pooled analyses indicated a significant reduction in anxiety, depression, stress, and insomnia from pre- to post-intervention. Improvements in anxiety were supported by physiological changes. Participants also reported significantly greater mindful awareness, access to emotion regulation strategies, and control over impulses.Conclusion and RelevanceThese findings suggest that our BCI-based intervention is feasible and potentially efficacious for participants to entrain anxiety regulation independently at home. A larger trial is warranted.Trial RegistrationClinicalTrials.govNCT04626713;https://tinyurl.com/27hn2m76