bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impacts of fine-tuning, phylogenetic distance, and sample size on big-data bioacoustics
Authors: Provost Kaiya L. , Yang Jiaying , Carstens Bryan C. 
Published: February 2022

AbstractVocalizations in animals, particularly birds, are critically important behaviors that influence their reproductive fitness. While recordings of bioacoustic data have been captured and stored in collections for decades, the automated extraction of data from these recordings has only recently been facilitated by artificial intelligence methods. These have yet to be evaluated with respect to accuracy of different automation strategies and features. Here, we use a recently published machine learning framework to extract syllables from ten bird species ranging in their phylogenetic relatedness from 1 to 85 million years, to compare how phylogenetic relatedness influences accuracy. We also evaluate the utility of applying trained models to novel species. Our results indicate that model performance is best on conspecifics, with accuracy progressively decreasing as phylogenetic distance increases between taxa. However, we also find that the application of models trained on multiple distantly related species can improve the overall accuracy to levels near that of training and analyzing a model on the same species. When planning big-data bioacoustics studies, care must be taken in sample design to maximize sample size and minimize human labor without sacrificing accuracy.
NSD2 E1099K drives relapse in pediatric acute lymphoblastic leukemia by disrupting 3D chromatin organization
Authors: Narang Sonali , Evensen Nikki A. , Saliba Jason , Pierro Joanna , Loh Mignon L. , Brown Patrick A. , Mulder Heather , Shao Ying , Easton John , Ma Xiaotu , Tsirigos Aristotelis , Carroll William L. 
Published: February 2022

ABSTRACTThe NSD2 p.E1099K (EK) mutation has been shown to be enriched in patients with relapsed ALL and found to play a role in clonal fitness dependent on the underlying genetic/epigenetic landscape of the cells. To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we systematically integrated Hi-C, ATAC-seq, RNA-seq and ChIP-seq data from three B-ALL cell lines heterozygous for NSD2 EK (RS4;11, RCH-ACV, SEM) and assessed changes upon knockdown. NSD2 knockdown revealed widespread remodeling of the 3D genome, specifically in terms of compartmentalization. Systematic integration of these datasets revealed significant switches in A/B compartments with a strong bias towards B compartments upon knockdown, suggesting that NSD2 EK plays a prominent role in maintaining A compartments through enrichment of H3K36me2 epigenetic marks. In contrast, we identified few changes in intra-TAD activity suggesting that the NSD2 EK impacts transcriptional changes through a remarkable dependence on compartmentalization. Furthermore, EK-mediated reorganization of compartments highlights the existence of a common core of compacting loci shared across the three cell lines that explain previously described phenotypes as well as serve as targets for therapeutic intervention. This study offers a novel mechanism by which NSD2 EK drives clonal evolution and drug resistance.
Monkeys exhibit human-like gaze biases in economic decisions
Authors: Lupkin Shira M. , McGinty Vincent B. 
Published: February 2022

AbstractIn economic decision-making individuals choose between items based on their perceived value. For both humans and nonhuman primates, these decisions are often carried out while shifting gaze between the available options. Recent studies in humans suggest that these shifts in gaze actively influence choice, manifesting as a bias in favor of the items that are viewed first, viewed last, or viewed for the overall longest duration in a given trial. This suggests a mechanism that links gaze behavior to the neural computations underlying value-based choices. In order to identify this mechanism, it is first necessary to develop and validate a suitable animal model of this behavior. To this end, we have created a novel value-based choice task for macaque monkeys that captures the essential features of the human paradigms in which gaze biases have been observed. Using this task, we identified gaze biases in the monkeys that were both qualitatively and quantitatively similar to those in humans. In addition, the monkeys’ gaze biases were well-explained using a sequential sampling model framework previously used to describe gaze biases in humans—the first time this framework has been used to assess value-based decision mechanisms in nonhuman primates. Together, these findings suggest a common mechanism that can explain gaze-related choice biases across species, and open the way for mechanistic studies to identify the neural origins of this behavior.
Meiotic DNA breaks activate a streamlined phospho-signaling response that largely avoids protein level changes
Authors: Kar Funda M. , Vogel Christine , Hochwagen Andreas 
Published: February 2022

AbstractMeiotic cells introduce a large number of programmed DNA breaks into their genome to stimulate meiotic recombination and ensure controlled chromosome inheritance and fertility. An intricate checkpoint network involving key kinases and phosphatases coordinates the repair of these DNA breaks during meiosis, but the precise DNA break-dependent phosphorylation targets remain poorly understood. It is also unknown whether meiotic DNA breaks change gene expression akin to the canonical DNA-damage response. To address these questions, we analyzed the meiotic DNA break response in Saccharomyces cerevisiae using multiple systems-level approaches. We identified 332 DNA break-dependent phosphorylation sites, vastly expanding the number of known DNA break-dependent phosphorylation events during meiotic prophase. Only about half of these events occurred in recognition motifs for the known meiotic checkpoint kinases Mec1 (ATR), Tel1 (ATM) and Mek1 (CHK2), suggesting that additional kinases contribute to the meiotic DNA break response. Surprisingly, the numerous changes in phosphorylation were accompanied by very few changes in protein levels despite a clearly detectable transcriptional response. To explain this dichotomy, we show that meiotic entry lowers the expression baseline of many mRNAs enough so that subsequent break-dependent mRNA production has no measurable effects on the largely stable proteome.
DLGAP1-AS2-Mediated Phosphatidic Acid Synthesis Confers Chemoresistance via Activation of YAP Signaling
Authors: Nan Yabing , Luo Qingyu , Wu Xiaowei , Liu Shi , Zhao Pengfei , Chang Wan , Zhou Aiping , Liu Zhihua 
Published: February 2022

AbstractSquamous cell carcinomas (SCCs) constitute a group of human malignancies that originate from the squamous epithelium. Most SCC patients experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and explore novel chemosensitizer targets, we performed whole-transcriptome sequencing of paired resistant/parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 associates with histones to regulate the distal elements of FAM3 metabolism regulating signaling molecule D (FAM3D) and reduces extracellular FAM3D protein secretion. FAM3D interacts with Gαi-coupled G protein-coupled receptor (GPCR) formyl peptide receptor (FPR) 1 and FPR2 to suppress phospholipase D (PLD) activity; thus, reduced FAM3D activates PLD signaling. Moreover, activated PLD promotes phosphatidic acid (PA) production and subsequent yes-associated protein (YAP) nuclear translocation. Accordingly, in vivo administration of a D-AS2-targeting antisense oligonucleotide sensitizes SCC to cisplatin treatment. In summary, our study reveals that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential in SCC chemoresistance and that D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents.SignificanceThis study identifies D-AS2 as a targetable lipid-related lncRNA that activates YAP signaling via PLD/PA axis to trigger chemoresistance in SCC.
A three gene signature predicts response to selinexor in multiple myeloma
Authors: Restrepo Paula , Bhalla Sherry , Aleman Adolfo , Leshchenko Violetta , Melnekoff David T , Agte Sarita , Jiang Joy , Madduri Deepu , Richter Joshua , Richard Shambavi , Chari Ajai , Cho Hearn Jay , Jagannath Sundar , Walker Christopher J , Landesman Yosef , Laganà Alessandro , Parekh Samir 
Published: February 2022

ABSTRACTSelinexor is the first selective inhibitor of nuclear export (SINE) to be approved for treatment of relapsed or refractory multiple myeloma (MM). There are currently no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aim to characterize transcriptomic correlates of response to selinexor-based therapy, and present a novel, three-gene expression signature that predicts selinexor response in MM. We analyzed RNA sequencing of CD138+ tumor cells from bone marrow of 100 MM patients who participated in the BOSTON study and identified three genes upregulated in responders. Then, we validated this gene signature in 64 patients from the STORM cohort of triple-class refractory MM, and additionally in an external cohort of 35 patients treated in a real world setting outside of clinical trials. We also found that the signature tracked with response in a cohort of 57 patients with recurrent glioblastoma treated with selinexor. Furthermore, the genes involved in the signature, WNT10A, DUSP1, and ETV7, reveal a potential mechanism through upregulated interferon-mediated apoptotic signaling that may prime tumors to respond to selinexor-based therapy. This signature has important clinical relevance as it could identify cancer patients that are most likely to benefit from treatment with selinexor-based therapy.
Loneliness and diurnal cortisol levels during COVID-19 lockdown: the roles of living situation, relationship status and relationship quality
Authors: Hopf Dora , Schneider Ekaterina , Aguilar-Raab Corina , Scheele Dirk , Ditzen Beate , Eckstein Monika 
Published: February 2022

AbstractLoneliness and social isolation have become increasing concerns during COVID-19 lockdown through neuroendocrine stress-reactions, physical and mental health problems. We investigated living situation, relationship status and quality as potential moderators for trait and state loneliness and salivary cortisol levels (hormonal stress-responses) in healthy adults during the first lockdown in Germany.N=1242 participants (mean age = 36.32, 78% female) filled out an online questionnaire on demographics, trait loneliness and relationship quality. Next,N=247 (mean age = 32.6, 70% female) completed ecological momentary assessment (EMA), collecting twelve saliva samples on two days and simultaneously reporting their momentary loneliness levels. Divorced/widowed showed highest trait loneliness, followed by singles and partnerships. The latter displayed lower momentary loneliness and cortisol levels compared to singles. Relationship satisfaction significantly reduced loneliness levels in participants with a partner and those who were living apart from their partner reported loneliness levels similar to singles living alone. Living alone was associated with lower loneliness levels. Hierarchical linear models revealed a significant cross-level interaction between relationship status and momentary loneliness in predicting cortisol. The results imply that widowhood, being single, living alone and low relationship quality represent risk factors for loneliness and having a partner buffers neuroendocrine stress responses during lockdown.
Waning Effectiveness of the Third Dose of the BNT162b2 mRNA COVID-19 Vaccine
Authors: Patalon Tal , Saciuk Yaki , Peretz Asaf , Perez Galit , Lurie Yoav , Maor Yasmin , Gazit Sivan 
Published: February 2022

AbstractThe duration of protection of the third (booster) dose of the BioNTech/Pfizer BNT162b2 mRNA Coronavirus Disease 2019 vaccine has yet to be sufficiently researched, while global discussions around the necessity and effectiveness of a fourth dose are already underway. By conducting a retrospective study implementing a test-negative case-control design, analyzing 546,924 PCR tests performed throughout January 2022 by 389,265 persons who received three doses of the vaccine, we found that the effectiveness in each month since vaccination decreased significantly. Compared to those vaccinated early, on August 2021, relative protection against infection waned from 53.4% a month after vaccination to 16.5% three months after vaccination. These results suggest that there is a significant waning of vaccine effectiveness against the Omicron variant of the third dose of the BNT162b2 vaccine within a few months after administration and should prompt policy discussion as to additional booster doses and vaccine development.
Post-malnutrition growth and its associations with child survival and non-communicable disease risk: A secondary analysis of the Malawi ‘ChroSAM’ cohort
Authors: Lelijveld Natasha , Cox Sioned , Anujuo Kenneth , Amoah Abena S , Opondo Charles , Cole Tim J. , Wells Jonathan C. , Thompson Debbie , McKenzie Kimberley , Abera Mubarek , Berhane Melkamu , Kerac Marko ,   CHANGE study collaborators group
Published: February 2022

AbstractBackgroundRapid catch-up growth after prenatal undernutrition is associated with increased risk of non-communicable diseases (NCDs) in high-income countries. Severe malnutrition treatment programmes in low- and middle-income countries promote rapid post-malnutrition growth (PMGr) as desirable. Our aim was to explore patterns of PMGr during and in the year following treatment, and describe associations with survival and NCD risk seven years post-treatment.MethodsSecondary data analysis from a cohort of children treated for severe malnutrition in Malawi in 2006/7. Six definitions of PMGr were derived based on a variety of timepoints, weight, weight-for-age z-score (WAZ) and height-for-age z-score (HAZ). Three categorisation methods included: no categorisation, quintiles, and latent class analysis (LCA). Associations with mortality risk, and with eight NCD indicators were analysed visually using scatter plots and boxplots, and statistically using simple and multivariable linear regression.FindingsFaster weight gain was associated with lower risk of death (g/day during treatment aOR 0.99, 95%CI 0.99 to 1.00, p=0.04; after treatment g/kg/month aOR 0.91, 95% CI 0.87 to 0.94, p<0.001). In survivors, it was associated with greater hand grip strength in some instances (g/day during treatment 0.02, 95%CI 0.00 to 0.03, p=0.007) and larger HAZ 7-years post-discharge (adjusted Δ WAZ per day during treatment 6.62, 95%CI 1.31 to 11.9, p=0.02), both indicators of better health. However, faster weight gain in treatment was also associated with increased waist:hip ratio (adjusted g/day during treatment 0.02, 95%CI 0.01 to 0.03, p=0.003), a key indicator of later life NCD risk. The clearest patterns of association were seen when defining PMGr based on weight gain in g/day during treatment, and using the LCA method to describe growth patterns. Weight deficit at admission was a major confounder.ConclusionWe found a complex pattern of benefits and risks associated with faster PMGr with a possible trade-off between short- and long-term benefits/risks. Peripheral versus visceral weight distribution in particular requires further exploration. Both initial weight deficit and rate of weight gain have important implications for future health. Because conclusions from observational studies can go only so far, future randomised intervention trials are needed.
Human neutrophil development and functionality are enabled in a humanized mouse model
Authors: Zheng Yunjiang , Sefik Esen , Astle John , Solis Angel G. , Öz Hasan H. , Jackson Ruaidhrí , Bruscia Emanuela M. , Halene Stephanie , Shan Liang , Flavell Richard A 
Published: February 2022

AbstractMice with a functional human immune system serve as an invaluable tool to study the development and function of human immune system in vivo. A major technological limitation of all current humanized mouse models is the lack of mature and functional human neutrophils in circulation and tissues. To overcome this, we generated a humanized mouse model named MISTRGGR, in which the mouse granulocyte colony stimulating factor (G-CSF) was replaced with human G-CSF and the mouse G-CSF receptor gene was deleted (G-CSFR) in existing MISTRG mice. By targeting the GCSF cytokine-receptor axis, we dramatically improved the reconstitution of mature circulating and tissue-infiltrating human neutrophils in MISTRGGR mice. Moreover, these functional human neutrophils in MISTRGGR are recruited upon inflammatory and infectious challenges and help reduce bacterial burden. MISTRGGR mice represent a unique mouse model that finally permits the study of human neutrophils in health and disease.Key PointsTargeting the GCSF cytokine-receptor axis dramatically improves circulating and tissue-infiltrating human neutrophils in MISTRGGR mice.Human neutrophils generated in MISTRGGR mice are functional and are able to respond robustly to inflammatory and infectious stimuli.
Novel mtDNA Imparts the Connective Tissue Disorder of a Tourette Pedigree
Authors: Schaefer Patrick M. , Alves Leonardo Scherer , Lvova Maria , Huang Jessica , Rathi Komal , Janssen Kevin , Butic Arrienne , Yardeni Tal , Morrow Ryan , Lott Marie , Keller Kierstin , Garcia Benjamin A. , Francomano Clair A. , Wallace Douglas C. 
Published: February 2022

AbstractMitochondrial dysfunction is associated with a range of clinical manifestations including neuropsychiatric and metabolic disorder. Here, we reanalyzed a family with an L-Histidine Decarboxylase (HDC) variant previously linked to Tourette syndrome but with associated connective tissue and metabolic features of unknown etiology. We identified a mitochondrial haplogroup J-defining mutation on the haplogroup H background that functionally interacts with the L-Histidine Decarboxylase variant via calcium homeostasis. Our findings establish how a common mtDNA variant on a different mtDNA background can result in mitochondrial dysfunction, demonstrate a role for histaminergic signaling in modifying mitochondrial phenotypes, and link mitochondria dysfunction to connective tissue phenotypes.
The BAF A12T mutation associated with premature aging impedes lamin A/C recruitment to sites of nuclear rupture, contributing to nuclear envelope fragility
Authors: Janssen A.F.J. , Marcelot A. , Breusegem S.Y. , Legrand P. , Zinn-Justin S. , Larrieu D. 
Published: February 2022

AbstractThe premature aging disorder Nestor Guillermo Progeria Syndrome (NGPS) is caused by a homozygous Alanine to Threonine mutation at position 12 (A12T) in Barrier-to- Autointegration Factor (BAF). BAF is a small essential protein that binds to DNA and nuclear envelope proteins. It contributes to important cellular processes including transcription regulation and nuclear envelope reformation after mitosis. More recently, BAF was identified as an important factor for nuclear envelope repair upon rupture in interphase. However, the mechanism by which the BAF A12T mutation causes NGPS has remained unclear. To investigate the effects of this mutation on nuclear envelope integrity, we used NGPS-derived patient cells and engineered an isogenic cell line by reversing the BAF A12T homozygous mutation using CRISPR/Cas9. Using a combination of cellular models, structural data and in vitro assays, we identified that the A12T mutation reduces the affinity of BAF for lamin A/C by tenfold. As a result, BAF A12T is unable to recruit lamin A/C to sites of nuclear envelope rupture. This leads to persistent lamin A/C gaps at sites of ruptures, and contributes to nuclear fragility in NGPS patient cells, which show increased frequency of nuclear envelope re- rupturing. Overexpression of wild-type BAF in a NGPS context rescues lamin A/C recruitment to sites of nuclear rupture, which could explain why the heterozygous A12T mutation does not cause premature aging.
Long-Term Culture of Patient-Derived Cardiac Organoids Recapitulated Duchenne Muscular Dystrophy Cardiomyopathy and Disease Progression
Authors: Marini Vittoria , Marino Fabiola , Aliberti Flaminia , Giarratana Nefele , Pozzo Enrico , Duelen Robin , Calabuig Álvaro Cortés , Larovere Rita , Vervliet Tim , Torella Daniele , Bultynck Geert , Sampaolesi Maurilio , Chai Yoke Chin 
Published: February 2022

AbstractDuchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to-date incurable. The major cause of death is dilated cardiomyopathy, however the pathogenesis is unclear as existing cellular and animal models do not fully recapitulate the human disease phenotypes. In this study, we generated cardiac organoids from patient-derived pluripotent stem cells (DMD-CO) and isogenic-corrected controls (DMD-Iso-CO) and studied if DMD-related cardiomyopathy and disease progression occur in the organoids upon long-term culture (up to 93 days). Histological analysis showed that DMD-CO lacks initial proliferative capacity, displayed a progressive loss of α-sarcoglycan localization and high stress in endoplasmic reticulum. Additionally, the cardiomyocyte deteriorated over time, and fibrosis and adipogenesis were observed in DMD-CO. RNA sequencing analysis confirmed a distinct transcriptomic profile in DMD-CO which were associated with functional enrichment in hypertrophy/dilated cardiomyopathy, arrhythmia, adipogenesis and fibrosis pathways. Moreover, five miRNAs were identified to be crucial in this dysregulated gene network. In conclusion, we generated patient-derived cardiac organoid model that displayed DMD-related cardiomyopathy and disease progression phenotypes in long-term culture. We envision the feasibility to develop a more complex, realistic and reliable in vitro 3D human cardiac-mimics to study DMD-related cardiomyopathies.
Event-related causality in Stereo-EEG discriminates syntactic processing of noun phrases and verb phrases
Authors: Cometa Andrea , D’Orio Piergiorgio , Revay Martina , Bottoni Franco , Repetto Claudia , Lo Russo Giorgio , Cappa Stefano F. , Moro Andrea , Micera Silvestro , Artoni Fiorenzo 
Published: February 2022

AbstractSyntax involves complex neurobiological mechanisms, which are difficult to disentangle for multiple reasons. Using a protocol able to separate syntactic information from sound information we investigated the neural causal connections evoked by the processing of homophonous phrases, either verb phrases (VP) or noun phrases (NP). We used event-related causality (ERC) from stereo-electroencephalographic (SEEG) recordings in 10 epileptic patients in multiple cortical areas, including language areas and their homologous in the non-dominant hemisphere. We identified the different networks involved in the processing of these syntactic operations (faster in the dominant hemisphere) showing that VPs engage a wider cortical network. We also present a proof-of-concept for the decoding of the syntactic category of a perceived phrase based on causality measures. Our findings help unravel the neural correlates of syntactic elaboration and show how a decoding based on multiple cortical areas could contribute to the development of speech prostheses for speech impairment mitigation.