bluuebunny/crossref_metadata_2025_split huggingface dataset:
DBT is a metabolic switch for maintenance of proteostasis under proteasomal impairment
Authors: Hwang Ran-Der , Lu Yu-Ning , Tang Qing , Periz Goran , Park Giho , Li Xiangning , Xiang Qiwang , Liu Yang , Zhang Tao , Wang Jiou 
Published: September 2023

AbstractProteotoxic stress impairs cellular homeostasis and underlies the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The proteasomal and autophagic degradation of proteins are two major pathways for protein quality control in the cell. Here, we report a genome-wide CRISPR screen uncovering a major regulator of cytotoxicity resulting from the inhibition of the proteasome. Dihydrolipoamide branched chain transacylase E2 (DBT) was found to be a robust suppressor, the loss of which protects against proteasome inhibition-associated cell death through promoting clearance of ubiquitinated proteins. Loss of DBT altered the metabolic and energetic status of the cell and resulted in activation of autophagy in an AMP-activated protein kinase (AMPK)-dependent mechanism in the presence of proteasomal inhibition. Loss of DBT protected against proteotoxicity induced by ALS-linked mutant TDP-43 inDrosophilaand mammalian neurons. DBT is upregulated in the tissues from ALS patients. These results demonstrate that DBT is a master switch in the metabolic control of protein quality control with implications in neurodegenerative diseases.
Reviving immunogenic cell death upon targeting TACC3 enhances T-DM1 response in HER2-positive breast cancer
Authors: Gedik Mustafa Emre , Saatci Ozge , Oberholtzer Nathaniel , Uner Meral , Akbulut Ozge , Cetin Metin , Aras Mertkaya , Ibis Kubra , Caliskan Burcu , Banoglu Erden , Wiemann Stefan , Uner Aysegul , Aksoy Sercan , Mehrotra Shikhar , Sahin Ozgur 
Published: September 2023

AbstractImmunogenic cell death (ICD), an immune-priming form of cell death, has been shown to be induced by several different anti-cancer therapies. Despite being the first and one of the most successful antibody-drug conjugates (ADCs) approved for refractory HER2-positive breast cancer, little is known if response and resistance to trastuzumab emtansine (T-DM1) involves ICD modulation that can be leveraged to enhance T-DM1 response. Here, we report that T-DM1 induces spindle assembly checkpoint (SAC)-dependent ICD in sensitive cells by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which are lost in resistance. Accordingly, an ICD-related gene signature correlates with clinical response to T-DM1-containing therapy. We found that transforming acidic coiled-coil containing 3 (TACC3) is overexpressed in T-DM1 resistant cells, and that T-DM1 responsive patients have reduced TACC3 protein while the non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 revives T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition elicits ICD in vivo shown by vaccination assay, and it potentiates T-DM1 by inducing dendritic cell (DC) maturation and enhancing infiltration of cytotoxic T cells in the human HER2-overexpressing MMTV.f.huHER2#5 (Fo5) transgenic model. Together, our results show that ICD is a key mechanism of action of T-DM1 which is lost in resistance, and that targeting TACC3 restores T-DM1-mediated ICD and overcomes resistance.Statement of SignificanceImmunogenic cell death (ICD) is a novel mechanism of T-DM1 cytotoxicity that is lost upon T-DM1 resistance. Targeting TACC3 reinstates T-DM1-induced ICD, thus representing an attractive strategy to overcome T-DM1 resistance.
Investigating Frontoparietal Networks and Activation in Children with Mathematics Learning Difficulties: Cases with Different Deficit Profiles
Authors: Wang Fengjuan , Jamaludin Azilawati 
Published: September 2023

AbstractApproximately 15%-20% of school-aged children suffer from Mathematics Learning Difficulties (MLD). Most children with developmental dyscalculia (DD) or MLD also have comorbid cognitive deficits. Recent literature suggests that research should focus on uncovering the neural underpinnings of MLD across more inclusive samples, rather than limiting studies to pure cases of DD or MLD with highly stringent inclusion criteria. Therefore, this study aims to identify neural aberrancies that may be common across multiple MLD cases with different deficit profiles. Nine MLD cases and forty-five typically developing (TD) children, all around seven years old (27 boys), were recruited. Using functional near-infrared spectroscopy (fNIRS), brain data were collected during an approximate resting state and a mathematical computation task (addition). Graph theory was then applied to assess global and nodal network indicators of brain function. When comparing the network indicators and brain activation of the MLD cases to those of TD children, no unified neural aberrancy was found across all cases. However, three MLD cases did show distinct neural aberrancies compared to TD children. The study discusses the implications of these findings, considering both the neural aberrancies in the three MLD cases and the neural similarities found in the other six cases, which were comparable to those of the TD children. This raises important questions about the presence and nature of aberrant neural indicators in MLD across large cohorts and highlights the need for further research in this area.
Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging
Authors: Jakobsen Niels Asger , Turkalj Sven , Zeng Andy G. X. , Stoilova Bilyana , Metzner Marlen , Nagree Murtaza S. , Shah Sayyam , Moore Rachel , Usukhbayar Batchimeg , Salazar Mirian Angulo , Gafencu Grigore-Aristide , Kennedy Alison , Newman Simon , Kendrick Benjamin J. L. , Taylor Adrian H. , Afinowi-Luitz Rasheed , Gundle Roger , Watkins Bridget , Wheway Kim , Beazley Debra , Murison Alexander , Aguilar-Navarro Alicia G. , Flores-Figueroa Eugenia , Dakin Stephanie G. , Carr Andrew J. , Nerlov Claus , Dick John E. , Xie Stephanie Z. , Vyas Paresh 
Published: September 2023

AbstractClonal hematopoiesis (CH) arises when hematopoietic stem cells (HSC) acquire mutations in genes, includingDNMT3AandTET2, conferring a competitive advantage through a mechanism that remains unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on CH bone marrow samples. Most of the selective advantage of mutant cells occurs within HSCs.DNMT3AandTET2-mutant clones expand further in early progenitors, whileTET2mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared to HSC from non-CH samples, revealing a non-cell autonomous mechanism. However,DNMT3AandTET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are more resistant to the deleterious impact of inflammation and aging.
The reuniens nucleus of the thalamus facilitates hippocampo-cortical dialogue during sleep
Authors: Basha Diellor , Azarmehri Amirmohammad , Proulx Eliane , Chauvette Sylvain , Ghorbani Maryam , Timofeev Igor 
Published: September 2023

SummaryMemory consolidation during sleep depends on the interregional coupling of slow waves, spindles, and sharp wave-ripples (SWRs), across the cortex, thalamus, and hippocampus. The reuniens nucleus of the thalamus, linking the medial prefrontal cortex (mPFC) and the hippocampus, may facilitate interregional coupling during sleep. To test this hypothesis we used intracellular, extracellular unit and local field potential recordings in anesthetized and head restrained non-anesthetized cats as well as computational modelling. Electrical stimulation of the reuniens evoked both antidromic and orthodromic intracellular mPFC responses, consistent with bidirectional functional connectivity between mPFC, reuniens and hippocampus in anesthetized state. The major finding obtained from behaving animals is that at least during NREM sleep hippocampo-reuniens-mPFC form a functional loop. SWRs facilitate the triggering of thalamic spindles, which later reach neocortex. In return, transition to mPFC UP states increase the probability of hippocampal SWRs and later modulate spindle amplitude. During REM sleep hippocampal theta activity provides periodic locking of reuniens neuronal firing and strong crosscorrelation at LFP level, but the values of reuniens-mPFC crosscorrelation was relatively low and theta power at mPFC was low. The neural mass model of this network demonstrates that the strength of bidirectional hippocampo-thalamic connections determines the coupling of oscillations, suggesting a mechanistic link between synaptic weights and the propensity for interregional synchrony. Our results demonstrate the presence of functional connectivity in hippocampo-thalamo-cortical network, but the efficacy of this connectivity is modulated by behavioral state.Impact StatementThe nucleus reuniens of the thalamus play a central role in synchronizing the mPFC-hippocampal network during sleep and integrates converging activity from hippocampal and mPFC oscillations.
Cerebellar Purkinje Cells Control Posture in Larval Zebrafish (Danio rerio)
Authors: Auer Franziska , Nardone Katherine , Matsuda Koji , Hibi Masahiko , Schoppik David 
Published: September 2023

ABSTRACTCerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically-tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.
Binding of Small Molecule Inhibitors to RNA Polymerase-Spt5 Complex Impacts RNA and DNA Stability
Authors: Gallardo Adan , Dutagaci Bercem 
Published: September 2023

ABSTRACTSpt5 is an elongation factor that associates with RNA polymerase II (Pol II) during transcription and has important functions in promoter-proximal pausing and elongation processivity. Spt5 was also recognized for its roles in the transcription of expanded-repeat genes that are related to neurodegenerative diseases. Recently, a set of Spt5-Pol II small molecule inhibitors (SPIs) were reported, which selectively inhibit mutant huntingtin gene transcription. Inhibition mechanisms as well as interaction sites of these SPIs with Pol II and Spt5 are not entirely known. In this study, we predicted the binding sites of three selected SPIs at the Pol II-Spt5 interface by docking and molecular dynamics simulations. Two molecules out of three demonstrated strong binding with Spt5 and Pol II, while the other molecule was more loosely bound and sampled multiple binding sites. Strongly bound SPIs indirectly affected RNA and DNA dynamics at the exit site as DNA became more flexible while RNA was stabilized by increased interactions with Spt5. Our results suggest that the transcription inhibition mechanism induced by SPIs can be related to Spt5-nucleic acid interactions, which were altered to some extent with strong binding of SPIs.
Validity of a smartphone app to objectively monitor performance outcomes in degenerative cervical myelopathy: an observational study
Authors: Yanez Touzet Alvaro , Houhou Tatiana , Rahic Zerina , Laufer Ilya , Margetis Konstantinos , Martin Allan R , Dea Nicolas , Ghogawala Zoher , Kapushesky Misha , Kotter Mark R N , Davies Benjamin M. 
Published: September 2023

ABSTRACTObjectivesTo assess the validity of MoveMed, a battery of performance outcome measures performed using a mobile phone application, in the measurement of degenerative cervical myelopathy (DCM).DesignProspective observational study.SettingDecentralised secondary care in England, United Kingdom.Participants27 adults aged 60 (SD: 11) who live with DCM and possess an approved smartphone.Primary and secondary outcome measuresCriteria from the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) manual were used to assess validity and risk of bias. Briefly, each MoveMed outcome was compared to two patient-reported comparators, and a priori hypotheses of convergence/divergence were tested against consensus thresholds. The primary outcome was the correlation coefficient between the MoveMed outcome and the patient-reported comparators. The secondary outcome was the percent of correlations in correspondence with a priori hypotheses. The comparators were the patient-derived modified Japanese Orthopaedic Association (P-mJOA) score and the World Health Organization Quality of Life Brief Version (WHOQOL-Bref) questionnaire. Thresholds for convergence/divergence were ≥0.3/<0.3, and >0/<0 for directionality.ResultsAs expected, MoveMed’s tests of neuromuscular function correlated most with questionnaires of neuromuscular function (≥0.3) and least with questionnaires of quality of life (<0.3). Furthermore, directly related constructs correlated positively to each other (>0), while inversely related constructs correlated negatively (<0). Over 70% and 50% of correlations (unidimensional and multidimensional, respectively) were in accordance with hypotheses. No risk of bias factors from the COSMIN Risk of Bias checklist were recorded. Overall, this was equivalent to ‘very good’ quality evidence of sufficient construct validity in DCM.ConclusionsCriteria from COSMIN provide ‘very good’ quality evidence of the validity of the MoveMed tests in an adult population living with DCM.
Unravelling Robust Brain-Behavior Links of Depressive Symptoms Through Granular Network Models: Understanding Heterogeneity and Clinical Implications
Authors: Freichel René , Lenartowicz Agatha , Douw Linda , Kruschwitz Johann D. , Banaschewski Tobias , Barker Gareth J. , Bokde Arun L.W. , Desrivières Sylvane , Flor Herta , Grigis Antoine , Garavan Hugh , Heinz Andreas , Brühl Rüdiger , Martinot Jean-Luc , Paillère Martinot Marie-Laure , Artiges Eric , Nees Frauke , Orfanos Dimitri Papadopoulos , Paus Tomáš , Poustka Luise , Holz Nathalie , Baeuchl Christian , Smolka Michael N. , Vaidya Nilakshi , Whelan Robert , Frouin Vincent , Schumann Gunter ,   IMAGEN Consortium, Walter Henrik , Blanken Tessa F. 
Published: September 2023

AbstractBackgroundDepressive symptoms are highly prevalent, present in heterogeneous symptom patterns, and share diverse neurobiological underpinnings. Understanding the links between psychopathological symptoms and biological factors is critical in elucidating its etiology and persistence. We aimed to evaluate the utility of using symptom-brain networks to parse the heterogeneity of depressive symptomatology in a large adolescent sample.MethodsWe used data from the third wave of the IMAGEN study, a multi-center panel cohort study involving 1,317 adolescents (52.49% female, mean±SD age=18.5±0.72). Two network models were estimated: one including an overall depressive symptom severity sum score based on the Adolescent Depression Rating Scale (ADRS), and one incorporating individual ADRS symptom/item scores. Both networks included measures of cortical thickness in several regions (insula, cingulate, mOFC, fusiform gyrus) and hippocampal volume derived from neuroimaging.ResultsThe network based on individual symptom scores revealed associations between cortical thickness measures and specific symptoms, obscured when using an aggregate depression severity score. Notably, the insula’s cortical thickness showed negative associations with cognitive dysfunction (partial cor.=-0.15); the cingulate’s cortical thickness showed negative associations with feelings of worthlessness (partial cor. = -0.10), and mOFC was negatively associated with anhedonia (partial cor. = -0.05).LimitationsThis cross-sectional study included participants who were relatively healthy and relied on the self-reported assessment of depression symptoms.ConclusionsThis study showcases the utility of network models in parsing heterogeneity in depressive symptoms, linking individual symptoms to specific neural substrates. We outline the next steps to integrate neurobiological and cognitive markers to unravel MDD’s phenotypic heterogeneity.
Biometric Contrastive Learning for Data-Efficient Deep Learning from Electrocardiographic Images
Authors: Sangha Veer , Khunte Akshay , Holste Gregory , Mortazavi Bobak J , Wang Zhangyang , Oikonomou Evangelos K , Khera Rohan 
Published: September 2023

ABSTRACTObjectiveArtificial intelligence (AI) detects heart disease from images of electrocardiograms (ECGs), however traditional supervised learning is limited by the need for large amounts of labeled data. We report the development of Biometric Contrastive Learning (BCL), a self-supervised pretraining approach for label-efficient deep learning on ECG images.Materials and MethodsUsing pairs of ECGs from 78,288 individuals from Yale (2000-2015), we trained a convolutional neural network to identify temporally-separated ECG pairs that varied in layouts from the same patient. We fine-tuned BCL-pretrained models to detect atrial fibrillation (AF), gender, and LVEF<40%, using ECGs from 2015-2021. We externally tested the models in cohorts from Germany and the US. We compared BCL with random initialization and general-purpose self-supervised contrastive learning for images (simCLR).ResultsWhile with 100% labeled training data, BCL performed similarly to other approaches for detecting AF/Gender/LVEF<40% with AUROC of 0.98/0.90/0.90 in the held-out test sets, it consistently outperformed other methods with smaller proportions of labeled data, reaching equivalent performance at 50% of data. With 0.1% data, BCL achieved AUROC of 0.88/0.79/0.75, compared with 0.51/0.52/0.60 (random) and 0.61/0.53/0.49 (simCLR). In external validation, BCL outperformed other methods even at 100% labeled training data, with AUROC of 0.88/0.88 for Gender and LVEF<40% compared with 0.83/0.83 (random) and 0.84/0.83 (simCLR).Discussion and ConclusionA pretraining strategy that leverages biometric signatures of different ECGs from the same patient enhances the efficiency of developing AI models for ECG images. This represents a major advance in detecting disorders from ECG images with limited labeled data.
ChatGPT Assisting Diagnosis of Neuro-ophthalmology Diseases Based on Case Reports
Authors: Madadi Yeganeh , Delsoz Mohammad , Lao Priscilla A. , Fong Joseph W. , Hollingsworth TJ , Kahook Malik Y. , Yousefi Siamak 
Published: September 2023

ABSTRACTPurposeTo evaluate the efficiency of large language models (LLMs) including ChatGPT to assist in diagnosing neuro-ophthalmic diseases based on case reports.DesignProspective studySubjects or ParticipantsWe selected 22 different case reports of neuro-ophthalmic diseases from a publicly available online database. These cases included a wide range of chronic and acute diseases that are commonly seen by neuro-ophthalmic sub-specialists.MethodsWe inserted the text from each case as a new prompt into both ChatGPT v3.5 and ChatGPT Plus v4.0 and asked for the most probable diagnosis. We then presented the exact information to two neuro-ophthalmologists and recorded their diagnoses followed by comparison to responses from both versions of ChatGPT.Main Outcome MeasuresDiagnostic accuracy in terms of number of correctly diagnosed cases among diagnoses.ResultsChatGPT v3.5, ChatGPT Plus v4.0, and the two neuro-ophthalmologists were correct in 13 (59%), 18 (82%), 19 (86%), and 19 (86%) out of 22 cases, respectively. The agreement between the various diagnostic sources were as follows: ChatGPT v3.5 and ChatGPT Plus v4.0, 13 (59%); ChatGPT v3.5 and the first neuro-ophthalmologist, 12 (55%); ChatGPT v3.5 and the second neuro-ophthalmologist, 12 (55%); ChatGPT Plus v4.0 and the first neuro-ophthalmologist, 17 (77%); ChatGPT Plus v4.0 and the second neuro-ophthalmologist, 16 (73%); and first and second neuro-ophthalmologists 17 (17%).ConclusionsThe accuracy of ChatGPT v3.5 and ChatGPT Plus v4.0 in diagnosing patients with neuro-ophthalmic diseases was 59% and 82%, respectively. With further development, ChatGPT Plus v4.0 may have potential to be used in clinical care settings to assist clinicians in providing quick, accurate diagnoses of patients in neuro-ophthalmology. The applicability of using LLMs like ChatGPT in clinical settings that lack access to subspeciality trained neuro-ophthalmologists deserves further research.Summary Highlights-The goal of this study was to explore the capabilities of ChatGPT for the diagnoses of different neuro-ophthalmic diseases using specific case examples.-There was general agreement between ChatGPT Plus v4.0 and two neuro-ophthalmologists in final diagnoses.-ChatGPT was more general while neuro-ophthalmologists were more methodical and specific when listing diagnoses.
An association betweenDnmt1andWntin the production of oocytes in the whiteflyBemisia tabaci
Authors: Cunningham Christopher B. , Shelby Emily A. , McKinney Elizabeth C. , Simmons Alvin M. , Moore Allen J. , Moore Patricia J. 
Published: September 2023

AbstractThe function of methylation in insects and the DNA methyltransferase (Dnmt) genes that influence methylation remains uncertain. We used RNAi to reduce the gene expression ofDnmt1within the whiteflyBemisia tabaci, a hemipteran species that relies onDnmt1for proper gametogenesis. We then used RNA-seq to test ana priorihypothesis that meiosis related genetic pathways would be perturbed. We generally did not find an overall effect on meiosis related pathways. However, we found that genes in theWntpathway, genes associated with the entry into meiosis in vertebrates, were differentially expressed. Our results are consistent withDnmt1knockdown influencing specific pathways and not causing general transcriptional response. This is a finding that is also seen with other insect species. We also characterized the methylome ofB. tabaciand assessed the influence ofDnmt1knockdown on cytosine methylation. This species has methylome characteristics comparable to other hemipterans regarding overall level, enrichment within gene bodies, and bimodal distribution of methylated/non-methylated genes. Very little differential methylation was observed, and difference of methylation were not associated with differences of gene expression. The effect onWntpresents an interesting new candidate pathway for future studies.