bluuebunny/crossref_metadata_2025 huggingface dataset:
The first report on the use of a zona pellucida binding assay to compare the effects of European bison (Bison bonasus) epididymal spermatozoa cryopreservation in two different extenders
Authors: Eberhardt Maria , Colombo Martina , Prochowska Sylwia , Luvoni Gaia C. , Olech Wanda , Niżański Wojciech
Published: September 2023

The wisent (or European bison) Bison bonasus is a species that has gone through a bottleneck, resulting in a narrow gene pool of the current population. Presently, the protection program for this species, in addition to protecting the habitat, is aimed at preserving gene pool. One of its elements is creating a bank of gametes with the intention of using them in constantly developed Assisted Reproductive Techniques in this species. In order to use the potential of the gametes stored in the bank as effectively as possible, it is extremely important to assess their post-freezing quality. Wisent epididymal spermatozoa stored in the bank are evaluated using basic semen analysis methods, the CASA system and flow cytometry. So far, functional tests of spermatozoa have not been introduced to the evaluation protocol of spermatozoa obtained post mortem from European bison. This article, for the first time describes the use of the zona pellucida binding test to assess the quality of cryopreserved wisent epididymal spermatozoa. Due to the close relationship between the species, the Zona binding Assay protocol developed for cattle was used. To exclude the influence of the composition of the extender used for cryopreservation, the spermatozoa were cryopreserved in the Extender based on Tris buffer, egg yolk and glycerol and in the commercial extender Andromed®. Regardless of the diluent used, 100% of the oocytes had sperm attached. The average number of spermatozoa attached to the oocyte was 66.26 for the Tris-based diluent group and 27.37 for the Andromed®- frozen group. The advantage of the Tris based extender resulted from ZBA seems to coincide with the results of the basic and advanced semen evaluation. The conducted experiment showed that the ZBA protocol developed for cattle is suitable for the evaluation of wisent epididymal spermatozoa.
Altered hepatic metabolism mediates sepsis preventive effects of reduced glucose supply in infected preterm newborns
Authors: Bæk Ole , Muk Tik , Wu Ziyuan , Ye Yongxin , Khakimov Bekzod , Casano Alessandra Maria , Gangadharan Bagirath , Bilic Ivan , Brunse Anders , Sangild Per Torp , Nguyen Duc Ninh
Published: September 2023

Preterm infants are susceptible to neonatal sepsis, a syndrome of pro-inflammatory activity, organ damage and altered metabolism following infection. Given the unique metabolic challenges and poor glucose regulatory capacity of preterm infants, their glucose intake during infection may have a high impact on the degree metabolism dysregulation and organ damage. Using a preterm pig model of neonatal sepsis, we previously showed that a drastic restriction in glucose supply during infection protects against sepsis via suppression of glycolysis-induced inflammation, but results in severe hypoglycemia. Now we explored clinically relevant options of reducing glucose intake to decrease sepsis risk, without causing hypoglycemia and further explore the involvement of the liver in these protective effects. We found that a reduced glucose regime during infection increased survival via reduced pro-inflammatory response, while maintaining normoglycemia. Mechanistically, this intervention enhanced hepatic oxidative phosphorylation and possibly gluconeogenesis, and dampened both circulating and hepatic inflammation. However, switching from a high to a reduced glucose supply after debut of clinical symptoms did not prevent sepsis, suggesting metabolic conditions at the start of infection are key in driving the outcome. Finally, an early therapy with purified human inter-alpha inhibitor protein, a liver derived anti-inflammatory protein, partially reversed the effects of low parenteral glucose provision, likely by inhibiting neutrophil functions that mediate pathogen clearance.

Our findings suggest a clinically relevant regime of reduced glucose supply for infected preterm infants could prevent or delay the development of sepsis in vulnerable neonates.
Temperature, phenology, and plant defenses predict fitness near colder range limit
Authors: Anstett Daniel N.
Published: September 2023

The space for time substitution posits that warmer locations can provide a source of genetic variation that could be adaptive for future climate change conditions. While this approximation might be useful for planning assisted gene flow, it relies on the importance of abiotic adaptations over biotic ones. Here I address this gap by assessing influence of anti-herbivore defenses, phenology, and morphology on the seed production of 146 populations ofOenothera biennisclose to the plant’s cold range limit. Genotypes from 2.1° South of the common garden produce more seeds than most northern lineages. Adaptations across space are a suitable substitute for climate change, but there is still substantial fitness variability. These differences were best explained by bolt date, flowering time, and greater defenses against herbivores. Given the impacts of climate change, plant defenses might already be of similar adaptive importance to phenology close to northern rage limits.
Coding of self and environment by Pacinian neurons in freely moving animals
Authors: Turecek Josef , Ginty David D.
Published: September 2023

Pacinian corpuscle neurons are specialized low-threshold mechanoreceptors (LTMRs) that are tuned to detect high-frequency vibration (∼40-2000 Hz), however it is unclear how Pacinians and other LTMRs encode mechanical forces encountered during naturalistic behavior. Here, we developed methods to record LTMRs in awake, freely moving mice. We find that Pacinians, but not other LTMRs, encode subtle vibrations of surfaces encountered by the animal, including low-amplitude vibrations initiated over two meters away. Strikingly, Pacinians are also highly active during a wide variety of natural behaviors, including walking, grooming, digging, and climbing. Pacinians in the hindlimb are sensitive enough to be activated by forelimb- or upper-body-dominant behaviors. Finally, we find that Pacinian LTMRs have diverse tuning and sensitivity. Our findings suggest a Pacinian population code for the representation of vibro-tactile features generated by self-initiated movements and low-amplitude environmental vibrations emanating from distant locations.
Pretrained transformers applied to clinical studies improve predictions of treatment efficacy and associated biomarkers
Authors: Arango-Argoty Gustavo , Kipkogei Elly , Stewart Ross , Patra Arijit , Kagiampakis Ioannis , Jacob Etai
Published: September 2023

Cancer treatment has made significant advancements in recent decades, leading to improved outcomes and quality of life for many patients. Despite the array of available therapies, including targeted, hormone, and checkpoint blockade immunotherapy, many patients experience treatment failure or eventual resistance. Attempts to predict the efficacy of therapies, particularly immuno-oncology therapies, have suffered from limited accuracy and difficulties in identifying molecular and other determinants of response. Improving treatment prediction alone is insufficient to create clinically meaningful research tools; additional prerequisites for this goal involve accommodating small data sets, effectively handling sparse features, integrating diverse clinical data, addressing missing measurements, ensuring interpretability, and extracting valuable biological insights for both clinical context and further research. Multimodal deep-learning models offer a promising avenue to surmount these challenges by leveraging their capacity and flexibility to learn from expansive and varied clinical and molecular data sets. Similar to their application in natural language and other domains, deep-learning models can uncover complex relationships within data that are pertinent to survival and treatment response. In this study, we introduce an explainable transformer-based deep-learning framework that addresses these challenges. This framework yields predictions of survival outcomes, as quantified by concordance index, that surpass the performance of state-of-the-art methods such as Cox proportional hazards, survival random forest, and tumor mutation burden, across diverse independent data sets. We developed the clinical transformer, a deep neural-network survival prediction framework that capitalizes on the flexibility of the deep-learning model, including training strategies like gradual and transfer learning, to maximize the use of available data to enhance survival predictions and generate actionable biological insights. Finally, we illustrate the future potential of the clinical transformer’s generative capability in early-stage clinical studies. By perturbing molecular features associated with immune checkpoint inhibition treatment in immunotherapy-naive patient profiles, we identified a subset of patients who may benefit from immunotherapy. These findings were subsequently validated across three independent immunotherapy treatment cohorts. We anticipate that this research will empower the scientific community to further harness data for the benefit of patients.
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

Proteotoxic 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

Immunogenic 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 Significance

Immunogenic 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

Approximately 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

Clonal 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

Memory 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 Statement

The 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

Cerebellar 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

Spt5 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

Objectives

To 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).

Design

Prospective observational study.

Setting

Decentralised secondary care in England, United Kingdom.

Participants

27 adults aged 60 (SD: 11) who live with DCM and possess an approved smartphone.

Primary and secondary outcome measures

Criteria 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.

Results

As 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.

Conclusions

Criteria 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

Background

Depressive 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.

Methods

We 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.

Results

The 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).

Limitations

This cross-sectional study included participants who were relatively healthy and relied on the self-reported assessment of depression symptoms.

Conclusions

This 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

Objective

Artificial 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 Methods

Using 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).

Results

While 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 Conclusion

A 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

Purpose

To evaluate the efficiency of large language models (LLMs) including ChatGPT to assist in diagnosing neuro-ophthalmic diseases based on case reports.

Design

Prospective study

Subjects or Participants

We 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.

Methods

We 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 Measures

Diagnostic accuracy in terms of number of correctly diagnosed cases among diagnoses.

Results

ChatGPT 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%).

Conclusions

The 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

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The goal of this study was to explore the capabilities of ChatGPT for the diagnoses of different neuro-ophthalmic diseases using specific case examples.

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There was general agreement between ChatGPT Plus v4.0 and two neuro-ophthalmologists in final diagnoses.

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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

The 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.
Temporal dynamics of short-term neural adaptation across human visual cortex
Authors: Brands Amber M. , Devore Sasha , Devinsky Orrin , Doyle Werner , Flinker Adeen , Friedman Daniel , Dugan Patricia , Winawer Jonathan , Groen Iris I. A.
Published: September 2023

Neural responses in visual cortex adapt to prolonged and repeated stimuli. While adaptation occurs across the visual cortex, it is unclear how adaptation patterns and computational mechanisms differ across the visual hierarchy. Here we characterize two signatures of short-term neural adaptation in time-varying intracranial electroencephalography (iEEG) data collected while participants viewed naturalistic image categories varying in duration and repetition interval. Ventraland lateral-occipitotemporal cortex exhibit slower and prolonged adaptation to single stimuli and slower recovery from adaptation to repeated stimuli compared to V1-V3. For category-selective electrodes, recovery from adaptation is slower for preferred than non-preferred stimuli. To model neural adaptation we augment our delayed divisive normalization (DN) model by scaling the input strength as a function of stimulus category, enabling the model to accurately predict neural responses across multiple image categories. The model fits suggest that differences in adaptation patterns arise from slower normalization dynamics in higher visual areas interacting with differences in input strength resulting from category selectivity. Our results reveal systematic differences in temporal adaptation of neural population responses across the human visual hierarchy and show that a single computational model of history-dependent normalization dynamics, fit with area-specific parameters, accounts for these differences.

Author summary

Neural responses in visual cortex adapt over time, with reduced responses to prolonged and repeated stimuli. Here, we examine how adaptation patterns differ across the visual hierarchy in neural responses recorded from human visual cortex with high temporal and spatial precision. To identify possible neural computations underlying short-term adaptation, we fit the response time courses using a temporal divisive normalization model. The model accurately predicts prolonged and repeated responses in lower and higher visual areas, and reveals differences in temporal adaptation across the visual hierarchy and stimulus categories. Our model suggests that differences in adaptation patterns result from differences in divisive normalization dynamics. Our findings shed light on how information is integrated in the brain on a millisecond-time scale and offer an intuitive framework to study the emergence of neural dynamics across brain areas and stimuli.
Transient structural properties of the Rho GDP-dissociation inhibitor
Authors: Gomez Sara Medina , Visco Ilaria , Merino Felipe , Bieling Peter , Linser Rasmus
Published: September 2023

Rho GTPases are master spatial regulators of the cytoskeleton that control a wide range of cellular processes. Their inactivation by removal from cellular membranes involves the stepwise formation of a stable complex with guanine nucleotide dissociation inhibitors (RhoGDIs), for which process the RhoGDI N-terminus is indispensable. The formation of this interface has been thought to emerge from an intrinsically disordered state of RhoGDI in its free, apo form. Here we use tailored solution NMR analyses, molecular dynamics simulations, and biochemical essays to pinpoint the site-specific structural features of full-length RhoGDI1 before and after binding its GTPase client Cdc42. In contrast to the current mechanistic understanding, a diverse set of NMR data unequivocally shows that the structural properties of the GDI N-terminus seen in crystal structures of the complex with GTPases already exist as largely preformed features in free, apo GDI. Even more interestingly, the required structural properties are imposed onto the terminus context-specifically by modulating interactions with the surface of the folded C-terminal domain. Lastly, upon Cdc42 binding, the flexibility of the N-terminus and its secondary-structural propensities are not largely abrogated. These observations change the textbook picture of the mechanism of membrane extraction of the GTPase. Rather than a disorder-to-order transition upon binding, an active role of the N-terminus with differentially preformed structural properties, suitably modulated by the specific surrounding along the multi-step process, seems required to leverage the intricate and highly selective extraction process.
Left-right asymmetry is formed in the basal bodies of the mouse node cilia in a cilia motility-dependent manner
Authors: Yoke Hiroshi , Taniguchi Atsushi , Nonaka Shigenori
Published: September 2023

Laterality of the shapes and arrangements of the visceral organs in mice is determined in the node, a small cavity found at the ventral side of 7.5 dpc (days post coitum) embryos. On the node cells, motile cilia which are tilted toward the posterior side of the embryos show clockwise movement and thus produce fluid flow in the node toward the left side of the embryos. This left-ward flow regulates left/right (L/R) asymmetric gene expressions and L/R asymmetric morphogenesis in later stages. Structurally, node cilia have the characteristics of primary cilia and their basal body (mother centriole) is accompanied by a daughter centriole. Here, to obtain insights into the process of symmetry breaking by node cilia, we investigated whether the structure of the cilia themselves have L/R asymmetry, and found that positions of the daughter centrioles become biased to the right side of the mother centrioles in a stage-dependent manner. We found that this L/R asymmetry of the basal bodies is absent inivmutant mice, in which node cilia are immotile, suggesting that formation of this L/R asymmetry in the basal bodies requires cilia motility. It has been reported that culturing embryos in a flow chamber with artificial counter-flow, which is toward the opposite direction to the endogenous leftward flow in the node, results in reversed laterality of the visceral organs in later stages. However, we found that applying such artificial counter-flow did not reverse the L/R asymmetry of the basal bodies, and the daughter centrioles were still biased to the right side of the mother centrioles, suggesting that the L/R asymmetry of the basal bodies is formed independently from the direction of the fluid flow in the node and that it is independent from the laterality of the visceral organs. Although the biological significance of this phenomenon is unknown so far, these results suggest that node cilia have a previously unknown mechanism to produce L/R asymmetry in the basal bodies inside the cells in early development, independently from the canonical fluid flow-dependent L/R determining pathway.
Discovery of peptides for targeted delivery of mRNA lipid nanoparticles to cystic fibrosis lung epithelia
Authors: Soto Melissa R. , Lewis Mae M. , Leal Jasmim , Pan Yuting , Mohanty Rashmi P. , Peng Sophie , Dong Tony , Ghosh Debadyuti
Published: September 2023

For cystic fibrosis (CF) patients, a lung targeted gene therapy would significantly alleviate pulmonary complications associated with morbidity and mortality. However, mucus in the airways and cell entry pose huge delivery barriers for local gene therapy. Here, we used phage display technology to select for and identify mucus- and cell-penetrating peptides against primary human bronchial epithelial cells (pHBECs) from CF patients cultured at air-liquid interface (ALI). At ALI, pHBECs produce mucus and reflect CF disease pathology, making it a clinically relevant model. Using this model, we discovered a lead candidate peptide, and incorporated it into lipid nanoparticles (LNPs) to deliver mRNA to pHBECs and mouse lungsin vivo. Compared to LNPs without our peptide, peptide-LNPs demonstrated 7.8-fold and 4.8-fold higher mRNA expressionin vitroandin vivo, respectively. Since gene delivery to pHBECs is a significant challenge, we are encouraged by these results and anticipate that our peptide could be used to successfully deliver CF gene therapies in future work.
Microsporidia Ser/Thr Protein Phosphatase PP1 Targets DCs MAPK Pathway and Impairs Immune Functions
Authors: Bao Jialing , Tang Yunlin , Chen Yebo , Jin Jiangyan , Wang Xue , An Guozhen , Cao Lu , Mo Biying , Zhang Huarui , Cheng Gong , Pan Guoqing , Zhou Zeyang
Published: September 2023

Microsporidia are difficult to completely eliminate. Their persistence may disrupt host cell functions. Here in this study, we aimed to elucidate the impairing effects and consequences of microsporidia infection upon dendritic cells (DCs). We used the zoonotic microsporidia species,Enterocytozoon hellem, in our studies.In vivoexperiments showed thatE. hellem-infected mice were more susceptible to further pathogenic challenges. DCs were identified as the most affected group of cells.In vitroassays revealed thatE. helleminfection impaired the immune functions of DCs as reflected by down-regulation of cytokine expression, lower extent of maturation and antigen presentation.E. helleminfection decreased the ability of DCs to prime and stimulate T cells, thereby hampering host immune cell functions. We further demonstrate thatE. hellemSer/Thr protein phosphatase PP1 directly interacts with host p38α(MAPK14) to manipulate the p38α (MAPK14)/NFAT-5 axis of the MAPK pathway. Our study is the first to elucidate the molecular mechanisms of the impairing effects of microsporidia on host DCs immune functions. The emerging of microsporidiosis may be great threat to public health.

Highlights

Persistence of Microsporidia within host impairs dendritic cell functions such as phagocytosis, maturation, antigen presentation and T cell priming, thereby disrupting both innate and adaptive immunities and making the host more vulnerable to secondary infections

Microsporidia impairs DCs function via Serine/Threonine Protein Phosphatase PP1 directly targeting DCs p38α/MAPK pathway

Latent Microsporidia infection and persistence is a great threat to public health when assessing acute and emerging pathogen risk
Defining the SPCA2C interactome identifies unique links to Store-Operated Ca2+Entry
Authors: Samardzija Petra , Fenech Melissa A , Lang Ryann , Carter McKenzie C , Chen Stephanie , Shi Selina , Stathopulos Peter B , Pin Christopher L
Published: September 2023

Calcium (Ca2+) is critical for normal cell function and several protein networks are required for Ca2+signaling. In the pancreas, regulated changes in cytosolic Ca2+allow for the exocytosis of zymogen granules and altered Ca2+signaling underlies pancreatic pathologies. Previously, our laboratory showed a pancreas-specific isoform of secretory pathway Ca2+-ATPase 2 (SPCA2C) affects multiple pathways involved in Ca2+homeostasis. The goal of this study was to define the SPCA2C interactome that contributes to these processes. Using proximity-dependent biotin identification, BioID, we expressed SPCA2C-BirA*HAin HEK293 cells with constitutive Orai1 expression.In silicomodeling of SPCA2C showed a highly dynamic cytosolic C-terminus, revealing a putative site for interactions and was selected for BirA* fusion. 150 candidate SPCA2C interactors were identified. Gene Ontology and KEGG Pathway analyses supported localization of SPCA2C to the endoplasmic reticulum as well as function in Ca2+signaling and suggested roles in vesicular transport. SPCA2C interactions with stromal interaction molecule 1 (STIM1), extended synaptotagmin-1 (ESYT1), and aspartate beta-hydroxylase (ASPH) were validated. Coiled-coil domain containing protein 47 (CCDC47) ranked as a high confidence SPCA2C-interactor which was confirmed through immunoprecipitation and co-localization with SPCA2C. CCDC47 interactions with SPCA2C, STIM1 and Orai1 were maintained following deletion of the CCDC47 luminal and cytosolic domains while deletion of only the coiled-coil domain altered CCDC47 localization and decreased interactions with STIM1 and Orai1. Overall, this study defines several novel protein interactions for SPCA2C and suggests it may be involved in affecting CCDC47, STIM1 and Orai1 function.
Collective Sensing in Electric Fish
Authors: Pedraja Federico , Sawtell Nathaniel B.
Published: September 2023

A number of organisms, including dolphins, bats, and electric fish, possess sophisticated active sensory systems that use self-generated signals (e.g. acoustic or electrical emissions) to probe the environment1,2. Studies of active sensing in social groups have typically focused on strategies for minimizing interference from conspecific emissions2-4. However, it is well-known from engineering that multiple spatially distributed emitters and receivers can greatly enhance environmental sensing (e.g. multistatic radar and sonar)5-8. Here we provide evidence from modeling, neural recordings, and behavioral experiments that the African weakly electric fishGnathonemus petersiiutilizes the electrical pulses of conspecifics to extend electrolocation range, discriminate objects, and increase information transmission. These results suggest a novel, collective mode of active sensing in which individual perception is enhanced by the energy emissions of nearby group members.
Deletion of exons 45 to 55 in theDMDgene: from the therapeutic perspective to thein vitromodel
Authors: Poyatos-García Javier , Soblechero-Martín Patricia , Liquori Alessandro , López-Martínez Andrea , González-Romero Elisa , Vázquez-Manrique Rafael P. , Muelas Nuria , García-García Gema , Ohana Jessica , Arechavala-Gomeza Virginia , Vílchez Juan J.
Published: September 2023

Gene editing therapies in development for correcting out-of-frameDMDmutations in Duchenne muscular dystrophy aim to replicate benign spontaneous deletions. Deletion of 45–55DMDexons (del45–55) was described in asymptomatic subjects, but recently serious skeletal and cardiac complications have been reported. Uncovering why a single mutation like del45–55 is able to induce diverse phenotypes and grades of severity may impact the strategies of emerging therapies. Cellular models are essential for this purpose, but their availability is compromised by scarce muscle biopsies. Here, we have introduced through CRISPR-Cas9 edition, a del45–55 mimicking the intronic breakpoints harboured by a subset of patients of this form of dystrophinopathy, into a Duchenne patient’s cell line. Dystrophin expression was restored in edited myoblasts and the myogenic defects were ameliorated. Besides confirming the potential of CRISPR-Cas9 to create tailored mutations as a useful approach to generatein vitromodels, we also generated an immortalized myoblast line derived from a patient with a specific del45–55. Overall, we provide helpful resources to deepen into unknown factors responsible for DMD-pathophysiology.

SUMMARY STATEMENT

We restored dystrophin expression in a DMD culture by replicating the exact deletion in exons 45-55 harboured by mild patients, testing this therapeutic approach, and creating a new cell model.