bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysfunction of proprioceptive sensory synapses is a pathogenic event and therapeutic target in mice and humans with spinal muscular atrophy
Authors: Simon CM , Delestree N , Montes J , Gerstner F , Carranza E , Sowoidnich L , Buettner JM , Pagiazitis JG , Prat-Ortega G , Ensel S , Donadio S , Garcia JL , Kratimenos P , Chung WK , Sumner CJ , Weimer LH , Pirondini E , Capogrosso M , Pellizzoni L , Vivo DC De , Mentis GZ 
Published: June 2024

ABSTRACTSpinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology. We demonstrate that SMA patients exhibit impaired proprioception, and their proprioceptive sensory synapses are dysfunctional as measured by the neurophysiological test of the Hoffmann reflex (H-reflex). We further show that loss of excitatory afferent synapses and altered potassium channel expression in SMA motor neurons are conserved pathogenic events found in both severely affected patients and mouse models. Lastly, we report that improved motor function and fatigability in ambulatory SMA patients and mouse models treated with SMN-inducing drugs correlate with increased function of sensory-motor circuits that can be accurately captured by the H-reflex assay. Thus, sensory synaptic dysfunction is a clinically relevant event in SMA, and the H-reflex is a suitable assay to monitor disease progression and treatment efficacy of motor circuit pathology.One-sentence summarySensory-motor circuit dysfunction involving impairment of proprioceptive synapses on motor neurons is a conserved pathogenic event and therapeutic target across animal models and humans with spinal muscular atrophy.
Bulwark Effect of Response in a Causal Model of Disruptive Clinician Behavior
Authors: Fujimoto Manabu , Shimamura Mika , Miyazaki Hiroaki , Inaba Kazuto 
Published: June 2024

ABSTRACTINTRODUCTIONDisruptive clinician behavior (DCB) refers to unethical and unprofessional behavior that seriously affects patient safety by disrupting relationships among healthcare professionals and causing dysfunctional communication and teamwork. DCB often persists as an organizational culture in Japanese healthcare settings because of problems in the conventional leadership system along with professional and positional hierarchies. Therefore, this study verified a causal model of DCB in Japanese healthcare, including triggers, response, and impact.METHODSStaff at two general hospitals (751 and 661 beds) were surveyed using a web-based questionnaire. In total, 256 staff who had experienced victimization and agreed to complete the questionnaire were included in this study. The questionnaire comprised demographic information, a DCB scale, and items covering causal indicators of DCB: triggers, response, and impact (psychological/social and medical/management).RESULTSMediation and moderated mediation analyses showed that: (1) DCB had a negative impact on the medical/managerial state, which was partially mediated by psychological/social impact; and (2) the responses of victims and others acted as a bulwark in reducing the psychological/social impact to some extent.DISCUSSIONA prompt response to DCB as a bulwark reduces victims’ psychological and social adaptation deterioration. Therefore, occurrences of DCB should not be overlooked, and the victim and those around them should respond positively. However, response as a bulwark cannot protect the organization’s medical care and management. Therefore, it is important to prevent DCB.
Detection of obstetric anal sphincter injuries using machine learning-assisted impedance spectroscopy: a prospective, comparative, multicentre clinical study
Authors: Borycka Katarzyna , Młyńczak Marcel , Rosoł Maciej , Korzeniewski Kacper , Iwanowski Piotr , Heřman Hynek , Janku Petr , Uchman-Musielak Małgorzata , Dosedla Erik , Diaz Enrique Gonzalez , Sudoł-Szopińska Iwona , Mik Michał , Ratto Carlo , Spinelli Antonino 
Published: June 2024

AbstractObjectiveTo evaluate the clinical performance and safety of the ONIRY system for obstetric anal sphincter injuries (OASI) detection versus three-dimensional endoanal ultrasound (EAUS).DesignA prospective, comparative, multicentre, international study. Setting: Poland, Czechia, Slovakia, and Spain.Population152 women between the first moments up to 8 weeks after vaginal delivery.MethodsParticipants underwent EAUS and were allocated to groups based on OASIS classification: A (no perineal tear), B (1st or 2nd degree tear), or C (3rd or 4th degree, anal sphincters affected). Electric impedance was measured in the anal canal using the ONIRY system. The primary endpoint was the diagnostic outcome of impedance spectroscopy versus EAUS. Adverse events were collected. Part II involved in silico modelling and 10-time 10-fold cross-validation for automated analysis.Main Outcome MeasuresAccuracy, sensitivity, and specificity.Results30 women were allocated to group A, 61 to group B, and 61 to group C. The diagnostic outcome was determined for 147 participants. The accuracy, sensitivity, and specificity of the ML-assisted impedance spectroscopy were 87.0 ± 0.5%, 90.6 ± 2.0%, and 84.6 ± 1.9%, respectively, compared with EAUS. After data cleaning, the performance metrics of the proposed final ML model for ONIRY were: 90.0 ± 0.4%, 90.0 ± 1.2%, and 90.0 ± 0.7%, respectively. No adverse device effects or deficiencies were observed.ConclusionML-assisted impedance spectroscopy offers a safe and accurate method for rapid OASI detection. This approach could effectively complement digital rectal examination in obstetric settings, supporting timely postpartum care.Funding informationThe study was financed by the Polish National Centre for Research and Development (POIR.01.01.01-00-0726/18).Key MessageWith 90% accuracy, the ONIRY system’s ML-assisted impedance spectroscopy offers a reliable, non-invasive method for detecting obstetric anal sphincter injuries, supporting timely postpartum diagnosis.
Complement-dependent virion lysis mediated by dengue-Zika virus cross-reactive antibodies correlates with protection from severe dengue disease
Authors: Dias Antonio G. , Duarte Elias , Zambrana Jose Victor , Cardona-Ospina Jaime A. , Bos Sandra , Roy Vicky , Kuan Guillermina , Balmaseda Angel , Alter Galit , Harris Eva 
Published: June 2024

AbstractPrimary infection with one of four dengue virus serotypes (DENV1-4) may generate antibodies that protect or enhance subsequent secondary heterotypic infections. However, the characteristics of heterotypic cross-reactive antibodies associated with protection from symptomatic infection and severe disease are not well-defined. We selected plasma samples collected before a secondary DENV heterotypic infection that was classified either as dengue fever (DF, n = 31) or dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS, n = 33) from our longstanding pediatric cohort in Nicaragua. We screened various antibody properties to determine the features correlated with protection from DHF/DSS. Protection was associated with high levels of binding of various antibody isotypes, IgG subclasses and effector functions, including antibody-dependent complement deposition, ADCD. Although the samples were derived from DENV-exposed, Zika virus (ZIKV)-naïve individuals, the protective ADCD association was stronger when assays were conducted with recombinant ZIKV antigens. Further, we showed that a complement-mediated virion lysis (virolysis) assay conducted with ZIKV virions was strongly associated with protection, a finding reproduced in an independent sample set collected prior to secondary heterotypic inapparent versus symptomatic DENV infection. Virolysis was the main antibody feature correlated with protection from DHF/DSS and severe symptoms, such as thrombocytopenia, hemorrhagic manifestations, and plasma leakage. Hence, anti-DENV antibodies that cross-react with ZIKV, target virion-associated epitopes, and mediate complement-dependent virolysis are correlated with protection from secondary symptomatic DENV infection and DHF/DSS. These findings may support the rational design and evaluation of dengue vaccines and development of therapeutics.One Sentence SummaryComplement-dependent virolysis mediated by a subset of ZIKV-cross-reactive antibodies protects from symptomatic DENV infection and severe disease.
Evaluating the Efficacy of Large Language Models for Systematic Review and Meta-Analysis Screening
Authors: Luo Ronald , Sastimoglu Ziya , Faisal Abu Ilius , Deen M. Jamal 
Published: June 2024

ABSTRACTBackgroundSystematic reviews and meta-analyses are essential for informed research and policymaking, yet they are typically resource-intensive and time-consuming. Recent advances in artificial intelligence and machine learning offer promising opportunities to streamline these processes.ObjectiveTo enhance the efficiency of systematic reviews, we explored the automation of various stages using GPT-3.5 Turbo. We assessed the model’s efficacy and performance by comparing it against three expert-conducted reviews across a comprehensive dataset of 24,534 studies.MethodsThe model’s performance was evaluated through a comparison with three expert reviews, utilizing a pseudo-K-folds permutation and a one-tailed ANOVA with an alpha level of 0.05 to ensure statistical validity. Key performance metrics such as accuracy, sensitivity, specificity, predictive values, F1-score, and the Matthews correlation coefficient were analyzed using two sets of prompts.ResultsOur approach significantly streamlined the systematic review process, which typically takes a year, reducing it to a few hours without sacrificing quality. In the initial screening phase, accuracy, specificity, and negative predictive values ranged between 80% and 95%. Sensitivity improved markedly during the second screening phase, demonstrating the model’s robustness when provided with more extensive data.ConclusionWhile ongoing refinements are needed, this tool represents a significant advancement in research methodologies, potentially making systematic reviews more accessible to a wider range of researchers.Impact StatementOur manuscript presents a novel review screening protocol built using open-source frameworks, which significantly enhances the systematic review process in terms of efficiency and cost-effectiveness. Leveraging the capabilities of GPT and embedding models, our protocol demonstrates the potential to transform a traditionally time-consuming and expensive task into an accelerated and economical operation, all while maintaining high standards of accuracy and reliability.Key PointsGPT screening can streamline systematic reviews from a year-long, expensive process to just hours at minimal cost.Validated across different topics, the protocol exhibits high reliability and consistency in study inclusion.The AI-driven process reduces human bias, with prompt optimization considerably improving sensitivity.
Acoustic chip for rapid label-free early-stage detection of rare leukemic cells
Authors: Matarèse Bruno F.E. , Flewitt Andrew , Huntly Brian J.P. 
Published: June 2024

AbstractWe present a promising approach for detecting as few as 1% of rare leukemia cells during the early stages of blood cancers. This study demonstrates a novel microfluidic chip utilizing a bulk piezoelectric ceramic device to manipulate cells with sound waves. By analyzing the movement patterns of normal mononuclear cells (MNCs) and abnormal THP-1 acute myeloid leukemia (AML) cells within an acoustic field, we observed distinct behaviors. Our findings suggest a label-free, non-targeted approach for sensitive detection of rare abnormal cells within a mixed population. This method, based on acoustophoresis principles, holds promise for analyzing biophysical properties of individual cells for early cancer diagnosis, potentially leading to earlier intervention and improved patient outcomes for leukemia. While this study focuses on microscopic analysis, we also discuss the potential for developing large-scale acoustophoresis-based methods for high-throughput rare cell detection using high-resolution nanofabrication techniques.
Tackling Anticancer Drug Resistance and Endosomal Escape in Aggressive Brain Tumors Using Bioelectronics
Authors: Jain Akhil , Wade Philippa , Stolnik Snow , Hume Alistair N. , Kerr Ian D. , Coyle Beth , Rawson Frankie 
Published: June 2024

AbstractChemotherapy resistance and endosomal entrapment, controlled by intracellular trafficking processes, are major factor in treatment failure. Here, we test the hypothesis that external electrical stimulus can be used to modulate intracellular trafficking of chemotherapeutic drugs in most common malignant brain tumors in childhood (medulloblastoma) and gold nanoparticles (GNPs) in adulthood (glioblastoma). We demonstrate that application of alternating current (AC) with frequencies ranging from KHz-MHz and low strength (1 V/cm) lead to killing of cisplatin and vincristine resistant (mediated by extracellular vesicles) medulloblastoma cell lines. On the other hand, in primary glioblastoma cells high frequency AC (MHz) regulated the endosomal escape of GNPs. No significant effect on the viability of the control medulloblastoma cells (resistant cells cultured in drug free media and non-resistant cells) and glioblastoma cells after AC treatment confirmed targeting of intracellular trafficking process. This work supports future application of AC in drug delivery and brain cancer therapy.
Time-division multiplexing (TDM) sequence removes bias in T2 estimation and relaxation-diffusion measurements
Authors: Liu Qiang , Gagoski Borjan , Shaik Imam Ahmed , Westin Carl-Fredrik , Wilde Elisabeth A. , Schneider Walter , Bilgic Berkin , Grissom William , Nielsen Jon‐Fredrik , Zaitsev Maxim , Rathi Yogesh , Ning Lipeng 
Published: June 2024

AbstractPurposeTo compare the performance of multi-echo (ME) and time-division multiplexing (TDM) sequences for accelerated relaxation-diffusion MRI (rdMRI) acquisition and to examine their reliability in estimating accurate rdMRI microstructure measures.MethodThe ME, TDM, and the reference single-echo (SE) sequences with six echo times (TE) were implemented using Pulseq with single-band (SB-) and multi-band 2 (MB2-) acceleration factors. On a diffusion phantom, the image intensities of the three sequences were compared, and the differences were quantified using the normalized root mean squared error (NRMSE). For the in-vivo brain scan, besides the image intensity comparison and T2-estimates, different methods were used to assess sequence-related effects on microstructure estimation, including the relaxation diffusion imaging moment (REDIM) and the maximum-entropy relaxation diffusion distribution (MaxEnt-RDD).ResultsTDM performance was similar to the gold standard SE acquisition, whereas ME showed greater biases (3-4× larger NRMSEs for phantom, 2× for in-vivo). T2 values obtained from TDM closely matched SE, whereas ME sequences underestimated the T2 relaxation time. TDM provided similar diffusion and relaxation parameters as SE using REDIM, whereas SB-ME exhibited a 60% larger bias in the <R2> map and on average 3.5× larger bias in the covariance between relaxation-diffusion coefficients.ConclusionOur analysis demonstrates that TDM provides a more accurate estimation of relaxation-diffusion measurements while accelerating the acquisitions by a factor of 2 to 3.
A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1
Authors: Koszela Joanna , Rintala-Dempsey Anne , Salzano Giulia , Pimenta Viveka , Kamarainen Outi , Gabrielsen Mads , Parui Aasna L. , Shaw Gary S. , Walden Helen 
Published: June 2024

AbstractMutations in the gene encoding for the E3 ubiquitin ligase Parkin have been linked to early-onset Parkinson’s disease. Besides many other cellular roles, Parkin is involved in clearance of damaged mitochondria via mitophagy - a process of particular importance in dopaminergic neurons. Upon mitochondrial damage, Parkin accumulates at the outer mitochondrial membrane and is activated, leading to ubiquitination of many mitochondrial substrates and recruitment of mitophagy effectors. While the activation mechanisms of autoinhibited Parkin have been extensively studied, it remains unknown how Parkin recognises its substrates for ubiquitination, and no substrate interaction site in Parkin has been reported. Here, we identify a conserved region in the flexible linker between the Ubl and RING0 domains of Parkin, which is indispensable for Parkin interaction with the mitochondrial GTPase Miro1. Our results explain the preferential targeting and ubiquitination of Miro1 by Parkin and provide a biochemical explanation for the presence of Parkin at the mitochondrial membrane prior to activation induced by mitochondrial damage. Our findings are important for understanding mitochondrial homeostasis and may inspire new therapeutic avenues for Parkinson’s disease.
Reversion to sensitivity explains limited transmission of resistance in a hospital pathogen
Authors: Tracy Kevin C. , McKaig Jordan , Kinnear Clare , Millar Jess , King Aaron A. , Read Andrew F. , Woods Robert J. 
Published: June 2024

1AbstractBacterial pathogens that are successful in hospital environments must survive times of intense antibiotic exposure and times of no antibiotic exposure. When these organisms are closely associated with human hosts, they must also transmit from one patient to another for the resistance to spread. The resulting evolutionary dynamics have, in some settings, led to rising levels of resistance in hospitals. Here, we focus on an important but understudied aspect of this dynamic: the loss of resistance when the resistant organisms evolve in environments where the antibiotic pressure is removed. Based on prior data, we hypothesize that resistance arising in the context of strong selection may carry a high cost and revert to sensitivity quickly once the selective pressure is removed. Conversely, resistant isolates that persist through times of no antibiotic pressure should carry a lower cost and revert less quickly. To test this hypothesis, we utilize a genetically diverse set of patient-derived, daptomycin-resistantEnterococcus faeciumisolates that include cases of bothde novoemergence of resistance within patients and putatively transmitted resistance. Both of these sets of strains have survived periods of antibiotic exposure, but only putatively transmitted resistant strains have survived extended periods without antibiotic exposure. These strains were then allowed to evolve in antibiotic free laboratory conditions. We find that putatively transmitted resistant strains tended to have lower level resistance but that evolution in antibiotic-free conditions resulted in minimal loss of resistance. In contrast, resistance that arosede novowithin patients was higher level but exhibited greater declines in resistancein vitro. Sequencing of the experimentally evolved isolates revealed that reversal of high level resistance resulted from evolutionary pathways that were frequently genetically associated with the unique resistance mutations of that strain. Thus, the rapid reversal of high-level resistance was associated with accessible evolutionary pathways where an increase in fitness is associated with decreased resistance. We describe how this rapid loss of resistance may limit the spread of resistance within the hospital and shape the diversity of resistance phenotypes across patients.
Protein Editing using a Concerted Transposition Reaction
Authors: Hua Yi , Tay Nicholas E. S. , Ye Xuanjia , Owen Jeremy A. , Liu Hengyuan , Thompson Robert E. , Muir Tom W. 
Published: June 2024

AbstractProtein engineering through the chemical or enzymatic ligation of polypeptide fragments has proven enormously powerful for studying countless biochemical processesin vitro. In general, this strategy necessitates a protein folding step following ligation of the unstructured fragments, a requirement that constrains the types of systems amenable to the approach. Here, we report anin vitrostrategy that allows internal regions of target proteins to be replaced in a single operation. Conceptually, our system is analogous to a DNA transposition reaction, but employs orthogonal pairs of split inteins to swap out a designated region of a host protein with an exogenous molecular cassette. We show using isotopic labeling experiments that this ‘protein transposition’ reaction is concerted when the kinetics for the embedded intein pairs are suitably matched. Critically, this feature allows for efficient manipulation of protein primary structure in the context of a native fold. The utility of this method is illustrated using several protein systems including the multi-subunit chromatin remodeling complex, ACF, where we also show protein transposition can occurin situwithin the cell nucleus. By carrying out a molecular ‘cut and paste’ on a protein or protein complex under native folding conditions, our approach dramatically expands the scope of protein semisynthesis.
A Novel Artificial Intelligence (AI) Method to Classify and Predict the Progression of Alzheimer’s Disease
Authors: Hasan Md Mehedi , Rahman Senjuti , Parmar Harshit , Chowdhury Suman K. 
Published: June 2024

AbstractPurposeThe objective of this study was to develop a novel AI-ensembled network based on the most important features and affected brain regions to accurately classify and exhibit the pattern of progression of the stages of Cognitive Impairment (CI).MethodsWe proposed a novel ensembled architecture, 3D ResNet-18 - RF (Random Forest), and used this network to categorize the stages of Alzheimer’s disease (AD). The residual unit (blocks of ResNet) was introduced to the 3D Convolutional Neural network (CNN) to solve the degradation problem. It was considered an innovative strategy since the combination with fine-tuning resulted in higher accuracy. This network was trained on selected features and affected brain regions. The structured magnetic resonance images (MRI) were collected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, and the random forest was used for determining the importance of the features and affected regions from the parcellated 170 regions of interest (ROIs) using Atlas, automated anatomical labeling 3(AAL-3). This framework classified five categories of AD and detected the progression pattern.ResultsThe proposed network showed promising results with a 66% F-1 score, 76% sensitivity, and 93.5% specificity, which outperformed the performance of conventional methods for categorizing five categories. Ventral Posterolateral and Pulvinar lateral regions were the regions most affected, indicating the progression from early MCI to AD. The five-fold validation accuracy for the developed model was 60.02%.ConclusionThe results showed that the gray matter to white matter ratio was the most significant feature, which also accurately predicted the progression pattern. The performance metrics fluctuated with different hyperparameters, but they never exceeded 0.05% of the estimated results, indicating the validity and originality of the suggested methodology.