bluuebunny/crossref_metadata_2025_split huggingface dataset:
Computational Models of High-Definition Electroconvulsive Therapy for Focal or Multitargeting Treatment
Authors: Khadka Niranjan , Deng Zhi-De , Lisanby Sarah H. , Bikson Marom , Camprodon Joan A. 
Published: August 2024

Abstract
Attempts to dissociate electroconvulsive therapy (ECT) therapeutic efficacy from cognitive side effects of ECT include modifying electrode placement, but traditional electrode placements employing 2 large electrodes are inherently nonfocal, limiting the ability to selectively engage targets associated with clinical benefit while avoiding nontargets associated with adverse side effects. Limited focality represents a technical limitation of conventional ECT, and there is growing evidence that the spatial distribution of the ECT electric fields induced in the brain drives efficacy and side effects. Computational models can be used to predict brain current flow patterns for existing and novel ECT montages. Using finite element method simulations (under quasi-static, nonadaptive assumptions, 800-mA total current), the electric fields generated in the superficial cortex and subcortical structures were predicted for the following traditional ECT montages (bilateral temporal, bifrontal, right unilateral) and experimental montages (focal electrically administered seizure therapy, lateralized high-definition [HD]-ECT, unilateral 4 × 1-ring HD-ECT, bilateral 4 × 1-ring HD-ECT, and a multipolar HD-ECT). Peak brain current density in regions of interest was quantified. Conventional montages (bilateral bifrontal, right unilateral) each produce distinct but diffuse and deep current flow. Focal electrically administered seizure therapy and lateralized HD-ECT produce unique, lateralized current flow, also impacting specific deep regions. A 4 × 1-ring HD-ECT restricts current flow to 1 (unilateral) or 2 (bilateral) cortical regions. Multipolar HD-ECT shows optimization to a specific target set. Future clinical trials are needed to determine whether enhanced control over current distribution is achieved with these experimental montages, and the resultant seizures, improve the risk/benefit ratio of ECT.
The Spherical Tokamak for Energy Production (STEP) in context: UK public sector approach to fusion energy
Authors: Baker Adam 
Published: August 2024

The UK’s fusion energy approach has developed over the past 5 years to include government policy initiatives and a range of public sector investments designed to be delivered in partnership with the private sector. These have aimed to create an environment that stimulates innovation and investment to deliver economic as well as scientific and environmental benefits throughout the lifetime of the public sector fusion energy programme. The Spherical Tokamak for Energy Production acts as a focus and anchor for both public and private sector efforts to develop fusion energy, developing the supply chain and potential for Intellectual Property development and export opportunities well ahead of the anticipated STEP completion date of 2040. This is maximized by the UK’s approach to a holistic research and innovation programme backed up by a regulatory and skills programme.
This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
Safety: a proportionate approach in an uncertain application
Authors: Afify Omar 
Published: August 2024

Fusion is inherently safer than fission due to the absence of nuclear chain reactions. However, operating fusion power plants will not be risk free. There will still be numerous hazards that will need careful management in order to safely build, operate and ultimately decommission a fusion power plant. Ensuring a robust safety demonstration that covers all radiological and non-radiological hazards is therefore vitally important for the future permissioning and consenting of fusion power plants. The safety case for the STEP prototype plant will be developed in line with a set of safety philosophies, safety functional requirements and design safety principles to ensure that the safety case production process is consistent and robust.
This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
The Spherical Tokamak for Energy Production: theme issue introduction
Authors: Chapman I. T. , Cowley S. C. , Wilson H. R. 
Published: August 2024

This theme issue collects together papers summarising the conceptual design of the Spherical Tokamak for Energy Production (STEP). In 2019, the UK government funded the first design stages of a prototype fusion powerplant based on a compact toroidal geometry, called STEP. The primary technical aims of STEP are to produce net energy, to be self-sufficient in tritium fuel and to demonstrate a maintenance regime that would extrapolate to appropriate availability for commercial powerplants. After 5 years and over 1000 person-years of detailed scientific and engineering conceptual design, this theme issue acts as a compendium of the current design basis for STEP, noting that this is a snapshot in time and that the design will continue to evolve.
This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
Identification of Antiviral Drug Candidates Against Monkeypox DNA Polymerase and Profilin-like Protein A42R Utilizing anIn-SilicoApproach
Authors: Amjid Muhammad , Khan Muhammad Maroof , Pastore Stephen F. , Vincent John B. , Muhammad Tahir 
Published: August 2024

ABSTRACTMonkeypox virus (MPXV) is emerging as a major concern in the field of infectious diseases. Current treatments are limited, highlighting the need for new therapeutic options. The use of computational methods, such as molecular docking and molecular dynamic (MD) simulations, is a valuable approach in identifying potential compounds that can target specific proteins of the virus, like the DNA polymerase and profilin-like protein A42R in this case, with the aim of controlling the disease. Our study focused on screening various libraries of compounds for predicted binding to MPXV DPol and A42R proteins, with the top-performing molecules identified based on their docking scores. Among these, Dorsilurin K and Mangostin in complex with DPol, whereas [2-oxo-2-[3-(3,4,5,6-tetrahydro-2H-azepin-7-ylsulfamoyl)anilino]ethyl] 3,5-dimethylbenzoate and N-[4-[2-[4-(4-methylphenyl)sulfonylpiperazin-1-yl]-2-oxoethoxy]phenyl]furan-2-carboxamide in complex with A42R stand out with notably high docking scores, suggesting they may have a good affinity for binding to the DPol and A42R proteins of MPXV respectively. MD simulations confirmed the stability of these ligand-protein complexes followed by evaluation of the ADMET and oral bioavailability analysis. However, it is important that computational methods can suggest promising candidates,in vitroand eventuallyin vivostudies are essential to validate these therapeutic candidates. Further studies on these compounds will provide insights into their efficacy, safety, and potential side effects. In conclusion, this study offers promising avenues for developing potential treatments for Monkeypox. If the identified compounds prove effective in further studies, it could be a significant breakthrough in managing this zoonotic disease.
High-Performance Classification of Breast Cancer Histopathological Images Using Fine-Tuned Vision Transformers on the BreakHis Dataset
Authors: Gella Venkat 
Published: August 2024

AbstractBreast cancer remains one of the most prevalent and deadly cancers worldwide, making accurate diagnosis critical for effective treatment. Histopathological image classification is a key task in medical diagnostics for cancer detection. This paper presents state-of-the-art performance in histopathological image classification of breast cancer using a novel approach with the Vision Transformer (ViT) model fine-tuned using the BreakHis dataset. The BreakHis dataset, comprising of 7,909 breast cancer histopathological images across various magnification levels, serves as a crucial benchmark for evaluating machine learning models in this domain. While previous works have explored the use of ViTs for this task, our approach fine-tunes a ViT pre-trained on ImageNet using the Ranger optimizer, achieving unprecedented performance. The experimental results show that our fine-tuned ViT model achieves an accuracy of 99.99%, precision of 99.98%, recall of 99.99%, F1 score of 99.99%, specificity of 100.00%, false discovery rate (FDR) of 0.00%, false negative rate (FNR) of 0.02%, false positive rate (FPR) of 0.00%, Matthews correlation coefficient (MCC) of 99.97%, and negative predictive value (NPV) of 99.96%. This model and approach represents the highest accuracy ever achieved for BreakHis binary classification in machine learning using any model, underscoring the potential of Vision Transformers to substantially enhance diagnostic accuracy in histopathological image analysis and improve clinical outcomes. Transfer learning was also performed on the BACH and a histopathological image dataset for breast invasive ductal carcinomas (IDC).
Emergence of antibiotic-specificMycobacterium tuberculosisphenotypes during prolonged treatment of mice
Authors: Wynn Elizabeth A , Dide-Agossou Christian , Al Mubarak Reem , Rossmassler Karen , Ektnitphong Victoria , Bauman Allison A , Massoudi Lisa M , Voskuil Martin I , Robertson Gregory T , Moore Camille M , Walter Nicholas D 
Published: August 2024

ABSTRACTA major challenge in tuberculosis (TB) therapeutics is that antibiotic exposure leads to changes in the physiologic state ofM. tuberculosis(Mtb) which may enable the pathogen to withstand treatment. While antibiotic-treatedMtbhave been evaluated in short-termin vitroexperiments, it is unclear if and how long-termin vivotreatment with diverse antibiotics with varying treatment-shortening activity (sterilizing activity) affectMtbphysiologic states differently. Here, we used SEARCH-TB, a pathogen-targeted RNA-sequencing platform, to characterize theMtbtranscriptome in the BALB/c high-dose aerosol infection mouse model following 4-week treatment with three sterilizing and three non-sterilizing antibiotics. Certain transcriptional changes were concordant among most antibiotics, including decreased expression of genes associated with protein synthesis and metabolism, and the induction of certain genes associated with stress responses. However, the magnitude of this concordant response differed between antibiotics. Sterilizing antibiotics rifampin, pyrazinamide, and bedaquiline generated a more quiescentMtbstate than did non-sterilizing antibiotics isoniazid, ethambutol, and streptomycin, as indicated by decreased expression of genes associated with translation, transcription, secretion of immunogenic proteins, metabolism, and cell wall synthesis. Additionally, we identified distinguishing transcriptional effects specific to each antibiotic, indicating that different mechanisms of action induce distinct patterns of cellular injury. In addition to elucidatingMtbphysiologic changes associated with antibiotic stress, this study demonstrates the value of SEARCH-TB as a highly granular pharmacodynamic assay that reveals antibiotic effects that are not apparent based on culture alone.
Large scale comparative wheat phosphoproteome profiling pinpoints temperature-associated molecular signatures
Authors: Fonseca de Lima Cássio Flávio , Zhu Tingting , Van den Broeck Lisa , Van De Cotte Brigitte , Locke Anna M. , Sozzani Rosangela , De Smet Ive 
Published: August 2024

ABSTRACTElevated temperatures resulting from climate change adversely affect natural and crop ecosystems, necessitating the development of heat-tolerant crops. We established a framework to precisely identify wheat protein-phosphorylated sites associated with varying temperature sensitivities. We identified specific kinases primarily associated with a specific temperature, but our results also suggest a striking overlap between cold and heat signaling. We furthermore demonstrated that the phosphorylation state of a specific set of proteins creates a unique signature for heat stress tolerance. These findings can potentially aid in the identification of targets for breeding or genome editing to enhance sub/supra optimal temperature tolerance.
Resolving interface structure and local internal mechanics of mitotic chromosomes
Authors: Ridolfi Andrea , Witt Hannes , Harju Janni , Clement Tinka V. M. , Peterman Erwin E. J. G. , Broedersz Chase P. , Wuite Gijs J. L. 
Published: August 2024

AbstractThe interface of chromosomes enables them to interact with the cell environment and is crucial for their mechanical stability during mitosis. Here, we use Atomic Force Microscopy (AFM) to probe the interface and local micromechanics of the highly condensed and complex chromatin network of native human mitotic chromosomes. Our AFM images provide detailed snapshots of chromatin loops and Sister-Chromatids Intertwines. A scaling analysis of these images reveals that the chromatin surface has fractal nature. AFM-based Force Spectroscopy and microrheology further show that chromosomes can resist severe deformations, elastically recovering their initial shape following two characteristic timescales. Localized indentations over the chromatids reveal that the spatially varying micromechanics of the chromatin network is largely governed by chromatin density. Together, our AFM investigation provides new insights into the structure and local mechanics of mitotic chromosomes, offering a toolbox for further characterization of complex biological structures, such as chromosomes, down to the nanoscale.
haCCA: Multi-module Integrating of spatial transcriptomes and metabolomes
Authors: Shen Xiao-Tian , Xu Jing , Zhang Chen , Zhang Xiao-Yun , Chen Zhou-Qing , Jiang Hu-Liang , Yang Lu-Yu 
Published: August 2024

AbstractSpatial techniques such as spatial transcriptomes and MALDI-MSI, offering insights into both transcripts and metabolite of tissue sections. However, integrating them with high accuracy is challenge due to no shared spots or features. We present haCCA, a workflow designed to integrate spatial transcriptomes and metabolomes data using high-correlated feature pairs and modified spatial morphological alignment. This approach ensures high-resolution and accurate spot-to-spot data integration across neighbor tissue section. We applied haCCA to both publicly available 10X Visium and MALDI-MSI datasets from mouse brain tissue and a custom spatial transcriptome and MALDI-MSI dataset from an intrahepatic cholangiocarcinoma (ICC) model, exploring the metabolic alteration of NETs(neutrophil extracellular traps) on ICC, and finding a potential mechanism that NETs upregulated Scd1 to activate fatty acid metabolism. Providing new insights into the dynamic crosstalk between genes and metabolites that regulates the tumor biological behavior and drives the response to treatment. We developed and published an easy-to-use Python package to facilitate its use.
In utero human intestine contains maternally derived bacterial metabolites
Authors: Wang Wenjia , Gu Weihong , Schweitzer Ron , Koren Omry , Khatib Soliman , Tseng George , Konnikova Liza 
Published: August 2024

AbstractUnderstanding when host-microbiome interactions are first established is crucial for comprehending normal development and identifying disease prevention strategies. Furthermore, bacterially derived metabolites play critical roles in shaping the intestinal immune system. Recent studies have demonstrated that memory T cells infiltrate human intestinal tissue early in the second trimester, suggesting that intestinal immune education begins in utero. Our previous study reported a unique fetal intestinal metabolomic profile with an abundance of several bacterially derived metabolites and aryl hydrocarbon receptor (AHR) ligands implicated in mucosal immune regulation. To follow up on this work, in the current study, we demonstrate that a number of microbial byproducts present in fetal intestines in utero are maternally derived and vertically transmitted to the fetus. Notably, these bacterially derived metabolites, particularly short chain fatty acids and secondary bile acids, are likely biologically active and functional in regulating the fetal immune system and preparing the gastrointestinal tract for postnatal microbial encounters, as the transcripts for their various receptors and carrier proteins are present in second trimester intestinal tissue through single-cell transcriptomic data.
The Role of Sex in Atherosclerotic Inflammation and Lipid-Handling Dysfunction
Authors: Liu Phydena Z , Zhang Lauren N , Matz Alyssa J 
Published: August 2024

AbstractResidual risk of cardiovascular events remains despite treatments that effectively lower cholesterol levels and hypertension, suggesting that there must be more variables to consider in atherosclerosis treatment. Several studies have suggested sex1,2,3and inflammation4,5as important variables. However, a cross-cohort analysis of sex and risk factors like inflammation and lipid-handling dysfunction is needed to strengthen their connection to atherosclerosis. By using blood transcriptomic profiles of 391 male and female participants, this study revealed that inflammation and lipid-handling dysfunction have sex-specific roles in atherosclerosis. Transcriptomics of 391 human blood samples with varying degrees of atherosclerosis were used to identify sex-specific changes in immune response and lipid-handling in circulating blood cells. Preliminary analyses of both FPKM and normalized counts datasets showed that inflammatory pathway activation and enrichment increased as atherosclerotic disease severity increased across all sexes. Analysis of sex-specific differentially expressed genes (DEGs) using IPA’s Canonical Pathways showed that severely impacted females had more enriched inflammatory pathways than severely impacted males. Further cross-cohort analysis of sex-specific inflammation and lipid-handling dysfunction was performed using AtheroSpectrum, a single-sample macrophage annotation tool. AtheroSpectrum confirmed that inflammation was more critical to female atherogenesis and revealed that lipid-handling dysfunction was more critical to male atherogenesis. Our study underscored the importance of inflammation and sex as variables to consider in atherosclerosis treatment, suggesting that treatment should target inflammation and consider sex. Our findings may be used for generating a model to predict atherosclerosis risk based on key DEGs, pathways, sex, and other clinical parameters when available.
Statins attenuate Wnt/β-catenin signaling by targeting SATB family proteins in colorectal cancer
Authors: Tripathi Sneha , Gupta Ekta , Naik Rutika , Khare Satyajeet , Mir Rafeeq , Desai Saarthi , Humane Swati , Yadav Subhash , Bal Munita , Saklani Avanish , Patil Prachi , Kamat Siddhesh , Galande Sanjeev 
Published: August 2024

AbstractColorectal cancer is the second leading cause of cancer-related deaths worldwide, highlighting the need for improved treatments and advanced molecular research. A recent therapeutic approach focuses on repurposing drugs to target dysregulated pathways involved in tumorigenesis. Among these, statins, commonly known for lowering cholesterol, have attracted attention for their potential anti-cancer properties. Here, we provide direct evidence for the same by assessing the impact of statin treatment on lipid, transcript, and protein levels. Our findings reveal that statins specifically target key components of the Wnt/β-catenin pathway, a major factor in adenoma formation, including the SATB (Special AT-rich Binding protein) family proteins. While SATB1 is recognized as a regulator of tumorigenesis, particularly under Wnt signaling, SATB2 appears to exert an opposing role. We demonstrate that statin treatment reciprocally alters the expression pattern of these proteins. Furthermore, a human clinical trial evaluating statins as an anti-cancer therapy supports the hypothesis that differential expression of SATB proteins is crucial in tumorigenic outcomes. In conclusion, this modulation by statin treatment suggests promising new therapeutic avenues through drug repurposing.
Neurons as biosensors for discriminating neurological disorders in a brain-on-chip platform: Application to Alzheimer’s Disease using patient CSF
Authors: Miny Louise , Rontard Jessica , Allouche Ahmad , Violle Nicolas , Dubuisson Louise , Batut Aurélie , Ponomarenko Alexandre , Talbi Rania , Gautier Hélène , Maisonneuve Benoît , Roux Serge , Larramendy Florian , Honegger Thibault , Quadrio Isabelle 
Published: August 2024

AbstractAlzheimer’s disease (AD) is characterized by the accumulation of aggregated amyloid beta peptide (Aβ) leading to progressive neuronal loss and dysfunction. Current AD’s diagnosis involves biomarkers assays in cerebrospinal fluid (CSF) as Aβ to validate the diagnosis. However, these methods are time-consuming, expensive, and can result in inaccurate diagnoses by not accounting for differential diagnose. To overcome these challenges, researchers are exploring new technologies for detecting AD biomarkers in biological fluids, though progress is hindered by an incomplete understanding of AD mechanisms and CSF composition. In this study, we used a standardized microfluidic platform to investigate the effects of synthetic Aβ peptides and cerebrospinal fluid (CSF) from AD and healthy patients on neuronal functional activity. First, human neurons derived from induced pluripotent stem cells (iPSCs) were characterized. Then, to modulate the functional activity of neurons, tetrodotoxin (TTX), a specific sodium channel blocker, was used as a control for inhibiting neuronal activity. Subsequently, glutamatergic neurons were chronically exposed to AβO and patients’ CSF. MEA recordings were performed before and after the treatments to assess changes in network activity. Our results demonstrated that extracting key electrophysiological metrics allows for discrimination between healthy and AD CSF samples. This system could offer the potential for differential diagnosis and development of personalized therapeutic strategies.
Assembly and performance of a cholera RDT prototype that detects bothVibrio choleraeand associated bacteriophage as a proxy for pathogen detection
Authors: Sayeed Md. Abu , Nabil Imrul Kayes , Bhattacharjee Piyash , Hossain Md. Shawkat , Akter Noor Jahan , Akter Romana , Kelley Karen L , Karim Mahbubul , Begum Yasmin Ara , Bhuiyan Taufiqur Rahman , Qadri Firdausi , Khan Ashraful Islam , Nelson Eric J 
Published: August 2024

ABSTRACTIntroductionCholera rapid diagnostic tests (RDTs) are vulnerable to virulent bacteriophage predation. We hypothesized that an enhanced cholera RDT that detects the common virulent bacteriophage ICP1 might serve as a proxy for pathogen detection. We previously developed a monoclonal antibody (mAb) to the ICP1 major capsid protein. Our objective herein was to design and assemble a first-of-its-kind RDT that detects both a bacterial pathogen (Vibrio cholerae) and associated virulent bacteriophage (ICP1).MethodCandidate mAbs were expanded to increase design options and evaluated by immunological assays (ELISA; western blot). A subset of mAbs were selected for gold conjugation and printing on the RDT. The limit of detection (LOD) of prototype RDTs were determined in diarrheal stools with the addition of ICP1.ResultsThree mAb candidates were developed and evaluated for the capsid decoration protein (ORF123) and tail fiber protein (ORF93), and the prior mAb for the major capsid protein (ORF122). A single mAb sandwich RDT prototype for ORF122 was able to detect ICP1; RDTs with mAbs to ORF123 and ORF93 failed to detect ICP1 in single or dual sandwich configurations. Biologically meaningful LODs for ICP1 were achieved only after boiling the stool with ICP1; analysis by electron microscopy suggested increased epitope availability after boiling.ConclusionIn this study, we demonstrate a proof of concept for a functional RDT that can detect both the primary pathogen and a common virulent bacteriophage as a proxy for pathogen detection. Further optimization is required before scaled production and implementation.