bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcranial Direct Current Stimulation in Children With Anisometropic Amblyopia
Authors: El Salmawy Dina Ahmed , Elhadidy Reem , Shuaib Asmaa , Ashraf Mahmoud Eman , Nada Mona M. 
Published: August 2024

Background:
Amblyopia is defined clinically as a difference in best-corrected visual acuity of two or more lines of acuity (0.2 logMAR) between the eyes. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that can transiently alter the excitability of targeted brain areas in a polarity-specific manner.

Purpose:
To detect the effect of tDCS on anisometropic amblyopia.

Methods:
This is a randomized controlled trial conducted on 78 patients with anisometropic amblyopia from 4.5 to 12 years of age. All patients presented with monocular amblyopia. They were divided into three groups; each group received five sessions of tDCS (anodal tDCS, cathodal tDCS, and sham tDCS). The active electrode was placed over occipital midline and the reference over central midline. Pattern visual-evoked potentials and contrast sensitivity tests were conducted before, immediately after, and 1 week after tDCS.

Results:
The amplitude of P100 was significantly decreased immediately after and 1 week after cathodal tDCS. The latency of P100 immediately after and 1 week after anodal tDCS was significantly decreased and increased significantly after cathodal tDCS. The amplitude of P100 and maximum and minimum contrast sensitivities were significantly increased immediately after and 1 week after anodal tDCS, and maximum contrast sensitivity was significantly decreased immediately after cathodal tDCS.

Conclusion:
Anodal tDCS is a promising noninvasive modality for improvement of anisometropic amblyopia.
Preserving friendships in school contacts: an algorithm to construct synthetic temporal networks for epidemic modelling
Authors: Calmon Lucille , Colosi Elisabetta , Bassignana Giulia , Barrat Alain , Colizza Vittoria 
Published: August 2024

AbstractHigh-resolution temporal data on contacts between hosts provide crucial information on the mixing patterns underlying infectious disease transmission. Publicly available data sets of contact data are however typically recorded over short time windows with respect to the duration of an epidemic. To inform models of disease transmission, data are thus often repeated several times, yielding synthetic data covering long enough timescales. Looping over short term data to approximate contact patterns on longer timescales can lead to unrealistic transmission chains because of the deterministic repetition of all contacts, without any renewal of the contact partners of each individual between successive periods. Real contacts indeed include a combination of regularly repeated contacts (e.g., due to friendship relations) and of more casual ones. In this paper, we propose an algorithm to longitudinally extend contact data recorded in a school setting, taking into account this dual aspect of contacts and in particular the presence of repeated contacts due to friendships. To illustrate the interest of such an algorithm, we then simulate the spread of SARS-CoV-2 on our synthetic contacts using an agent-based model specific to the school setting. We compare the results with simulations performed on synthetic data extended with simpler algorithms to determine the impact of preserving friendships in the data extension method. Notably, the preservation of friendships does not strongly affect transmission routes between classes in the school but has a clear impact on the infection pathways between individual students. Our results moreover indicate that gathering contact data during two days in a population is sufficient to generate realistic synthetic contact sequences between individuals in that population on longer timescales. The proposed tool will allow modellers to leverage existing contact data, and contributes to the design of optimal future field data collection.
Amber Codon Mutational Scanning and Bioorthogonal PEGylation for Mapping Antibody Binding Sites on Human Arginase-1
Authors: Fernández de Santaella Jaime , Koch Nikolaj G. , Widmer Lorenz , Nash Michael A. 
Published: August 2024

AbstractEpitope mapping is crucial for understanding immunological responses to protein therapeutics. Here, we combined genetic code expansion and bacterial surface display to incorporate S-allylcysteine (SAC) into human arginase-1 (hArg1) viaMethanococcoides burtoniipyrrolysyl-tRNA synthetase. Using an amber codon deep mutational scanning and sequencing workflow, we mapped SAC incorporation efficiency across the hArg1 sequence, providing insights into structural and sequence dependencies of non-canonical amino acid incorporation. We used mutually bioorthogonal allyl/tetrazine and azide/DBCO chemistries to achieve site-specific PEGylation and fluorescent labeling of hArg1, revealing insights into SAC side chain reactivity and solvent accessibility of residues in hArg1. This system was further applied to determine the binding epitope of a monoclonal antibody on the surface of hArg1, providing high-resolution data on the impact of PEGylation on antibody binding. Our method produces high dimensional data of non-canonical amino acid incorporation efficiency, site-specific functionalization enabled by mutually bioorthogonal chemistries, and epitope mapping of therapeutic proteins.
High throughput mutational scanning of a protein via alchemistry on a high-performance computing resource
Authors: Guclu Tandac F. , Tayhan Busra , Cetin Ebru , Atilgan Ali Rana , Atilgan Canan 
Published: August 2024

AbstractAntibiotic resistance presents a significant challenge to public health, as bacteria can develop resistance to antibiotics through random mutations during their life cycles, making the drugs ineffective. Understanding how these mutations contribute to drug resistance at the molecular level is crucial for designing new treatment approaches. Recent advancements in molecular biology tools have made it possible to conduct comprehensive analyses of protein mutations. Computational methods for assessing molecular fitness, such as binding energies, are not as precise as experimental techniques like deep mutational scanning. Although full atomistic alchemical free energy calculations offer the necessary precision, they are seldom used to assess high throughput data as they require significantly more computational resources. We generated a computational library using deep mutational scanning for dihydrofolate reductase (DHFR), a protein commonly studied in antibiotic resistance research. Due to resource limitations, we analyzed 33 out of 159 positions, identifying 16 single amino acid replacements. Calculations were conducted for DHFR in its drug-free state and in the presence of two different inhibitors. We demonstrate the feasibility of such calculations, made possible due to the enhancements in computational resources and their optimized use.
Sex and APOE4-specific links between cardiometabolic risk factors and white matter alterations in individuals with a family history of Alzheimer’s disease
Authors: Tremblay Stefanie A. , Spreng R. Nathan , Wearn Alfie , Alasmar Zaki , Pirhadi Amir , Tardif Christine L. , Chakravarty Mallar M. , Villeneuve Sylvia , Leppert Ilana R. , Carbonell Felix , Iturria Medina Yasser , Steele Christopher J. , Gauthier Claudine J. ,   PREVENT-AD Research Group
Published: August 2024

ABSTRACTINTRODUCTIONWhite matter (WM) alterations are among the earliest changes in Alzheimer’s disease (AD), yet limited work has comprehensively characterized the effects of AD risk factors on WM.METHODSIn older adults with a family history of AD, we investigated the sex-specific and APOE genotype-related relationships between WM microstructure and risk factors. Multiple MRI-derived metrics were integrated using a multivariate approach based on the Mahalanobis distance (D2). The links between WM D2 and cognition were also explored.RESULTSWM D2 in several regions was associated with high systolic blood pressure, BMI, and glycated hemoglobin, and low cholesterol, in both males and females. APOE4+ displayed a distinct risk pattern, with LDL-cholesterol having a detrimental effect only in carriers, and this pattern was linked to immediate memory performance. Myelination was the main mechanism underlying WM alterations.DISCUSSIONOur findings reveal that combined exposure to multiple cardiometabolic risk factors negatively impacts microstructural health, which may subsequently affect cognition. Notably, APOE4 carriers exhibited a different risk pattern, especially in the role of LDL, suggesting distinct underlying mechanisms in this group.
Evolutionary mismatch between nuclear and mitochondrial genomes does not promote reversion mutations in mtDNA
Authors: Franco Melissa , Popadin Konstantin , Woods Dori , Khrapko Konstantin 
Published: August 2024

AbstractSerrano et al. (Serrano et al., 2024) use a high-fidelity somatic mtDNA mutation analysis in conplastic mice in which mtDNA was replaced with exogenous mtDNA of different mouse strains. Serrano reported apparent abundant somatic reversion mutations in the exogenous mtDNA that seemed to restore the original mito-nuclear match. If real, such a phenomenon would have important implications for health and genetics. In today’s highly mixed human population, the pairing of potentially mismatched nuclear and mitochondrial genomes is widespread, so the proposed reversion mutagenesis should be commonplace. We demonstrate, however, that thesereversion mutationsare not real but originate from cross-contamination between samples and from NUMTs, the mtDNA pseudogenes located in the nuclear genome.
Optimized tacrolimus dosing strategy in kidney transplant recipients receiving nirmatrelvir-ritonavir for COVID-19
Authors: Yan Han , Hu Shanbiao , Zhang Hedong , Zhou Yangang , Fu Rao , Xu Ping , Cai Hualin , Li Xi , Lan Gongbin 
Published: August 2024

Kidney transplantation recipients (KTRs) represent a vulnerable population for COVID-19 infection and severe disease. Nirmatrelvir-ritonavir has demonstrated efficacy in treating COVID-19 among KTRs, and interacts with tacrolimus leading to a precipitous increase in tacrolimus blood levels when co-administered, potentially resulting in toxicity. This study conducted a real-world analysis of KTRs treated with nirmatrelvir-ritonavir for COVID-19 to investigate the relationship between tacrolimus levels and dosing during and within 10 days post-discontinuation of nirmatrelvir-ritonavir. In the experimental group, tacrolimus was initiated at 20-25% of the baseline dose 48 hours after discontinuation of nirmatrelvir-ritonavir, with daily increments of 20-25% until the baseline dose was restored. The patients who did not adhere to the experimental protocol were included in the control group. Findings indicated that withholding tacrolimus 12 hours prior to commencing nirmatrelvir-ritonavir maintained tacrolimus blood levels above 83% of the baseline throughout the nirmatrelvir-ritonavir treatment period. Compared to the control group, the experimental group achieved target trough concentrations of tacrolimus more rapidly and maintained a higher proportion within the therapeutic range (p=0.029), and exhibited significantly lower rates of adverse events (p<0.001). This investigation provides a safe and effective pharmacological strategy for KTRs infected with COVID-19, enabling the safe co-administration of nirmatrelvir-ritonavir and tacrolimus.
Social risk coding by amygdala activity and connectivity with dorsal anterior cingulate cortex
Authors: Kim Jae-Chang , Zangemeister Leopold , Tobler Philippe N. , Schultz Wolfram , Grabenhorst Fabian 
Published: August 2024

AbstractRisk is a fundamental factor affecting individual and social economic decisions, but its neural correlates are largely unexplored in the social domain. The amygdala, together with the dorsal anterior cingulate cortex (dACC), is thought to play a central role in risk taking. Here, we investigated in human volunteers (n=20; 11 females) how risk (defined as variance of reward probability distributions) in a social situation affects decisions and concomitant neural activity as measured with fMRI. We found social variance-risk signals in the amygdala. Activity in lateral parts of the amygdala increased parametrically with social reward variance of the presented options. Behaviorally, 75% of participants were averse to social risk as estimated in a Becker-DeGroot-Marschak auction-like procedure. The stronger this aversion, the more negative was the coupling between risk-related amygdala regions and dACC. This negative relation was significant for social risk attitude but not for the attitude towards variance-risk in juice outcomes. Our results indicate that the amygdala and its coupling with dACC process objective and subjectively evaluated social risk. Moreover, while social risk can be captured with a framework originally established by finance theory for individual risk, the amygdala appears to processes social risk largely separately from individual risk.
Enhancing Challenging Target Screening via Multimodal Protein-Ligand Contrastive Learning
Authors: Wang Zhen , Wang Zhanfeng , Yang Maohua , Pang Long , Nie Fangyuan , Liu Siyuan , Gao Zhifeng , Zhao Guojiang , Ji Xiaohong , Huang Dandan , Zhu Zhengdan , Li Dongdong , Yuan Yannan , Zheng Hang , Zhang Linfeng , Ke Guolin , Wang Dongdong , Yu Feng 
Published: August 2024

AbstractRecent advancements in genomics and proteomics have identified numerous clinically significant protein targets, with notably 85% categorized as undruggable. These targets present widespread challenges due to their complex structures and dynamics, rendering conventional drug design strategies not always effective. In this study, we introduce Uni-Clip, a contrastive learning framework that incorporates multi-modal features of proteins (structure and residue) and ligands (conformation and graph). Optimized with a specifically designed CF-InfoNCE loss, Uni-Clip enhances the modeling of protein-ligand interactions for both undruggable and druggable proteins. Uni-Clip demonstrates superior performance in benchmark evaluations on widely acknowledged datasets, LIT-PCBA and DUD-E, achieving a 147% and 218% improvements in enrichment factors at 1% compared to baselines. Furthermore, Uni-Clip proves to be a practical tool for various drug discovery applications. In virtual screening for the challenging protein target GPX4 with flat surface, it identified non-covalent inhibitors with an IC50of 4.17 μM, in contrast to the predominantly covalent inhibitors currently known. Through target fishing for benzbromarone, Uni-Clip identified the intrinsically disordered protein c-Myc as a potential target, highlighting benzbromarone’s potential for repurposing in cancer therapy. Explainable analyses effectively identified binding sites consistent with molecular dynamics and experimental results, even for challenging undruggable targets.
Tetramethylrhodamine self-quenching is a probe of conformational change on the scale of 15 – 25 Å
Authors: Girvan Paul , Ying Liming , Dodson Charlotte A 
Published: August 2024

AbstractTetramethylrhodamine (TMR) is a fluorescent dye whose self-quenching has been used as a probe of multiple biological phenomena. We determine the distance-dependence of self-quenching and place bounds on the timescale of TMR dissociation. Our results validate fluorescence self-quenching as an alternative to FRET and enable future assays to be designed with confidence.
A Novel Combinatorial Approach Integrating Experimental and Computational Analysis of Antioxidant Activity: Evaluating Catechin and L-Ascorbic Acid in Serum
Authors: Rasool Ayeshum , Chidi Chinanu , Rigaut Sophie , Carty Symone , Soubra-Ghaoui Chirine , Chandra Richa 
Published: August 2024

AbstractCardiovascular disease (CVD) remains the leading cause of morbidity and mortality globally, with oxidative stress playing a pivotal role in its progression. Free radicals produced via oxidative stress contribute to lipid peroxidation, leading to subsequent inflammatory responses, which then result in atherosclerosis. Antioxidants inhibit these harmful effects through their reducing ability, thereby preventing oxidative damage. In this study, we introduce a with computational models simulating hydrophilic and hydrophobic serum environments. We optimized the Ferric Reducing Ability of Plasma (FRAP) assay at a microscale level to evaluate the antioxidant activity of L-ascorbic acid (vitamin C) and catechin, a phytochemical found in green tea, in normal and hypertriglyceridemic serum. Hypertriglyceridemic serum, characterized by increased hydrophobic lipid content, provides a model to examine the impact of serum triglycerides on antioxidant activity. Additionally, we employed computational models using the Gaussian software to simulate the hydrogen atom transfer (HAT) mechanism, calculating free energy changes and bond dissociation energy (BDE) to assess the antioxidant potency of the studied compounds in both hydrophilic and hydrophobic environments. The computational results align with the experimental finding offering a unique combinatorial approach to assess antioxidant activity in both normal and hypertriglyceridemic serum, with potential implications for clinical interventions.
Vaccination against helminth IL-33-modulators permits immune-mediated parasite ejection
Authors: Smyth Danielle J , Hodge Suzanne , Ong Nicole , Richards Josh , Colomb Florent , Shek Vivien , Frangova Tania , McSorley Henry J 
Published: August 2024

AbstractThe murine intestinal nematodeHeligmosomoides polygyrus bakeripowerfully modulates the host immune response. This is achieved in part through the HpARI family (HpARI1/2/3), which act on IL-33, and the HpBARI family (HpBARI and HpBARI_Hom2), which act on ST2. Here, we find that this immunomodulation is evident only in the first week of infection, with abrogation of ST2 detection and systemic suppression of IL-33-dependent responses. Vaccination with individual HpARI or HpBARI family members raised antibody responses which could block these proteins’ immunomodulatory activities. During infection, vaccination could release the host from immunosuppression: HpARI2 vaccination resulted in much increased ILC2 and Th2 immunity, with heightened serum IL-4 and IL-5 responses, but did not abrogate ST2 suppression. In contrast, a HpBARI+HpBARI_Hom2 vaccination cocktail resulted in abrogation of ST2 suppression, and again increased Th2 immunity and serum cytokine responses. Either of the HpARI2 or the HpBARI cocktail vaccinations provided significant protection against subsequentH. polygyrus bakeriinfection. We therefore show a proof of principle that vaccination with immunomodulatory proteins can protect the host against infection, and can be used as a tool for blocking the effects of specific parasite-derived proteins.
Dysfunctional mechanotransduction regulates the progression of PIK3CA-driven vascular malformations
Authors: Aw Wen Yih , Sawhney Aanya , Rathod Mitesh , Whitworth Chloe P. , Doherty Elizabeth L. , Madden Ethan , Lu Jingming , Westphal Kaden , Stack Ryan , Polacheck William J. 
Published: August 2024

AbstractSomatic activating mutations inPIK3CAare common drivers of vascular and lymphatic malformations. Despite common biophysical signatures of tissues susceptible to lesion formation, including compliant extracellular matrix and low rates of perfusion, lesions vary in clinical presentation from localized cystic dilatation to diffuse and infiltrative vascular dysplasia. The mechanisms driving the differences in disease severity and variability in clinical presentation and the role of the biophysical microenvironment in potentiating progression are poorly understood. Here, we investigate the role of hemodynamic forces and the biophysical microenvironment in the pathophysiology of vascular malformations, and we identify hemodynamic shear stress and defective endothelial cell mechanotransduction as key regulators of lesion progression. We found that constitutive PI3K activation impaired flow-mediated endothelial cell alignment and barrier function. We show that defective shear stress sensing inPIK3CAE542Kendothelial cells is associated with reduced myosin light chain phosphorylation, junctional instability, and defective recruitment of vinculin to cell-cell junctions. Using 3D microfluidic models of the vasculature, we demonstrate thatPIK3CAE542Kmicrovessels apply reduced traction forces and are unaffected by flow interruption. We further found that draining transmural flow resulted in increased sprouting and invasion responses inPIK3CAE542Kmicrovessels. Mechanistically, constitutive PI3K activation decreased cellular and nuclear elasticity resulting in defective cellular tensional homeostasis in endothelial cells which may underlie vascular dilation, tissue hyperplasia, and hypersprouting inPIK3CA-driven venous and lymphatic malformations. Together, these results suggest that defective nuclear mechanics, impaired cellular mechanotransduction, and maladaptive hemodynamic responses contribute to the development and progression ofPIK3CA-driven vascular malformations.
Transmembrane channel-like 4 and 5 proteins at microvillar tips are potential ion channels and lipid scramblases
Authors: Ebrahim Seham , Ballesteros Angela , Sharon Zheng W. , Mukherjee Shounak , Hu Gaizun , Weng Wei-Hsiang , Montgomery Jonathan S. , Agyemang Yaw , Cui Runjia , Sun Willy , Krystofiak Evan , Foster Mark P. , Sotomayor Marcos , Kachar Bechara 
Published: August 2024

AbstractMicrovilli—membrane bound actin protrusions on the surface of epithelial cells—are sites of critical processes including absorption, secretion, and adhesion. Increasing evidence suggests microvilli are mechanosensitive, but underlying molecules and mechanisms remain unknown. Here, we localize transmembrane channel-like proteins 4 and 5 (TMC4 and 5) and calcium and integrin binding protein 3 (CIB3) to microvillar tips in intestinal epithelial cells, near glycocalyx insertion sites. We find that TMC5 colocalizes with CIB3 in cultured cells and that a TMC5 fragment forms a complex with CIB3in vitro. Homology and AlphaFold2 models reveal a putative ion permeation pathway in TMC4 and 5, and molecular dynamics simulations predict both proteins can conduct ions and perform lipid scrambling. These findings raise the possibility that TMC4 and 5 interact with CIB3 at microvillar tips to form a mechanosensitive complex, akin to TMC1 and 2, and CIB2 and 3, within the mechanotransduction channel complex at the tips of inner ear stereocilia.
CD4+T cells recruit, then engage macrophages in cognate interactions to clearMycobacterium tuberculosisfrom the lungs
Authors: Becker Samuel H , Ronayne Christine E , Bold Tyler D , Jenkins Marc K 
Published: August 2024

SummaryIFN-γ-producing CD4+T cells are required for protection against lethalMycobacterium tuberculosis(Mtb) infections. However, the ability of CD4+T cells to suppressMtbgrowth cannot be fully explained by IFN-γ or other known T cell products. In this study, we show that CD4+T cell-derived IFN-γ promoted the recruitment of monocyte-derived macrophages (MDMs) to the lungs ofMtb-infected mice. Although the recruited MDMs became quickly and preferentially infected withMtb, CD4+T cells rapidly disinfected the MDMs. Clearance ofMtbfrom MDMs was not explained by IFN-γ, but rather by MHCII-mediated cognate interactions with CD4+T cells. These interactions promoted MDM expression of glycolysis genes essential forMtbcontrol. Thus, by recruiting MDMs, CD4+T cells initiate a cycle of bacterial phagocytosis,Mtbantigen presentation and disinfection in an attempt to clear the bacteria from the lungs.