bluuebunny/crossref_metadata_2025_split huggingface dataset:
A large-scale Boolean model of the Rheumatoid Arthritis Fibroblast-Like Synoviocytes predicts drug synergies in the arthritic joint
Authors: Singh Vidisha , Naldi Aurelien , Soliman Sylvain , Niarakis Anna 
Published: January 2023

AbstractRheumatoid arthritis (RA) is a complex autoimmune disease with an unknown aetiology. However, rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) play a significant role in initiating and perpetuating destructive joint inflammation by expressing immuno-modulating cytokines, adhesion molecules, and matrix remodelling enzymes. In addition, RA-FLS are primary drivers of inflammation, displaying high proliferative rates and an apoptosis-resistant phenotype. Thus, RA-FLS-directed therapies could become a complementary approach to immune-directed therapies by predicting the optimal conditions that would favour RA-FLS apoptosis, limit inflammation, slow the proliferation rate and minimise bone erosion and cartilage destruction. In this paper, we present a large-scale Boolean model for RA-FLS that consists of five submodels focusing on apoptosis, cell proliferation, matrix degradation, bone erosion and inflammation. The five phenotype-specific submodels can be simulated independently or as a global model.In-silicosimulations and perturbations reproduced the expected biological behaviour of the system under defined initial conditions and input values. The model was then used to mimic the effect of mono or combined therapeutic treatments and predict novel targets and drug candidates through drug repurposing analysis.
Non-photosynthetic bacteria produce photocurrent mediated by NADH
Authors: Shlosberg Yaniv , Limwongyut Jakkarin , Moreland Alex S. , Bazan Guillermo C. 
Published: January 2023

AbstractIn recent years, the concern from the global climate change has driven an urgent need to develop clean energy technologies that do not involve combustion process that emit carbon into the atmosphere. A promising concept is microbial fuel cells that utilize bacteria as electron donors in a bio-electrochemical cell performing a direct electron transfer via conductive protein complexes or by secretion of redox active metabolites such as quinone or phenazine derivatives. In the case of photosynthetic bacteria (cyanobacteria) electrons can also be extracted from the photosynthetic pathway mediated mostly by NADH and NADPH. In this work, we show for the first time that the intact non-photosynthetic bacteriaEscherichia colican produce photocurrent that is enhanced upon addition of an exogenous electron mediator. Furthermore, we apply 2D-fluorescence measurement to show that NADH is released from the bacterial cells, which may apply as a native electron mediator in microbial fuel cells.
Large-scale in-cell photocrosslinking at single residue resolution reveals the molecular basis for glucocorticoid receptor regulation by immunophilins
Authors: Baischew Asat , Engel Sarah , Geiger Thomas M. , Hausch Felix 
Published: January 2023

AbstractThe large immunophilins FKBP51 and FKBP52 play key roles in the Hsp90-mediated maturation of steroid hormone receptors, which is crucial for stress-related disorders and correct sexual embryonic development, respectively1–3. A prominent regulatory target is the glucocorticoid receptor (GR), whose activation is repressed by FKBP514,5and facilitated by FKBP526,7. Despite their vital roles, the molecular modes of action of FKBP51 and FKBP52 are poorly understood since the transient key states of FKBP-mediated GR-regulation have remained experimentally elusive. Here we present the architecture and functional annotation of FKBP51-, FKBP52- and p23-containing Hsp90-apoGR preactivation complexes, trapped by systematic incorporation of photoreactive amino acids8,9inside human cells. The identified crosslinking sites depended on a functional Hsp90 chaperone cycle, were disrupted by GR activation, and clustered in characteristic patterns, defining the relative orientation and contact surfaces within the FKBP/p23-apoGR complexes. Strikingly, GR binding to the FKBPFK1but not the FKBPFK2domains were modulated by FKBP ligands, explaining the lack of FKBP51-mediated GR derepression by certain classes of FKBP ligands. These findings show how FKBP51 and FKBP52 differentially interact with the apoGR ligand binding domain, they explain the differentiated pharmacology of FKBP51 ligands, and provide a structural basis for the development of FKBP ligands with higher efficacy.
Determining latent features and forecasting of COVID-19 hospitalisations in Malaysia using a national patient assessment data platform: a study of machine learning modelling against expert system
Authors: Yee Hui-Jia , Boo Ivan , Tan Ian K.T. , Tan Jih Soong , Zakariah Helmi 
Published: January 2023

AbstractCOVID-19 had a severe impact on Malaysia, as cases increased dramatically as the pandemic spread. In order to combat the pandemic, the Ministry of Health has established a number of standard operating procedures (SOP) and started operating COVID-19 Assessment Centers (CAC). This study compares the expert system created using the current patient evaluation standards to the capabilities of machine learning approaches in capturing the potential of being admitted directly or during home quarantine, based on the different clinical symptoms and age group. Boruta is a feature selection method that is employed to rank and extract significant characteristics.Treatment for imbalance has been carried out by under-sampling with K-Means and over-sampling with SMOTE. It appeared that the machine learning method using Random Forest would perform better than the expert systems. There are five performance metrics used in this study, i.e. accuracy, precision, recall, F1-score, and specificity. This study focused to maximize the true positive rate while minimize the false negative rates, it is to make sure that the patient who really need to be hospitalized will not be missed out. Therefore, recall becomes the main evaluation metrics when comparing the machine learning model and the expert system. The results shown that the recall score for machine learning approach is vastly higher then of expert systems. For age group 18-59, machine learning has 32.75% recall more than the expert system to predict if a patient requires direct admission, while for age group more than 60, the recall of machine learning is 18.11% more than expert system. In addition, to predict if a patient require admission during their home quarantine due to their health deterioration, machine learning recorded 76.72% recall more than the expert system for patient aged 18 to 59, and 70.59% difference for patient more than 60 years old. This supports the potential application of machine learning for clinical decision making for COVID-19 patients.
Building resilient cervical cancer prevention through gender-neutral HPV vaccination
Authors: Man Irene , Georges Damien , Sankaranarayanan Rengaswamy , Basu Partha , Baussano Iacopo 
Published: January 2023

ABSTRACTThe COVID-19 pandemic has disrupted HPV vaccination programmes worldwide. Using an agent-based model, EpiMetHeos, recently calibrated to Indian data, we illustrate how shifting from girls-only (GO) to gender-neutral (GN) vaccination strategy could improve the resilience of cervical cancer prevention against disruption of HPV vaccination. In the base case of 5-year disruption with no coverage, shifting from GO to GN strategy under 60% coverage (before disruption) would increase the resilience, in terms of cervical cancer cases still prevented in the disrupted birth cohorts per 100,000 girls born, by 2.8-fold from 107 to 302 cases, and by 2.2-fold from 209 to 464 cases under 90% coverage. Furthermore, shifting to GN vaccination helped in reaching the WHO elimination threshold. Under GO vaccination with 60% coverage, the age-standardised incidence rate (ASIR) of cervical cancer in India in the long-term with vaccination decreased from 11.0 to 4.7 cases per 100,000 woman-years (above threshold), as compared to 2.8 cases (below threshold) under GN with 60% coverage and 2.4 cases (below threshold) under GN with 90% coverage. In conclusion, GN HPV vaccination is an effective strategy to improve the resilience to disruption of cancer prevention programmes and to enhance the progress towards cervical cancer elimination.
Assessment of Willingness to Receive COVID-19 Vaccine and Associated Factors among Teachers in Dambi Dollo Town, Qellem Wallaga Zone, Oromia Regional State, Ethiopia: Institution based cross sectional study
Authors: Shiferaw Desalegn , Melaku Chara , Assefa Lamessa , Kinati Tadele 
Published: January 2023

AbstractBackgroundCOVID-19 devastated the routine life of all human kind since its discovery in Wuhan, China in 2019 and caused by the severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infections. Vaccination is an effective means for controlling the communicability of the disease and every effort has to be done to increase the proportion of vaccinated people against COVID-19.ObjectiveThe main objective of this study was to assess the willingness of teachers to receive COVID-19 vaccine and its associated factors in dambi dollo town, 2022.MethodsSchool based cross sectional study design was applied. The data were collected self-administered questionnaire and analysed by SPSS version 23.0. Variables which showed association with dependent variable in the bivariate analyses at 0.25 were entered into multiple stepwise logistic regression model. P-Value 0.05 was considered statistically significant in this study. Adjusted Odds ratios together with corresponding 95% confidence intervals was used to interpret the findings.ResultsAbout 92% of the teachers in dambi dollo town have heard covid-19 vaccine and 67.2% of them know that the vaccine can prevent the COVID-19 disease. On the other hand 51 %(95%CI: 44.8, 57.2) of the respondents had good knowledge about COVID-19 vaccine. From the total 247 participants who have responded to our inquiry on their willing to receive the COVID-19 vaccine, 68.4% (95%CI: 62.5, 74.3) of them were willing to receive the vaccine immediately while the remaining were either not willing or not ready at the time of data collection. Those participants having good knowledge of the vaccine were about six times more willing to get vaccinated, (AOR=5.85, 95%CI: 2.74, 12.47) in comparison with those having poor knowledge of the vaccine.ConclusionIn conclusion, the level of willingness to receive the COVID-19 Vaccine was 68.4% and relatively low in the current study population and participants’ religion and knowledge status are the two variables significantly associated with willingness to receive the vaccine.
Biochemical and structural characterisation of a family GH5 cellulase from endosymbiont of shipwormP. megotara
Authors: Junghare Madan , Manavalan Tamilvendan , Fredriksen Lasse , Leiros Ingar , Altermark Bjørn , Eijsink Vincent G.H. , Vaaje-Kolstad Gustav 
Published: January 2023

AbstractCellulases play a key role in enzymatic conversion of plant cell-wall polysaccharides into simple and economically relevant sugars. The discovery of novel cellulases from exotic biological niches is of interest as they may present properties that are valuable in biorefining of lignocellulose. We have characterized a glycoside hydrolase 5 (GH5) domain of a bi-catalytic GH5-GH6 multidomain enzyme from the unusual bacterial endosymbiontTeredinibacter waterburyiof the wood-digesting shipwormPsiloteredo megotara. The cellulase enzyme,TwCel5, was produced with and without a native C-terminal family 10 carbohydrate-binding module belongs to GH5, subfamily 2. Both variants showed hydrolytic endo-activity on soluble substrates such as, β-glucan, carboxymethylcellulose and konjac glucomannan. However, low activity was observed towards a crystalline form of cellulose. Interestingly, when co-incubated with a cellulose active LPMO, a clear synergy was observed that boosted hydrolysis of crystalline cellulose. The crystal structure of the GH5 catalytic domain was solved to 1.0 Å resolution and revealed a substrate binding cleft containing a putative +3 subsite, which is uncommon in this enzyme family. The enzymeTwCel5 was active in a wide range of pH and temperatures and showed high tolerance for NaCl. This study provides an important advance on discovery new enzymes from shipworm and shed new light on biochemical and structural characterization of cellulolytic cellulase and showed boost in hydrolytic activity of cellulase on crystalline cellulose when co-incubated with cellulose active LPMO. These findings will be relevant for the development of future enzyme cocktail that may be useful for the biotechnological conversion of lignocellulose.
Early β-amyloid accumulation in the brain is associated with peripheral T cell alterations
Authors: Gericke Christoph , Kirabali Tunahan , Flury Roman , Mallone Anna , Rickenbach Chiara , Kulic Luka , Tosevski Vinko , Hock Christoph , Nitsch Roger M. , Treyer Valerie , Ferretti Maria Teresa , Gietl Anton 
Published: January 2023

ABSTRACTFast and minimally invasive approaches for early, preclinical diagnosis of neurodegenerative Alzheimer’s disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral β-amyloidosis, one of the pathological hallmarks of AD, has raised the question of whether immune markers could be used as proxies for β-amyloid accumulation in the brain. Here, we deploy multidimensional mass cytometry combined with unbiased machine learning techniques to immunophenotype peripheral blood mononuclear cells from study participants in cross-sectional and longitudinal cohorts. We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain β-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help in the future to identify and develop novel diagnostic tools for early AD assessment and to better understand clinical outcomes.
A hybrid approach for predicting multi-label subcellular localization of mRNA at genome scale
Authors: Choudhury Shubham , Bajiya Nisha , Patiyal Sumeet , Raghava Gajendra P. S. 
Published: January 2023

AbstractIn the past, number of methods have been developed for predicting single label subcellular localization of mRNA in a cell. Only limited methods had been built to predict multi-label subcellular localization of mRNA. Most of the existing methods are slow and cannot be implemented at transcriptome scale. In this study, a fast and reliable method had been developed for predicting multi-label subcellular localization of mRNA that can be implemented at genome scale. Firstly, deep learning method based on convolutional neural network method have been developed using one-hot encoding and attained an average AUROC - 0.584 (0.543 – 0.605). Secondly, machine learning based methods have been developed using mRNA sequence composition, our XGBoost classifier achieved an average AUROC - 0.709 (0.668 - 0.732). In addition to alignment free methods, we also developed alignment-based methods using similarity and motif search techniques. Finally, a hybrid technique has been developed that combine XGBoost models and motif-based searching and achieved an average AUROC 0.742 (0.708 - 0.816). Our method – MRSLpred, developed in this study is complementary to the existing method. One of the major advantages of our method over existing methods is its speed, it can scan all mRNA of a transcriptome in few hours. A publicly accessible webserver and a standalone tool has been developed to facilitate researchers (Webserver:https://webs.iiitd.edu.in/raghava/mrslpred/).Key PointsPrediction of Subcellular localization of mRNAClassification of mRNA based on Motif and BLAST searchCombination of alignment based and alignment free techniquesA fast method for subcellular localization of mRNAA web server and standalone software
Comparison of cell response to chromatin and DNA damage
Authors: Luzhin Artyom , Rajan Priyanka , Safina Alfiya , Leonova Katerina , Stablewski Aimee , Wang Jianmin , Pal Mahadeb , Kantidze Omar , Gurova Katerina 
Published: January 2023

AbstractDNA-targeting drugs may damage DNA or chromatin. Many anti-cancer drugs damage both, making it difficult to understand their mechanisms of action. Using molecules causing DNA breaks without altering nucleosome structure (bleomycin) or destabilizing nucleosomes without damaging DNA (curaxin), we investigated the consequences of DNA or chromatin damage in normal and tumor cells. As expected, DNA damage caused p53-dependent growth arrest followed by senescence. Chromatin damage caused higher p53 accumulation than DNA damage; however, growth arrest was p53-independent and did not result in senescence. Chromatin damage activated the transcription of multiple genes, including classical p53 targets, in a p53-independent manner. Although these genes were not highly expressed in basal conditions, they had chromatin organization around the transcription start sites (TSS) characteristic of most highly expressed genes and the highest level of paused RNA polymerase. We hypothesized that nucleosomes around the TSS of these genes were the most sensitive to chromatin damage. Therefore, nucleosome loss upon curaxin treatment would enable transcription without the assistance of sequence-specific transcription factors. We confirmed this hypothesis by showing greater nucleosome loss around the TSS of these genes upon curaxin treatment and activation of a p53-specific reporter in p53-null cells by chromatin-damaging agents but not DNA-damaging agents.
Insulin-mediated endothelin signaling is antiviral during West Nile virus infection
Authors: Trammell Chasity E. , Rowe Evelyn H. , Jones Brianne J. , Char Aditya B. , Fawcett Stephen , Ahlers Laura R.H. , Goodman Alan G. 
Published: January 2023

ABSTRACTWest Nile virus (WNV) is the most prevalent mosquito-borne virus in the United States with approximately 2,000 cases each year. There are currently no approved human vaccines and a lack of prophylactic and therapeutic treatments. Understanding host responses to infection may reveal potential intervention targets to reduce virus replication and disease progression. The use ofDrosophila melanogasteras a model organism to understand innate immunity and host antiviral responses is well established. Previous studies revealed that insulin-mediated signaling regulates WNV infection in invertebrates by regulating canonical antiviral pathways. Because insulin signaling is well-conserved across insect and mammalian species, we sought to determine if results usingD. melanogastercan be extrapolated for the analysis of orthologous pathways in humans. Here, we identify insulin-mediated endothelin signaling using theD. melanogastermodel and evaluate an orthologous pathway in human cells during WNV infection. We demonstrate that endothelin signaling reduces WNV replication through the activation of canonical antiviral signaling. Taken together, our findings show that endothelin-mediated antiviral immunity is broadly conserved across species and reduces replication of viruses that can cause severe human disease.IMPORTANCEArboviruses, particularly those transmitted by mosquitoes, pose a significant threat to humans and are an increasing concern because of climate change, human activity, and expanding vector-competent populations. West Nile virus is of significant concern as the most frequent mosquito-borne disease transmitted annually within the continental United States. Here, we identify a previously uncharacterized signaling pathway that impacts West Nile virus infection, namely endothelin signaling. Additionally, we demonstrate that we can successfully translate results obtained fromD. melanogasterinto the more relevant human system. Our results add to the growing field of insulin-mediated antiviral immunity and identifies potential biomarkers or intervention targets to better address West Nile virus infection and severe disease.
Human-derived cortical neurospheroids coupled to passive, high-density and 3D MEAs: a valid platform for functional tests
Authors: Muzzi L. , Di Lisa D. , Falappa M. , Pepe S. , Maccione A. , Pastorino L. , Martinoia S. , Frega M. 
Published: January 2023

AbstractWith the advent of human-induced pluripotent stem cells (hiPSCs) differentiation protocols, different methods to createin-vitrohuman-derived neuronal networks have been proposed. Although monolayer cultures represent a valid model, adding three-dimensionality would make them more representative of anin-vivoenvironment. Thus, human-derived neurospheroids and brain-organoids are becoming increasingly used forin-vitrodisease modeling. Achieving control over the final cell composition and investigating the exhibited electrophysiological activity is still a challenge. Thence, platforms capable of measuring and characterizing the functional aspects of these samples are needed. Here, we propose a method to rapid generate neurospheroids of human origin with control over cell composition that can be used for functional investigations. We show a characterization of the electrophysiological activity exhibited by the neurospheroids by presenting for the first-time results from the main micro-electrodes arrays (MEAs) types available on the market (passive electrode, C-MOS electrodes, 3D electrodes). Neurospheroids grown in free culture and transferred on MEA exhibited functional activity that can be chemically and electrically modulated. Our results indicates that this model holds great potential for in-depth study of signal transmission to drug screening, disease modeling and offers a reproducible and stable platform forin-vitrofunctional testing.
A standardised test to evaluate audio-visual speech intelligibility in French
Authors: Rhun Loïc Le , Llorach Gerard , Delmas Tanguy , Suied Clara , Arnal Luc H , Lazard Diane S 
Published: January 2023

ObjectiveLipreading, which plays a major role in the communication of the hearing impaired, lacked a French standardised tool. Our aim was to create and validate an audio-visual (AV) version of the French Matrix Sentence Test (FrMST).DesignVideo recordings were created by dubbing the existing audio files.SampleThirty-five young, normal-hearing participants were tested in auditory and visual modalities alone (Ao, Vo) and in AV conditions, in quiet, noise, and open and closed-set response formats.ResultsLipreading ability (Vo) varied from 1% to 77%-word comprehension. The absolute AV benefit was 9.25ℒdB SPL in quiet and 4.6ℒdB SNR in noise. The response format did not influence the results in the AV noise condition, except during the training phase. Lipreading ability and AV benefit were significantly correlated.ConclusionsThe French video material achieved similar AV benefits as those described in the literature for AV MST in other languages. For clinical purposes, we suggest targeting SRT80 to avoid ceiling effects, and performing two training lists in the AV condition in noise, followed by one AV list in noise, one Ao list in noise and one Vo list, in a randomised order, in open or close set-format.