bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neonatal hepatic myeloid progenitors expand and propagate liver inflammation in mice
Authors: Alkhani Anas , Korsholm Cathrine , Mohamedaly Sarah , Levy Claire S. , Duwaerts Caroline C. , Pietras Eric M. , Nijagal Amar 
Published: June 2022

ABSTRACTBackground and AimsBiliary atresia is a rapidly progressive pediatric inflammatory disease of the liver that leads to cirrhosis and necessitates liver transplantation. The rapid progression from liver injury to fulminant liver failure in children with biliary atresia suggests that factors specific to the perinatal hepatic environment are important for disease propagation. Hematopoietic stem and progenitor cells (HSPCs) serve as central hubs of inflammation and rely on inflammatory signals for their emigration from the liver to the bone marrow in neonatal mice. We hypothesized that HSPCs are critical for the propagation of perinatal liver inflammation (PLI).MethodsNewborn BALB/c mice were injected intraperitoneally with 1.5×106 focus forming units of Rhesus Rotavirus (RRV) to induce PLI or with PBS as control. Livers from RRV- and PBS-injected mice were compared using histology and flow cytometry. To determine the effects of HSPCs on perinatal inflammation, RRV-infected neonatal mice were injected with anti-CD47 and anti-CD117 to deplete HSPCs.ResultsRRV-induced PLI led to a significant increase in the number of common myeloid progenitors (Flt3+ CMPs: PBS=4426±247.2 vs RRV=9856±2009, p=0.0316; Flt3- CMPs: PBS=3063±254.9 vs RRV=9743±1539, p=0.0012). We corroborated these findings by observing a significant increase in CD34+ hematopoietic progenitors/cm2 in histological sections of RRV-infected livers (PBS=4.977±2.573 vs RRV=27.09±12.49, p=0.0075). Elimination of progenitors through antibody-mediated myeloablation rescued animals from PLI and significantly increased survival (RRV+isotype control 55.56% vs RRV+myeloablation 94.12%, Chi-test=0.01).ConclusionsThese data demonstrate that RRV causes expansion of HSPCs and propagates PLI. Targeting of HSPCs may be useful in preventing and treating neonatal inflammatory diseases of the liver like biliary atresia.SYNOPSISHematopoietic progenitors reside in juvenile mouse livers even after the main site of hematopoiesis has shifted to the bone marrow. These progenitors are critical for the pathogenesis of perinatal liver inflammation as myeloablation rescues animals from disease.
Direct Generation of Protein Conformational Ensembles via Machine Learning
Authors: Janson Giacomo , Valdes-Garcia Gilberto , Heo Lim , Feig Michael 
Published: June 2022

ABSTRACTDynamics and conformational sampling are essential for linking protein structure to biological function. While challenging to probe experimentally, computer simulations are widely used to describe protein dynamics, but at significant computational costs that continue to limit the systems that can be studied. Here, we demonstrate that machine learning can be trained with simulation data to directly generate physically realistic conformational ensembles of proteins without the need for any sampling and at negligible computational cost. As a proof-of-principle a generative adversarial network based on a transformer architecture with self-attention was trained on coarse-grained simulations of intrinsically disordered peptides. The resulting model, idpGAN, can predict sequence-dependent ensembles for any sequence demonstrating that transferability can be achieved beyond the limited training data. idpGAN was also retrained on atomistic simulation data to show that the approach can be extended in principle to higher-resolution conformational ensemble generation.
aiCRISPRL: An Artificial Intelligence Platform for Stem Cell and Organoid Simulation with Extensive Gene Editing Capabilities
Authors: Danter WR 
Published: June 2022

ABSTRACTCRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated nuclease 9) provides powerful gene-editing tools that are applicable for gene therapy of a variety of diseases including, but not limited to cancer, rare diseases, and heart disease. In the current study, we first re-examined our artificial stem cell and organoid simulations that were generated by our literature validated DeepNEU AI platform from the perspective of gene-editing. We then evaluated the aiCRISPRL (aiCRISPR-Like) application of the DeepNEU platform by directly comparing the CRISPR-Cas9 gene-editing approach with the DeepNEU derived aiCRISPRL capabilities using artificial simulated HeLa cells (aiHeLa). To accomplish this, we evaluated the aiCRISPRL like capabilities of DeepNEU to introduce a series of specific mutations into the MutS homolog 2 (MSH2) gene to assess DNA Mismatch Repair (MMR). This approach permits a comparative assessment of CRISPR-Cas9 and aiCRISPRL technologies following the introduction of specific MSH2 mutations. When combined with our previous body of gene editing research, the current data indicates that aiCRISPRL is an advanced AI platform technology that can be used for rapid prototyping and multiple scenario simulation in genomic research to complement wet-lab based gene-editing technologies.
A wheat chromosome segment substitution line series supports characterisation and use of progenitor genetic variation
Authors: Horsnell Richard , Leigh Fiona J , Wright Tally IC , Burridge Amanda J , Ligeza Aleksander , Przewieslik-Allen Alexandra M. , Howell Philip , Uauy Cristobal , Edwards Keith J. , Bentley Alison R 
Published: June 2022

AbstractGenome-wide introgression and substitution lines have been developed in many plant species, enhancing mapping precision, gene discovery and the identification and exploitation of variation from wild relatives. Created over multiple generations of crossing and/or backcrossing accompanied by marker-assisted selection, the resulting introgression lines are a fixed genetic resource. In this study we report the development of spring wheat chromosome segment substitution lines generated to systematically capture genetic variation from tetraploid (Triticum turgidum ssp dicoccoides) and diploid (Aegilops tauschii) progenitor species. Generated in a common genetic background over four generations of backcrossing, the material is a base resource for the mapping and characterisation of wheat progenitor variation. To facilitate further exploitation the final population was genetically characterised using a high- density genotyping array and a range of agronomic and grain traits assessed to demonstrate the the potential use of the populations for trait localisation in wheat.
ExplorePipolin: reconstruction and annotation of bacterial mobile elements from draft genomes
Authors: Chuprikova L. , Mateo-Cáceres V. , de Toro M. , Redrejo-Rodríguez M. 
Published: June 2022

AbstractMotivationDetailed and accurate analysis of mobile genetic elements (MGEs) in bacteria is essential to deal with the current threat of multiresistant microbes. The overwhelming use of draft, contig-based genomes hinder the delineation of the genetic structure of these plastic and variable genomic stretches, as in the case of pipolins, a superfamily of MGEs that spans diverse integrative and plasmidic elements, characterized by the presence of a primer-independent DNA polymerase.ResultsExplorePipolin is a Python-based pipeline that screens for the presence of the element and performs its reconstruction and annotation. The pipeline can be used on virtually any genome from diverse organisms and of diverse quality, obtaining the highest-scored possible structure, and reconstructed out of different contigs if necessary. Then, predicted pipolin boundaries and pipolin encoded genes are subsequently annotated using a custom database, returning the standard file formats suitable for comparative genomics of this mobile element.AvailabilityAll code is available and can be accessed here: github.com/pipolinlab/ExplorePipolinContactmodesto.redrejo@uam.es
Reduction of a heme cofactor initiates N-nitroglycine degradation by NnlA
Authors: Strickland Kara A. , Holland Ashley A. , Trudeau Alan , Szlamkowicz Ilana , Beazley Melanie J. , Anagnostopoulos Vasileios A. , Graham David E. , Caranto Jonathan D. 
Published: June 2022

AbstractThe NnlA enzyme from Variovorax sp. strain JS1663 degrades the linear nitramine N-nitroglycine (NNG)—a natural product produced by some bacteria—to glyoxylate and nitrite (NO2−). Ammonium (NH4+) was predicted as the third product of this reaction. A source of non-heme FeII was shown to be required for initiation of NnlA activity. However, it was unclear if this FeII was being used as a metallocofactor or a reductant. This study reveals that NnlA contains a b-type heme cofactor. Reduction of this heme is required to initiate NnlA activity. Reduction can occur either by addition of a non-heme FeII source or by reduction with dithionite. Therefore, FeII is not an essential substrate for holoenzyme activity. Data are presented showing that reduced NnlA (FeII-NnlA) can catalyze at least 100 turnovers. In addition, this catalysis occurred in the absence of O2. Finally, NH4+ was verified as the third product, accounting for the complete nitrogen mass balance. Size exclusion chromatography showed that NnlA is a dimer in solution. Additionally, FeII-NnlA is oxidized by O2 and NO2− and binds carbon monoxide (CO) and nitric oxide (NO). These are characteristics shared with PAS domains; NnlA was previously shown to exhibit homology with such domains. Providing further evidence, a structural homology model of NnlA was generated based on the structure of the PAS domain from Pseudomonas aeruginosa Aer2. The structural homology model suggested His73 is the axial ligand of the NnlA heme. Site-directed mutagenesis of His73 to alanine decreased the heme occupancy of NnlA and eliminated NNG activity, providing evidence that the homology model is valid. We conclude that NnlA forms a homodimeric heme-binding PAS domain protein that requires reduction for initiation of the activity.ImportanceLinear nitramines are potential carcinogens. These compounds result from environmental degradation of high-energy cyclic nitramines and as by-products of carbon capture technologies. Mechanistic understanding of the biodegradation of linear nitramines is critical to inform approaches for their remediation. The best understood biodegradation of a linear nitramine is NNG degradation by NnlA from Variovorax sp. strain JS 1663; however, it is unclear why non-heme iron was required to initiate enzymatic turnover. This study shows that non-heme iron is unnecessary. Instead, our study reveals that NnlA contains a heme cofactor, the reduction of which is critical for activating NNG degradation activity. These studies constrain the proposals for NnlA reaction mechanisms, thereby informing mechanistic studies of degradation of anthropogenic nitramine contaminants. In addition, these results will future work to design biocatalysts to degrade these nitramine contaminants.
Demographic history and genetic structure in pre-Hispanic Central Mexico
Authors: Villa-Islas Viridiana , Izarraras-Gomez Alan , Larena Maximilian , Campos Elizabeth Mejía Perez , Sandoval-Velasco Marcela , Rodríguez-Rodríguez Juan Esteban , Bravo-Lopez Miriam , Moguel Barbara , Fregel Rosa , Tretmanis Jazeps Medina , Velázquez-Ramírez David Alberto , Herrera-Muñóz Alberto , Sandoval Karla , Nieves-Colón Maria A. , Zepeda Gabriela , Villanea Fernando A , Medina Eugenia Fernández Villanueva , Aguayo-Haro Ramiro , Valdiosera Cristina , Ioannidis Alexander , Moreno-Estrada Andrés , Jay Flora , Huerta-Sanchez Emilia , Sánchez-Quinto Federico , Ávila-Arcos María C. 
Published: June 2022

AbstractAridoamerica and Mesoamerica are two distinct cultural areas that hosted numerous pre-Hispanic civilizations between 2,500 BCE and 1,521 CE. The division between these regions shifted southward due to severe droughts ca. 1,100 years ago, allegedly driving demographic changes and population replacement in some sites in central Mexico. Here, we present shotgun genome-wide data from 12 individuals and 26 mitochondrial genomes from eight pre-Hispanic archaeological sites across Mexico, including two at the shifting border of Aridoamerica and Mesoamerica. We find population continuity spanning the climate change episode and a broad preservation of the genetic structure across present-day Mexico for the last 2,300 years. Lastly, we identify a contribution to pre-Hispanic populations of northern and central Mexico from an ancient unsampled ‘ghost’ population.
Beyond Drift Diffusion Models: Fitting a broad class of decision and RL models with HDDM
Authors: Fengler Alexander , Bera Krishn , Pedersen Mads L. , Frank Michael J. 
Published: June 2022

AbstractComputational modeling has become a central aspect of research in the cognitive neurosciences. As the field matures, it is increasingly important to move beyond standard models to quantitatively assess models with richer dynamics that may better reflect underlying cognitive and neural processes. For example, sequential sampling models (SSMs) are a general class of models of decision making intended to capture processes jointly giving rise to reaction time distributions and choice data in n-alternative choice paradigms. A number of model variations are of theoretical interest, but empirical data analysis has historically been tied to a small subset for which likelihood functions are analytically tractable. Advances in methods designed for likelihood-free inference have recently made it computationally feasible to consider a much larger spectrum of sequential sampling models. In addition, recent work has motivated the combination of SSMs with reinforcement learning (RL) models, which had historically been considered in separate literatures. Here we provide a significant addition to the widely used HDDM Python toolbox and include a tutorial for how users can easily fit and assess a (user extensible) wide variety of SSMs, and how they can be combined with RL models. The extension comes batteries included, including model visualization tools, posterior predictive checks, and ability to link trial-wise neural signals with model parameters via hierarchical Bayesian regression.
Host genetic variants regulates CCR5 expression on immune cells: a study in people living with HIV and healthy controls
Authors: dos Santos Jéssica C. , Zhang Zhenhua , van Eekeren Louise E. , Fok Ezio T. , Vadaq Nadira , van de Wijer Lisa , van der Heijden Wouter A. , Koeken Valerie A. C. M. , Koenen Hans J.P.M. , Mhlanga Musa , Netea Mihai G. , van der Ven André J. , Li Yang 
Published: June 2022

AbstractC-C chemokine receptor 5 (CCR5) is the main HIV co-receptor affecting susceptibility and disease course. Quantitative trait loci (QTL) mapping analysis was performed to assess genetic variants associated with CCR5 expression on circulating immune cells in 209 PLHIV using ART and 304 healthy controls, all of Western European ancestry. The proportions of CCR5 positive cells and CCR5 mean fluorescence intensity (MFI) were assessed by flow cytometry in monocytes and CD4+ and CD8+ T cell subsets using flow cytometry. We identified the rs60939770, which is an intergenic variant in cis-region to CCR5 gene not in linkage disequilibrium with CCR5d32, related to the proportion of CCR5+ memory T regulatory cells, both in PLHIV and healthy controls. Two genome-wide significant loci, in linkage equilibrium with CCR5d32, were found to be associated with CCR5 MFI of multiple subsets of mostly differentiated memory T cells in both groups. The expression of nearby chemokines receptors (CCR1, CCR2, CCR3, CCRL2), existing in the same the same topologically associating domain, were also influenced by these genetic variants. Furthermore, we show the genetic variants which modulate CCR5 surface expression affect the production of other inflammatory mediators, including monocyte- and lymphocyte-derived cytokines as well as CCL4 and IL-8. Our data indicate that the genetic regulation of CCR5 expression is cell-specific and affects the production of various inflammatory mediators.Author SummaryCCR5 plays a important role in the acquisition of HIV and it is associated to immune activation in people living with HIV (PLHIV). Using samples of cohorts composed of healthy individuals and PLHIV, we sought to map genomic regions that influence CCR5 expression on monocytes and subsets of CD4+ and CD8+ cells. We identified distinct genetic variants that are associated with CCR5 cell proportions or mean fluorescence intensity in subpopulations of T cells with memory functions in both healthy and PLHIV. The genetic variants also influenced the expression of other nearby chemokine receptors and the production of inflammatory mediators. Thus, we demonstrated that the genetic regulation of CCR5 expression is cell-type specific and may impact HIV susceptibility and disease progression.
In silico EsxG·EsxH Rational Epitope Selection: Candidate Epitopes for Vaccine Design against Pulmonary Tuberculosis
Authors: Martinez-Olivares Constanza Estefania , Hernández-Pando Rogelio , Mixcoha Edgar 
Published: June 2022

AbstractRational design of new vaccines against pulmonary tuberculosis is imperative. EsxG·EsxH complex is involved in metal uptake, drug resistance, and immune response evasion. These characteristics make it an ideal target for rational vaccine development. The aim of this study is to show the rational design of epitope-based peptide vaccines by using bioinformatics and structural vaccinology tools. A total of 4.15 µs of Molecular Dynamics simulations were carried out to describe the behavior in solution of heterodimer, single epitopes, and epitopes loaded into MHC-II complexes. In order to predict T and B cell epitopes for antigenic activation, bioinformatic tools were used. Hence, we propose three epitopes with the potential to design pulmonary tuberculosis vaccines. The possible use of the proposed epitopes includes subunit vaccines, as a booster in BCG vaccination to improve its immune response, as well as the generation of antibodies that interfere with the mycobacterium tuberculosis homeostasis, affecting its survival.
Pathogenic Rickettsia species evade autophagosomal maturation and reduce anti-microbicidal pro-inflammatory IL-1 responses to support their intracellular survival
Authors: Voss Oliver H. , Gaytan Hodalis , Rahman M. Sayeedur , Azad Abdu F. 
Published: June 2022

AbstractSpecies of genus Rickettsia are obligate intracellular bacterial parasites of a wide range of arthropod and vertebrate hosts. Some Rickettsia species are responsible for several serious human diseases. One fascinating feature of these stealthy group of pathogens is their ability to exploit host cytosolic defense responses to their benefits. However, the precise mechanism by which pathogenic Rickettsia elude host immune defense responses remains to be determined. Here, we observed that pathogenic R. typhi and R. rickettsii, but not non-pathogenic R. montanensis become ubiquitinated and induce autophagy upon entry into bone-marrow-derived macrophages. Moreover, unlike R. montanensis, R. typhi, and R. rickettsii colocalized with LC3B but not with Lamp2 upon host cell entry. Finally, we observed that pathogenic but not non-pathogenic Rickettsia reduce pro-inflammatory IL-1 responses. In sum, we identified a previously unappreciated pathway by which pathogenic, but not non-pathogenic, Rickettsia become ubiquitinated and induced autophagy, but avoided autophagolysosomal destruction as well as inflammasome-mediated anti-microbicidal IL-1 cytokine responses to establish an intracytosolic niche in macrophages.
Cohort Profile: Longitudinal population-based study of COVID-19 in UK adults (COVIDENCE UK)
Authors: Holt Hayley , Relton Clare , Talaei Mohammad , Symons Jane , Davies Molly R , Jolliffe David A , Vivaldi Giulia , Tydeman Florence , Williamson Anne E , Pfeffer Paul E , Orton Christopher , Ford David V , Davies Gwyneth A , Lyons Ronan A , Griffiths Christopher J , Kee Frank , Sheikh Aziz , Breen Gerome , Shaheen Seif O , Martineau Adrian R 
Published: June 2022

ABSTRACTBackgroundCoronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is estimated to have caused more than 18 million deaths worldwide as of end-May 2022.MethodsCOVIDENCE UK is a longitudinal population-based study that investigates risk factors for, and impacts of, COVID-19 in UK residents aged ≥16 years. A unique feature is the capacity to support trial-within-cohort studies to evaluate interventions for prevention of COVID-19 and other acute respiratory illnesses. Participants complete a detailed online baseline questionnaire capturing self-reported information relating to their socio-demographic characteristics, occupation, lifestyle, quality of life, weight, height, longstanding medical conditions, medication use, vaccination status, diet and supplemental micronutrient intake. Follow-up on-line questionnaires capturing incident symptoms of COVID-19 and other acute respiratory infections, incident swab test-confirmed COVID-19, doses of SARS-CoV-2 vaccine received, and quality of life are completed at monthly intervals.ResultsThe study was launched on 1st May 2020 and closed to recruitment on 6th October 2021. A total of 19,981 participants enrolled and consented to 5-year follow-up with medical record linkage. Their mean age was 59.1 years (range 16.0 to 94.4 years), 70.2% were female, and 93.7% identified their ethnic origin as White. Analyses conducted to date have provided key insights into risk factors for SARS-CoV-2 infection and COVID-19 disease, determinants of SARS-CoV-2 vaccine immunogenicity and efficacy, and impacts of COVID-19 on health economic outcomes. The cohort has also supported conduct of a Phase 3 randomised trial-within-cohort study (CORONAVIT) evaluating implementation of a test-and-treat approach to correcting sub-optimal vitamin D status on incidence and severity of acute respiratory infections, including COVID-19.ConclusionsThe COVIDENCE UK dataset represents a valuable resource containing granular information on factors influencing susceptibility to, and impacts of, COVID-19 in UK adults. Researchers wishing to access anonymised participant-level data should contacting the corresponding author for further information.
Metformin, empagliflozin and their combination modulate ex-vivo macrophage inflammatory gene expression
Authors: Arefin Adittya , Gage Matthew C. 
Published: June 2022

AbstractType-2 Diabetes Mellitus is a complex, chronic illness characterized by persistent high blood glucose levels. Patients can be prescribed anti-diabetes drugs as single agents or in combination depending on the severity of their condition. Metformin and empagliflozin are two commonly prescribed anti-diabetes drugs which reduce hyperglycemia, however their direct effects on macrophage inflammatory responses alone or in combination are unreported. Here we show that metformin and empagliflozin elicit proinflammatory responses on mouse bone-marrow derived macrophages with single agent challenge, which are modulated when added in combination. In-silico docking experiments suggested that empagliflozin can interact with both TLR2 and DECTIN1 receptors and we observed that both empagliflozin and metformin increase expression of Tlr2 and Clec7a. Thus, findings from this study suggest that metformin and empagliflozin as single agents or in combination can directly modulate inflammatory gene expression in macrophages and upregulate the expression of their receptors.