bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic perspectives of SARS CoV-2 in liver disease patients with its clinical correlation: A single centre retrospective study
Authors: Bhugra Arjun , Agarwal Reshu , Gautam Pramod , Suroliya Varun , Chhabra Ruchita , Pandey Amit , Garg Prince , Rao Pooja , Babu Rosmy , Kumar Guresh , Shastry SM , Bihari Chhagan , Sarin Shiv Kumar , Gupta Ekta 
Published: February 2023

ABSTRACTBackgroundSevere Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2), is a causative agent of current global pandemic of Coronavirus disease-19 (COVID-19). Due to propagated outbreak and global vaccination drive an immense immunological selection pressure has been exerted on SARS CoV-2 leading to evolution of new variants. This study was performed to compare the mutational and clinical profile of liver disease patients infected with different variants of SARS CoV-2.MethodologyThis was a single-centre, retrospective, cohort study in which clinicogenomic analysis of liver disease (LD) patients infected with SARS CoV-2 was performed. Complete demographic and clinical details were retrieved from Hospital Information System (HIS). QC-threshold passed FASTA files containing sequences from COVID-19 patients (n=174) were compared with a reference genome of SARS-CoV-2 isolate named Wuhan-Hu-1 (NCBI Reference Sequence: NC_045512.2) for mutational analysis.ResultsOut of 232 finally analysed patients 137 (59.1%) were LD-CoV (+) and 95 (40.9%) were LD-CoV(-). LD patients with comorbidities were affected more with COVID-19 (p=0.002). On comparing the outcome in the terms of mortality, LD-CoV (+) had 2.29 times (OR 2.29, CI 95%, 1.25-4.29) higher of odds of succumbing to COVID-19 (p=0.006). Multivariate regression analysis revealed, abdominal distention (p=0.05), severe COVID-19 pneumonia (p=0.046) and the change in serum bilirubin levels (p=0.005) as well as Alkaline phosphatase (ALP) levels (p=0.003) to have an association with adverse outcome in LD patients with COVID-19. In Delta (22%) and Omicron (48%) groups, Spike gene harboured maximum mutations. On comparing the mutations between LD-CoV(+/D) and LD-CoV(+/O) a total of nine genes had more mutations in LD-CoV(+/O) whereas three genes had more mutations in LD-CoV(+/D).ConclusionWe concluded that LD patients are more susceptible to COVID-19 as compared to a healthy adult with associated adverse clinical outcomes in terms of mortality and morbidity. Therefore this special group should be given priority while devising and introducing new vaccination and vaccination policies. The infection with different variants did not result in different outcome in our group of patients.
Bcl-2 supports survival and metabolic fitness of quiescent tissue-resident ILC3
Authors: King James I. , Melo-Gonzalez Felipe , Malengier-Devlies Bert , Tachó-Piñot Roser , Magalhaes Marlene S , Hodge Suzanne H. , Ros Xavier Romero , Gentek Rebecca , Hepworth Matthew R. 
Published: February 2023

AbstractGroup 3 innate lymphoid cells (ILC3) are potent effector cells with critical roles in enforcing immunity, barrier integrity and tissue homeostasis along the gastrointestinal tract. ILC3 are considered to be primarily tissue-resident cells, seeding the gastrointestinal tract during embryonic stages. However, the mechanisms through which ILC3 are maintained within these tissues are poorly understood. Here, we report that ILC3 are minimally replenished from bone marrow precursors in healthy adult mice, persist in the tissue for extended periods of time in the gut, and display a quiescent phenotype. Strikingly, despite robustly producing cytokines, LTi-like ILC3 remain non-proliferative during enteric bacterial infection. Survival of LTi-like ILC3 was found to be dependent upon the balance of the metabolic activity required to drive effector function and anti-apoptotic programs. Notably, the pro-survival protein Bcl-2 was required for the survival of LTi-like ILC3 but was rendered partially dispensable if mitochondrial respiration was inhibited. Together we demonstrate LTi-like ILC3 are a quiescent-like population that persists independently of haematopoietic replenishment to survive within the tissue microenvironment.
Revealing the chassis-effect on a broad-host-range genetic switch and its concordance with interspecies bacterial physiologies
Authors: Chan Dennis Tin Chat , Baldwin Geoff S. , Bernstein Hans C. 
Published: February 2023

ABSTRACTBroad-host-range synthetic biology is an emerging frontier that aims to expand our current engineerable domain of microbial hosts for biodesign applications. As more novel species are brought to “model status”, synthetic biologists are discovering that identically engineered genetic circuits can exhibit different performances depending on the organism it operates within, an observation referred to as the “chassis-effect”. It remains a major challenge to uncover which genome encoded and physiological biological determinants will underpin chassis effects that govern the performance of engineered genetic devices. In this study, we compared model and novel bacterial hosts to ask whether phylogenomic relatedness or similarity in host physiology is a better predictor of toggle switch performance. This was accomplished using comparative framework based on multivariate statistical approaches to systematically demonstrate the chassis-effect and characterize the performance dynamics of a genetic toggle switch operating within six Gammaproteobacteria. Our results solidify the notion that genetic devices are significantly impacted by host-context. Furthermore, we formally determined that hosts exhibiting more similar metrics of growth and molecular physiology also exhibit more similar toggle switch performance, indicating that specific bacterial physiology underpins measurable chassis effects. The result of this study contributes to the field of broad-host-range synthetic biology by lending increased predictive power to the implementation of genetic devices in less-established microbial hosts.
Nanoparticle targeting of mechanically modulated glycocalyx
Authors: Kohon Afia Ibnat , Man Kun , Mathis Katelyn , Webb Jade , Yang Yong , Meckes Brian 
Published: February 2023

ABSTRACTThe mechanical properties and forces in the extracellular environment surrounding alveolar epithelial cells have the potential to modulate their behavior. Particularly, breathing applies 3-dimensional cyclic stretches to the cells, while the stiffness of the interstitium changes in disease states, such as fibrosis and cancer. A platform was developed that effectively imitates the active forces in the alveolus, while allowing one to control the interstitium matrix stiffnesses to mimic fibrotic lung tumor microenvironments. Alveolar epithelial cancer cells were cultured on these platforms and changes in the glycocalyx expression were evaluated. A complex combination of stiffness and dynamic forces altered heparan sulfate and chondroitin sulfate proteoglycan expressions. Consequently, we designed liposomal nanoparticles (LNPs) modified with peptides that can target heparan sulphate and chondroitin sulfates of cell surface glycocalyx. Cellular uptake of these modified nanoparticles increased in stiffer conditions depending on the stretch state. Namely, chondroitin sulfate A targeting improved uptake efficiency in cells experiencing dynamic stretches, while cells seeded on static stiff interstitium preferentially took up heparan sulfate targeting LNPs. These results demonstrate the critical role that mechanical stiffness and stretching play in the alveolus and the importance of including these properties in nanotherapeutic design for cancer treatment.
Uncovering the hidden threat: single-organoid analysis reveals clinically relevant treatment-resistant and invasive subclones in pancreatic cancer
Authors: Compte Maxim Le , Cardenas De La Hoz Edgar , Peeters Sofía , Rodrigues Fortes Felicia , Hermans Christophe , Domen Andreas , Smits Evelien , Lardon Filip , Vandamme Timon , Lin Abraham , Vanlanduit Steve , Roeyen Geert , Van Laere Steven , Prenen Hans , Peeters Marc , Deben Christophe 
Published: February 2023

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, characterized by a treatment-resistant and invasive nature. In-line with these inherent aggressive characteristics, only a subset of patients show a clinical response to the standard of care therapies, thereby highlighting the need for a more personalized treatment approach. In this study, we comprehensively unraveled the intra-patient response heterogeneity and intrinsic aggressive nature of PDAC on bulk and single-organoid resolution. We leveraged a fully characterized PDAC organoid panel (N=8) and matched our artificial intelligence-driven, live-cell organoid image analysis with retrospective clinical patient response. In-line with the clinical outcomes, we identified patient-specific sensitivities to the standard of care therapies (gemcitabine-paclitaxel and FOLFIRINOX) using a growth rate-based and normalized drug response metric. Moreover, the single-organoid analysis was able to detect resistant as well as invasive PDAC organoid clones, which was orchestrates on a patient, therapy, drug, concentration and time-specific level. Furthermore, ourin vitroorganoid analysis indicated a strong correlation with the matched patient progression-free survival (PFS) compared to the current, conventional drug response readouts. This work not only provides valuable insights on the response complexity in PDAC, but it also highlights the potential applications (extendable to other tumor types) and clinical translatability of our approach in drug discovery and the emerging era of personalized medicine.
Kinematic markers of skill in first-person shooter video games
Authors: Warburton Matthew , Campagnoli Carlo , Mon-Williams Mark , Mushtaq Faisal , Morehead J. Ryan 
Published: February 2023

AbstractVideo games present a unique opportunity to study motor skill. First-person shooter (FPS) games have particular utility because they require visually-guided hand movements that are similar to widely studied planar reaching tasks. However, there is a need to ensure the tasks are equivalent if FPS games are to yield their potential as a powerful scientific tool for investigating sensorimotor control. Specifically, research is needed to ensure that differences in visual feedback of a movement do not affect motor learning between the two contexts. In traditional tasks, a movement will translate a cursor across a static background, whereas FPS games use movements to pan and tilt the view of the environment. To this end, we designed an online experiment where participants used their mouse or trackpad to shoot targets in both contexts. Kinematic analysis showed player movements were nearly identical between conditions, with highly correlated spatial and temporal metrics. This similarity suggests a shared internal model based on comparing predicted and observed displacement vectors, rather than primary sensory feedback. A second experiment, modelled on FPS-style aim-trainer games, found movements exhibited classic invariant features described within the sensorimotor literature. We found that two measures of mouse control, the mean and variability in distance of the primary sub-movement, were key predictors of overall task success. More broadly, these results show that FPS games offer a novel, engaging, and compelling environment to study sensorimotor skill, providing the same precise kinematic metrics as traditional planar reaching tasks.Significance statementSensorimotor control underpins human behaviour and is a predictor of education, health, and socioemotional wellbeing. First-person shooter (FPS) games hold promise for studying sensorimotor control at scale, but the visual feedback provided differs from traditional laboratory tasks. There is a need to ensure they provide measures that relate to traditional tasks. We designed an experiment where the visual contingency of movements could be varied whilst participants shot targets. Participant’s movements were similar between contexts, suggesting the use of a common internal model despite the sensory differences. A second experiment observed canonical learning patterns with practice and found two measures of mouse control strongly predicted overall performance. Our results highlight the opportunity offered by FPS games to study situated skilled behaviour.
A novel implementation of spinal fMRI demonstrates segmental organisation of functionally connected networks in the cervical spinal cord: A test-retest reliability study
Authors: Kowalczyk Olivia S. , Medina Sonia , Tsivaka Dimitra , McMahon Stephen B. , Williams Steven C. R. , Brooks Jonathan C. W. , Lythgoe David J. , Howard Matthew A. 
Published: February 2023

AbstractResting fMRI studies have identified intrinsic spinal cord activity, which forms organised motor (ventral) and sensory (dorsal) resting-state networks. However, to facilitate the use of spinal fMRI in, for example, clinical studies, it is crucial to first assess the reliability of the method, particularly given the unique anatomical, physiological, and methodological challenges associated with acquiring the data. Here we demonstrate a novel implementation for acquiring BOLD-sensitive resting-state spinal fMRI, which was used to characterise functional connectivity relationships in the cervical cord and assess their test-retest reliability in 23 young healthy volunteers. Resting-state networks were estimated in two ways: (1) by extracting the mean timeseries from anatomically constrained seed masks and estimating voxelwise connectivity maps and (2) by calculating seed-to-seed correlations between extracted mean timeseries. Seed regions corresponded to the four grey matter horns (ventral/dorsal and left/right) of C5-C8 segmental levels. Test-retest reliability was assessed using the intraclass correlation coefficient (ICC) in the following ways: for each voxel in the cervical spine; each voxel within an activated cluster; the mean signal as a summary estimate within an activated cluster; and correlation strength in the seed-to-seed analysis. Spatial overlap of clusters derived from voxelwise analysis between sessions was examined using Dice coefficients. Following voxelwise analysis, we observed distinct unilateral dorsal and ventral organisation of cervical spinal resting-state networks that was largely confined in the rostro-caudal extent to each spinal segmental level, with more sparse connections observed between segments (Bonferroni correctedp< 0.003, threshold-free cluster enhancement with 5000 permutations). Additionally, strongest correlations were observed between within-segment ipsilateral dorso-ventral connections, followed by within-segment dorso-dorsal and ventro-ventral connections. Test-retest reliability of these networks was mixed. Reliability was poor when assessed on a voxelwise level, with more promising indications of reliability when examining the average signal within clusters. Reliability of correlation strength between seeds was highly variable, with highest reliability achieved in ipsilateral dorso-ventral and dorso-dorsal/ventro-ventral connectivity. However, the spatial overlap of networks between sessions was excellent. We demonstrate that while test-retest reliability of cervical spinal resting-state networks is mixed, their spatial extent is similar across sessions, suggesting that these networks are characterised by a consistent spatial representation over time.
Smaug regulates germ plasm synthesis and primordial germ cell number in Drosophila embryos by repressing theoskarandbruno 1mRNAs
Authors: Siddiqui Najeeb U. , Karaiskakis Angelo , Goldman Aaron L. , Eagle Whitby V.I. , Smibert Craig A. , Gavis Elizabeth R. , Lipshitz Howard D. 
Published: February 2023

AbstractDuring Drosophila oogenesis, the Oskar (OSK) RNA-binding protein (RBP) determines the amount of germ plasm that assembles at the posterior pole of the oocyte. Here we identify the mechanisms that regulate theoskmRNA in the early embryo. We show that the Smaug (SMG) RBP is transported into the germ plasm of the early embryo where it accumulates in the germ granules. SMG binds to and represses translation of theoskmRNA itself as well as thebruno 1(bru1) mRNA, which encodes an RBP that we show promotes germ plasm production. Loss of SMG or mutation of SMG’s binding sites in theoskorbru1mRNAs results in ectopic translation of these transcripts in the germ plasm and excess PGCs. SMG therefore triggers a post-transcriptional regulatory pathway that attenuates germ plasm synthesis in embryos, thus modulating the number of PGCs.
The Big (Genetic) Sort? Reassessing Migration Patterns and Their Genetic Imprint in the UK
Authors: Furuya Shiro , Liu Jihua , Sun Zhongxuan , Lu Qiongshi , Fletcher Jason M. 
Published: February 2023

AbstractThis study reassesses Abdel Abdellaoui et al.’s findings that genetically selective migration may lead to persistent and accumulating socioeconomic and health inequalities between “types” (rich or poor) of places in the UK. Their work categorized migrants who moved to the same “type” of place (rich-to-rich or poor-to-poor) as non-migrants. We re-investigate the question of genetically selective migration by examining migration patterns between places rather than “place-types” and find genetic selectively inwhetherpeople migrate rather thanwhere. For example, we find evidence of positive selection of people with genetic variants correlated better education moving from rich to poor places with our measure of migration that was obscured in the earlier work that used a non-standard measure of migration.
Gene conversion drives allelic dimorphism in two paralogous surface antigens of the malaria parasiteP. falciparum
Authors: Letcher Brice , Maciuca Sorina , Iqbal Zamin 
Published: February 2023

AbstractWhile the malaria parasiteP. falciparumhas low average genome-wide diversity levels, likely due to its recent introduction from a gorilla-infecting ancestor (∼10,000-50,000 years ago), some genes display extremely high diversity levels. In particular, certain proteins expressed on the surface of human red-blood-cell-infecting merozoites (merozoite surface proteins, MSPs) possess exactly two deeply-diverged allelic forms that have not recombined. This phenomenon, called allelic dimorphism, is of considerable interest, but its origin and maintenance remains unknown.In this study, we analysed the dimorphism in two highly-variable and paralogous MSPs, DBLMSP and DBLMSP2. Despite thousands of available Illumina WGS datasets from malaria-endemic countries, diversity in these genes has been hard to fully characterise as reads containing highly-diverged alleles fail to align to the reference genome. To solve this, we developed a pipeline leveraging genome graphs, enabling us to genotype them at high accuracy and completeness in comparison to a state-of-the-art GATK-based pipeline.Using our newly-resolved sequences we found both genes are dimorphic in a specific protein domain (DBL), and that one of the two forms is shared across the genes. We identified clear evidence of non-allelic gene conversion between the two genes as the likely mechanism behind sharing, leading us to propose a new model for allelic dimorphism through gene conversion between diverged paralogs. This model is consistent with high diversity levels in these two genes despite the strong historicalP. falciparumtransmission bottleneck.
An interchangeable prion-like domain is required for Ty1 retrotransposition
Authors: Beckwith Sean L. , Nomberg Emily J. , Newman Abigail C. , Taylor Jeannette V. , Guerrero Ricardo C. , Garfinkel David J. 
Published: February 2023

AbstractRetrotransposons and retroviruses shape genome evolution and can negatively impact genome function.Saccharomyces cerevisiaeand its close relatives harbor several families of LTR-retrotransposons, the most abundant being Ty1 in several laboratory strains. The cytosolic foci that nucleate Ty1 virus-like particle (VLP) assembly are not well-understood. These foci, termed retrosomes or T-bodies, contain Ty1 Gag and likely Gag-Pol and the Ty1 mRNA destined for reverse transcription. Here, we report a novel intrinsically disordered N-terminalprion-likedomain (PrLD) within Gag that is required for transposition. This domain contains amino-acid composition similar to known yeast prions and is sufficient to nucleate prionogenesis in an established cell-based prion reporter system. Deleting the Ty1 PrLD results in dramatic VLP assembly and retrotransposition defects but does not affect Gag protein level. Ty1 Gag chimeras in which the PrLD is replaced with other sequences, including yeast and mammalian prionogenic domains, display a range of retrotransposition phenotypes from wildtype to null. We examine these chimeras throughout the Ty1 replication cycle and find that some support retrosome formation, VLP assembly, and retrotransposition, including the yeast Sup35 prion and the mouse PrP prion. Our interchangeable Ty1 system provides a useful, genetically tractablein vivoplatform for studying PrLDs, complete with a suite of robust and sensitive assays, and host modulators developed to study Ty1 retromobility. Our work invites study into the prevalence of PrLDs in additional mobile elements.SignificanceRetrovirus-like retrotransposons help shape the genome evolution of their hosts and replicate within cytoplasmic particles. How their building blocks associate and assemble within the cell is poorly understood. Here, we report a novelprion-likedomain (PrLD) in the budding yeast retrotransposon Ty1 Gag protein that builds virus-like particles. The PrLD has similar sequence properties to prions and disordered protein domains that can drive the formation of assemblies that range from liquid to solid. We demonstrate that the Ty1 PrLD can function as a prion and that certain prion sequences can replace the PrLD and support Ty1 transposition. This interchangeable system is an effective platform to study additional disordered sequences in living cells.