bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pancreatic Tumor Eradication via Selective PIN1 Inhibition in Cancer Associated Fibroblasts and T Lymphocytes Engagement
Authors: Liu Jiaye , Li Meng , Li Kewei , Wang Yang , Li Shan , Wu Wenshuang , Du Lingyao , Mu Chunyang , Zhang Xiaoyun , Li Chuan , Peng Wei , Shen Junyi , Liu Yang , Yang Dujiang , Zhang Kaixiang , Ning Qingyang , Fu Xiaoying , Zeng Yu , Ni Yinyun , Pan Qiuwei , Zhou Zongguang , Liu Yi , Hu Yiguo , Wen Tianfu , Li Zhihui , Liu Yong 
Published: February 2022

ABSTRACTCancer associated fibroblasts (CAFs) support tumors via multiple mechanisms, including maintaining the immunosuppressive tumor microenvironment and limiting infiltration of immune cells. The prolyl isomerase PIN1, whose overexpression in CAFs hasn’t been fully profiled yet, plays critical roles in tumor initiation and progression. To decipher effects of selective PIN1 inhibition in CAFs on pancreatic cancer, we formulate DNA-barcoded micellular systems (DMS) encapsulating PIN1 inhibitor. DMS functionalized with CAFs-targeting antibodies (antiCAFs-DMS) can selectively inhibit PIN1 in CAFs of the tumor, leading to efficacious but temporal tumor inhibitions. We further integrate DNA aptamers (AptT), which can engage CD8+ T lymphocytes, to antiCAFs-DMS and thus prepare the bispecific antiCAFs-DMS-AptT system. AntiCAFs-DMS-AptT shows its potent capacity to eradicate pre-established subcutaneous and orthotopic pancreatic cancer on mice.
Generative pretraining from large-scale transcriptomes: Implications for single-cell deciphering and clinical translation
Authors: Shen Hongru , Shen Xilin , Hu Jiani , Liu Jilei , Zhang Chao , Wu Dan , Feng Mengyao , Yang Meng , Li Yang , Yang Yichen , Wang Wei , Zhang Qiang , Yang Jilong , Chen Kexin , Li Xiangchun 
Published: February 2022

AbstractExponential accumulation of single-cell transcriptomes poses great challenge for efficient assimilation. Here, we present an approach entitledtGPTtowards integration of 22.3 million single-cell transcriptomes by modeling gene expression rankings as generative pretraining task.tGPTis conceptually simple in that it autoregressively models the ranking of a gene in the context of its preceding neighbors. We demonstrated the high performance oftGPTon a range of fundamental single-cell analysis tasks and novel applications on bulk tissues. The single-cell clusters and cell lineage trajectories derived fromtGPTare highly aligned with known cell labels and states. The feature patterns of tumor bulk tissues learned bytGPTare associated with a wide range of genomic alteration events, prognosis and treatment outcome of immunotherapy.tGPTrepresents a new analytical paradigm for integrating and deciphering massive amount of transcriptome data and it will facilitate the interpretation and clinical translation of single-cell transcriptomes.
The clinical impact of maternal COVID-19 on mothers, their infants, and placentas with an analysis of vertical transfer of maternal SARS-CoV-2-specific IgG antibodies
Authors: Ward JD , Cornaby C , Kato T , Gilmore RC , Bunch D , Miller MB , Boucher RC , Schmitz JL , Askin FA , Scanga LR 
Published: February 2022

ABSTRACTIntroductionThe effect of SARS-CoV-2 infection on pregnant mothers, the placenta, and infants is not fully understood and sufficiently characterized.MethodsWe performed a retrospective, observational cohort study in Chapel Hill, NC of 115 mothers with SARS-CoV-2 and singleton pregnancies from December 1, 2019 to May 31, 2021. We performed a chart review to document the infants’ weight, length, head circumference, survival, congenital abnormalities, and hearing loss, maternal complications, and placental pathology classified by the Amsterdam criteria.ResultsThe average infant weight, length, and head circumference were all within the normal range for gestational age, the infants had no identifiable congenital abnormalities, and all infants and mothers survived. Only one infant (0.870%) became infected with SARS-CoV-2. Moderate and severe maternal COVID-19 were associated with increased caesarean section, premature delivery, infant NICU admission, and maternal respiratory failure, and were more likely in Type 1 (p=0.0055) and Type 2 (p=0.0285) diabetic mothers. Most placentas (n=63, 54.8%) showed normal or non-specific findings, while a subset had mild maternal vascular malperfusion (n=26, 22.6%) and/or mild microscopic ascending intrauterine infection (n=28, 24.3%).DiscussionMost mothers with SARS-CoV-2 and their infants had a routine clinical course. Maternal SARS-CoV-2 infection was not associated with intrauterine fetal demise, infant death, congenital abnormalities, or hearing loss. Infant infection with SARS-CoV-2 was rare and not via the placenta. Most placentas had non-specific findings and a subset showed mild maternal vascular malperfusion and/or mild microscopic ascending intrauterine infection, which were not associated with maternal COVID-19 severity.
Unravelling the population structure and transmission patterns of Mycobacterium tuberculosis in Mozambique, a high TB/HIV burden country
Authors: Saavedra B. , López M.G. , Chiner-Oms Á. , García A.M. , Cancino I , Torres-Puente M. , Villamayor L. , Madrazo C. , Mambuque E. , Sequera VG. , Respeito D. , Blanco S. , Augusto O. , López-Varela E. , García-Basteiro AL. , Comas I. 
Published: February 2022

AbstractGenomic studies of Mycobacterium tuberculosis complex (MTBC) might shed light on the dynamics of its transmission, especially in high-burden settings, where recent outbreaks are embedded in the complex natural history of the disease. We applied Whole-genome sequencing (WGS) to characterize the local population of MTBC, unravel potential transmission links and evaluate associations with host and pathogen factors.MethodsA one-year prospective study was conducted in Mozambique, a high HIV/TB burden country. WGS was applied to 295 positive cultures. We combined phylogenetic, geographical and clustering analysis, and investigated associations between risk factors of transmission.FindingsA significant high proportion of strains were in recent transmission (45.5%). We fully characterized MTBC isolates by using phylogenetic approaches and dating evaluation. We found two likely endemic clades, comprised of 67 strains, belonging to L1.2, dating from the late XIX century and associated with recent spread among PLHIV.InterpretationOur results unveil the population structure of MTBC in our setting. The clustering analysis revealed an unexpected pattern of spread and high rates of progression, suggesting the failure of control measures. The long-term presence of local strains in Mozambique, which were responsible for large transmission among HIV/TB coinfected patients, hint at possible coevolution with sympatric host populations and challenge the role of HIV in TB transmission.FundingMinistry of Enterprise and Knowledge (Government of Catalonia & European Social Fund, AGAUR fellowship); European Research Council (ERC) European Union’s Horizon 2020.
Variation in English Covid booster uptake
Authors: Dropkin Greg 
Published: February 2022

AbstractIntroductionVariable and low takeup of the Covid booster is a recognised problem, associated with age, gender, ethnicity, and deprivation. Are there other relevant predictors?MethodsData was downloaded from the UK Government Coronavirus Dashboard for Middle Super Output Areas in England, along with demographic, employment, and health data from public sources. Mixed models with a random factor for Upper Tier Local Authority were analysed as quasibinomial Generalized Additive Models, and the estimated random factors were then fitted with Bayesian linear mixed models using flu vaccination uptake, change in public health budgets, vaccination centres, and Region.ResultsModels for the MSOA Covid 1st and 2nd vaccinations and the 3rd injection (including the booster), fit the data well. Index of Multiple Deprivation, proportion Aged 15-24 and 25-44, and ethnicity groupings Other White, Indian-Pakistani-Bangladeshi, and African-Caribbean-Other, are highly significant predictors of lower uptake. The estimated random factors vary widely amongst local authorities, and can be predicted by flu vaccine uptake, rise in public health budgets, and regional effects which are positive for London and South East, and negative for North West and North East. Vaccination centres did not reach 90% significance.DiscussionCovid vaccination rates at each stage are very well modelled if local authority random effects are included along with non-linear terms for demographic, employment and health data. Deprivation, younger age, and Other White, South Asian, and Afro-Caribbean ethnicities are associated with lower uptake. Modelling the local effects indicates that increasing public health budgets would improve vaccination uptake.
The role of CYP2C19 gene polymorphisms on antiplatelet activity of clopidogrel among Arabs: systematic review and meta-analysis
Authors: Alkattan Abdullah N. , Radwan Nashwa M. , Mahmoud Nagla E. , Alfaleh Amjad F. , Alfaifi Amal , Alabdulkareem Khaled I. 
Published: February 2022

AbstractThis study aimed to predict the preventive effect of clopidogrel against recurrent cardiovascular events (CVEs) among the Arab population carrying different CYP2C19 mutations and to determine the frequency of polymorphic alleles and genotypes of CYP2C19 among them. The review included all the studies that reported data related to the CYP2C19 polymorphisms among Arab populations. The review included Arab CVDs patients who are categorized into carriers (cases) and non-carriers (controls) of CYP2C19 alleles and used clopidogrel as secondary prophylaxis. The patients who had recurrent CVEs or had high on-treatment platelet reactivity (HTPR) while using clopidogrel treatment were described as (events). The results showed a significantly increased risk of recurrent CVDs events by about three folds was associated with carriers of CYP2C19*2 and CYP2C19*3 mutations compared to non-carriers (OR= 3.32, CI=1.94-5.67, and OR=3.53, CI=1.17-10.63 respectively). However, no significant difference was recorded between both studied groups regarding the presence of CYP2C19*17 mutation (OR=0.80, (CI=0.44-1.44). The results also revealed that 59 (4.16%) of Arabs carrying two CYP2C19*2 alleles (homozygous), and 356 (25.12%) have one CYP2C19*2 allele and one CYP2C19*1 allele (heterozygous). Moreover, 42 (2.96%) were carrying two CYP2C19*17 alleles (homozygous), and 262 (18.49%) were carrying one CYP2C19*17 allele and one wild-type allele of CYP2C19 (heterozygous). The most common CYP2C19 genotypes reported among Arabs was the wild-type *1/*1, of which 49.26% of them had the homozygous form of the CYP2C19*1 allele. The frequency of the CYP2C19*1 allele was 71.07%, followed by the CYP2C19*2 allele (16.73%) and CYP2C19*17 (12.21%), respectively. The CYP2C19*3 allele was detected rarely among Arabs (<1%) compared to CYP2C19*1, *2, and *17 alleles. The present study revealed that Arabs carrying CYP2C19*2 and CYP2C19*3 alleles may not respond to clopidogrel and may put those patients at risk of recurrent CVEs. Carriers of the CYP2C19*17 allele, on the other hand, did not show a significant role either in increasing or decreasing the antiplatelet efficacy of clopidogrel. The CYP2C19 genotypes including *1/*1, *1/*2, *1/*17, *2/*2, and *17/*17 are commonly distributed among the Arabs.
The tryptophan catabolite or kynurenine pathway in COVID-19 and critical COVID-19: a systematic review and meta-analysis
Authors: Almulla Abbas F. , Supasitthumrong Thitiporn , Tunvirachaisakul Chavit , Algon Ali Abbas Abo , Al-Hakeim Hussein K. , Maes Michael 
Published: February 2022

AbstractCoronavirus disease 2019 (COVID-19) is accompanied by activated immune-inflammatory pathways and oxidative stress, which both may induce indoleamine-2,3- dioxygenase (IDO), a key enzyme of the tryptophan (TRP) catabolite (TRYCAT) pathway. The aim of the current study was to systematically review and meta-analyze the TRYCAT pathway status including levels of TRP and kynurenine (KYN) and IDO activity, as assessed using the KYN/TRP ratio. This systematic review was performed in December 2021 and searched data in PubMed, Google Scholar, and Web of sciences. In our meta-analysis we included 14 articles which examine TRP and TRYCATs in COVID-19 patients versus non-COVID-19 controls, and severe/critical versus mild/moderate COVID-19. Overall, the analysis was performed on 1269 individuals, namely 794 COVID-19 patients and 475 controls. The results show a significant (p <0.0001) increase in the KYN/TRP ratio (standardized mean difference, SMD=1.099, 95% confidence interval, CI: 0.714; 1.484) and KYN (SMD= 1.123, 95% CI: 0.730;1.516) and significantly lower TRP ((SMD= - 1.002, 95%CI: -1.738; -0.266) in COVID-19 versus controls. The KYN/TRP ratio (SMD= 0.945, 95%CI: 0.629; 1.262) and KYN (SMD= 0.806, 95%CI: 0.462; 1.149) were also significantly (p <0.001) higher and TRP lower (SMD= -0.909, 95% CI: -1.569; -0.249) in severe/critical versus mild/moderate COVID-19. No significant difference was detected in the kynurenic acid (KA)/KYN ratio and KA between COVID-19 patients and controls. Our results indicate increased activity of the IDO enzyme in COVID-19 and in severe/critical patients. The TRYCAT pathway is probably implicated in the pathophysiology and progression of COVID-19 and may signal a worse outcome of the disease.One-sentence summaryThe current meta-analysis study revealed a significant increase in peripheral blood IDO activity and kynurenine levels and a significant reduction in tryptophan in COVID-19 versus controls and in severe/critical COVID-19 versus mild/moderate COVID-19.
Rare and population-specific functional variation across pig lines
Authors: Ros-Freixedes Roger , Valente Bruno D. , Chen Ching-Yi , Herring William O. , Gorjanc Gregor , Hickey John M , Johnsson Martin 
Published: February 2022

AbstractBackgroundIt is expected that functional, mainly missense and loss-of-function (LOF), and regulatory variants are responsible for phenotypic differences among breeds, genetic lines, and varieties of livestock and crop species that have undergone diverse selection histories. However, there is still limited knowledge about the existing missense and LOF variation in livestock commercial populations, in particular regarding population-specific variation and how it can affect applications such as across-breed genomic prediction.MethodsWe re-sequenced the whole genome of 7,848 individuals from nine commercial pig breeding lines (average sequencing coverage: 4.1x) and imputed whole-genome genotypes for 440,610 pedigree-related individuals. The called variants were categorized according to predicted functional annotation (from LOF to intergenic) and prevalence level (number of lines in which the variant segregated; from private to widespread). Variants in each category were examined in terms of distribution along the genome, minor allele frequency, Wright’s fixation index (FST), individual load, and association to production traits.ResultsOf the 46 million called variants, 28% were private (called in only one line) and 21% were widespread (called in all nine lines). Genomic regions with low recombination rate were enriched with private variants. Low-prevalence variants (called in one or a few lines only) were enriched for lower allele frequencies, lower FST, and putatively functional and regulatory roles (including loss-of-function and deleterious missense variants). Only a small subset of low-prevalence variants was found at intermediate allele frequencies and had large estimated effects on production traits. Individuals on average carried less private deleterious missense alleles than expected compared to other predicted consequence types. A small subset of low-prevalence variants with intermediate allele frequencies and higher FST were detected as significantly associated to the production traits and explained small fractions of phenotypic variance (up to 3.2%). These associations were tagged by other more widespread variants, including intergenic variants.ConclusionsMost low-prevalence variants are kept at very low allele frequency and only a small subset contributed detectable fractions of phenotypic variance. Not accounting for low-prevalence variants is therefore unlikely to hinder across-breed analyses, in particular for genomic prediction of breeding values using reference populations of a different genetic background.
Influenza virus-like particle-based hybrid vaccine containing RBD induces immunity against influenza and SARS-CoV-2 viruses
Authors: Bommireddy Ramireddy , Stone Shannon , Bhatnagar Noopur , Kumari Pratima , Munoz Luis E. , Oh Judy , Kim Ki-Hye , Berry Jameson T. L. , Jacobsen Kristen M. , Jaafar Lahcen , Naing Swe-Htet , Blackerby Allison N. , Gaag Tori Van der , Wright Chloe N. , Lai Lilin , Pack Christopher D. , Ramachandiran Sampath , Suthar Mehul S. , Kang Sang-Moo , Kumar Mukesh , Reddy Shaker J. C. , Selvaraj Periasamy 
Published: February 2022

AbstractSeveral approaches have produced an effective vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the influence of immune responses induced by other vaccinations on the durability and efficacy of the immune response to SARS-CoV-2 vaccine is still unknown. We have developed a hybrid vaccine for SARS-CoV-2 and influenza viruses using influenza virus-like particles (VLP) incorporated by protein transfer with glycosylphosphatidylinositol (GPI)-anchored SARS-CoV-2 S1 RBD fused to GM-CSF as an adjuvant. GPI-RBD-GM-CSF fusion protein was expressed in CHO-S cells, purified and incorporated onto influenza VLPs to develop the hybrid vaccine. Our results show that the hybrid vaccine induced a strong antibody response and protected mice from both influenza virus and mouse-adapted SARS-CoV-2 challenges, with vaccinated mice having significantly lower lung viral titers compared to naive mice. These results suggest that the hybrid vaccine strategy is a promising approach for developing multivalent vaccines to prevent influenza A and SARS-CoV-2 infections.
Epithelial uptake ofAspergillus fumigatusdrives efficient fungal clearancein vivoand is aberrant in Chronic Obstructive Pulmonary Disease (COPD)
Authors: Bertuzzi M. , Howell G.J. , Thomson D.D. , Fortune-Grant R. , Möslinger A. , Dancer P. , Van Rhijn N. , Motsi N. , Du X. , Codling A. , Sash R. , Demirbag M. , Bignell E.M. 
Published: February 2022

AbstractHundreds of spores of the common mouldAspergillusfumigatus (Af)are inhaled daily by human beings, representing a constant, often fatal, threat to our respiratory health. The small size ofAfspores suggest that interactions withAirwayEpithelialCells (AECs) are frequent and we and others have previously demonstrated that AECs are able to internaliseAfspores. We thus hypothesised thatAfspore uptake and killing by AECs is important for driving efficient fungal clearancein vivoand that defective spore uptake and killing would represent major risk factors forAspergillus-related diseases. In order to test this, we utilised single-cell approaches based onImagingFlowCytometry (IFC) and live-cell microfluidic imaging to measure spore uptake and outcomesin vitro,in vivoand using primary human AECs.In vitro, viability of immortalised AECs was largely unaffected byAfuptake and AECs were able to significantly curtail the growth of internalised spores. Applying our approach directly to infected mouse lungs we demonstrated, for the first time, thatAfspores are internalised and killed by AECs during whole animal infection, whereby only ~3% of internalised spores remained viable after 8 hours of co-incubation with murine AECs. Finally,in vitroanalysis of primary human AECs from healthy and at-risk donors revealed significant alterations in the uptake and consequent outcomes in Chronic Obstructive Pulmonary Disease (COPD), whereby gorging COPD-derived AECs were unable to quell intracellularAfas efficiently as healthy primary AECs. We have thus demonstrated that AECs efficiently killAfspores upon uptakein vivoand that this process is altered in COPD, a well-known risk factor for debilitating fungal lung disease, thereby suggesting that AECs critically contribute to the efficient clearance of inhaledAfspores and that dysregulation of curative AEC responses represents a potent driver ofAspergillus-related diseases.
Activation of a bacterial flow sensor by hypochlorous acid from stimulated neutrophils
Authors: Foik Ilona P. , Urban Lauren A. , Huang Andy P. , Downing Timothy L. , Siryaporn Albert 
Published: February 2022

ABSTRACTBacteria sense environmental stressors and activate responses to improve their survival in harsh growth conditions. Neutrophils respond to the presence of bacteria by producing oxidative antibacterial species including hypochlorous acid (HOCl). However, the extent that bacteria detect activated neutrophils or HOCl has not been known. Here, we report that the opportunistic bacterial pathogen Pseudomonas aeruginosa responds to activated neutrophils by activating the fro system, which regulates the expression of antioxidative factors. We show that this response is specific to HOCl and that other oxidative factors including H2O2, do not trigger a fro response. The fro system has been previously shown to detect flow that is present in host vasculature, such as in animal circulatory systems. Our data thus suggest a model in which fro serves as an early host detection system in P. aeruginosa that improves its survival against neutrophil-mediated defenses, which could promote colonization in human tissue and increase pathogenicity.One Sentence SummaryP. aeruginosa primes its defenses against neutrophils by sensing flow and hypochlorous acid via the fro system.