bluuebunny/crossref_metadata_2025_split huggingface dataset:
The clinical and prognostic significance of Protein Arginine Deiminase 2 and 4 (PADI2 & PADI4) in colorectal cancer
Authors: Gijon Mohamed , Metheringham Rachael L , Toss Michael S , Paston Samantha J , Durrant Lindy G 
Published: August 2020

ABSTRACTAimsProtein arginine deiminase (PADs) are a family of enzymes that catalyse the post translational modification (PTM) of proteins. Association between PAD expression with clinicopathology, protein expression and outcome was determined.MethodsPADI2 and PADI4 expression was assessed immunohistochemically in a cohort of CRC patients.ResultsCRC tissues expressed variable levels of PADI2 which was mainly localised in the cytoplasm and correlated with patient survival (p=0.005); high expression increased survival time from 43.5 to 67.6 months. Expression of cytoplasmic PADI2 correlated with expression of nuclear β catenin, PADI4 and alpha-enolase. In contrast expression of nuclear PADI2 correlated with a decrease in survival (p=0.010), with high expression decreasing survival from 76.4 to 42.9 months. CRC tissues expressed variable levels of PADI4 in both the nucleus and cytoplasm. Expression of cytoplasmic PADI4 correlated with survival (p=0.001) with high expression increasing survival time from 48.1 to 71.8 months. Expression of cytoplasmic PADI4 correlated with expression of, nuclear β catenin, alpha-enolase (p≤0.0001,p=0.002) and the apoptotic related protein, Bcl-2. Expression of nuclear PADI4 also correlated with survival (p=0.011) with high expression of nuclear PADI4 increasing survival time from 55.4 to 74 months. Expression of nuclear PADI4 correlated with p53, alpha-enolase and Bcl-2. Multivariate analysis showed that TNM stage, cytoplasmic PADI2 and PADI4 remained independent prognostic factors in CRC. Both PADI2 and PADI4 are good prognostic factors in CRC.ConclusionsHigh expression of cytoplasmic PADI2, PADI4 and nuclear PADI4 were associated with an increase in overall survival.
An Analysis of Self-reported Longcovid Symptoms on Twitter
Authors: Singh Shubh Mohan , Reddy Chaitanya 
Published: August 2020

AbstractObjectivesA majority of patients suffering from acute COVID-19 are expected to recover symptomatically and functionally. However there are reports that some people continue to experience symptoms even beyond the stage of acute infection. This phenomenon has been called longcovid.Study designThis study attempted to analyse symptoms reported by users on twitter self-identifying as longcovid.MethodsThe search was carried out using the twitter public streaming application programming interface using a relevant search term.ResultsWe could identify 89 users with usable data in the tweets posted by them. A majority of users described multiple symptoms the most common of which were fatigue, shortness of breath, pain and brainfog/concentration difficulties. The most common course of symptoms was episodic.ConclusionsGiven the public health importance of this issue, the study suggests that there is a need to better study post acute-COVID symptoms.
The Prevalence of Non-Adherence in Patients with Resistant Hypertension: a Systematic Review and Meta-Analysis
Authors: Bourque Gabrielle , Ilin Julius Vladimir , Ruzicka Marcel , Davis Alexandra , Hundemer Gregory , Hiremath Swapnil 
Published: August 2020

ABSTRACTBackgroundResistant hypertension is quite prevalent and a risk factor for cardiovascular events. Patients with suspected resistant hypertension undergo more screening intensity for secondary hypertension, despite some of them being non-adherent to prescribed pharmacotherapy. The prevalence of non-adherence in this setting varies from about 5 to 80% in the published literature. Apart from the wide range, the relation between method of assessment and prevalence is not well established. Our objective was to establish the overall prevalence of non-adherence in the apparent treatment resistant hypertension population, explore causes of heterogeneity, and evaluate the effect of the method of assessment on the estimate of non-adherence.MethodsWe performed a systematic review and meta-analysis. MEDLINE, EMBASE Classic+EMBASE, Cochrane, CINAHL, and Web of Science were searched for relevant articles. Details about the method of adherence assessment were extracted from each included article and grouped into direct and indirect. Pooled analysis was performed using the random effects model and heterogeneity was explored with metaregression and subgroup analyses.ResultsThe literature search yielded 1428 studies, of which 36 were included. The pooled prevalence of non-adherence was 35% (95% confidence interval 25 – 46 %). For indirect methods of adherence assessment, it was 25% (95% CI 15 – 39 %), whereas for direct methods of assessment, it was 44% (95% CI 32 – 57 %). Metaregression suggested gender, age, and time of publication as potential factors contributing to the heterogeneity.ConclusionsNon-adherence to pharmacotherapy is quite common in resistant hypertension, with the prevalence varying with the methods of assessment.Brief SummaryResistant hypertension is known to be a risk factor for cardiovascular events. These patients also undergo higher screening intensity for secondary hypertension. However, not all patients with apparent treatment resistant hypertension have true resistant hypertension, with some of them being non-adherent to prescribed pharmacotherapy. This systematic review aims to establish the overall prevalence of non-adherence in the apparent treatment resistant hypertension population and assess the relative contributions of non-adherence assessed with direct and indirect measures.
Bidirectional associations between COVID-19 and psychiatric disorder: a study of 62,354 COVID-19 cases
Authors: Taquet Maxime , Luciano Sierra , R Geddes John , J Harrison Paul 
Published: August 2020

SummaryBackgroundAdverse mental health consequences of COVID-19, including anxiety and depression, have been widely predicted but not yet accurately measured. There are a range of physical health risk factors for COVID-19, but it is not known if there are also psychiatric risk factors.MethodsWe addressed both questions using cohort studies derived from an electronic health records (EHR) network of 69 million patients including over 62,000 cases of COVID-19. Propensity score matching was used to control for confounding by risk factors for COVID-19 and for more severe illness.FindingsIn patients with no prior psychiatric history, COVID-19 was associated with an increased incidence of psychiatric diagnoses in the three months after infection compared to 6 other health events (hazard ratio [95% CI] 2.1 [1.8–2.5] compared to influenza; 1.7 [1.5–1.9] compared to other respiratory tract infections; 1.6 [1.4–1.9] compared to skin infection; 1.6 [1.3–1.9] compared to cholelithiasis; 2.2 [1.9–2.6] compared to urolithiasis, and 2.1 [1.9–2.5] compared to fracture of a large bone; all p< 0.0001). The increase was greatest for anxiety disorders but also present for depression, insomnia, and dementia. The results were robust to several sensitivity analyses. There was a ∼30% reduction in psychiatric diagnoses in the total EHR population over the same period. A psychiatric diagnosis in the previous year was associated with a 65% higher incidence of COVID-19 (relative risk 1.65, 95% CI: 1.59–1.71, p< 0.0001). This was independent of known physical health risk factors for COVID-19.InterpretationCOVID-19 infection has both psychiatric sequelae and psychiatric antecedents. Survivors have an increased rate of new onset psychiatric disorders, and prior psychiatric disorders are associated with a higher risk of COVID-19. The findings have implications for research into aetiology and highlight the need for clinical services to provide multidisciplinary follow-up, and prompt detection and treatment.
Newborn dried blood spots for serological surveys of COVID-19
Authors: Liu Feimei , Nguyen Mytien , Vijayakumar Pavithra , Kaplan Alanna , Meir Amit , Dai Yile , Wang Eric , Walsh Hannah , Ring Aaron M. , Omer Saad B. , Farhadian Shelli F. 
Published: August 2020

AbstractThere is an urgent need for inexpensive, population-wide surveillance testing for COVID-19. We tested newborn dried blood spots (DBS) anti-SARS-COV-2 antibodies for all infants born at Yale from March-May 2020, and found that newborn DBS serologies reflect maternal and population-wide infection rates during the study period. This suggests a role for DBS in COVID-19 surveillance in areas where viral testing is limited.
Detection of Prenatal Alcohol Exposure Using Machine Learning Classification of Resting-State Functional Network Connectivity Data
Authors: Rodriguez Carlos I. , Vergara Victor , Davies Suzy , Calhoun Vince , Savage Daniel D. , Hamilton Derek A. 
Published: August 2020

ABSTRACTIntroductionPrevious work utilizing resting state fMRI to measure functional network connectivity in rodents with moderate prenatal alcohol exposure (PAE) revealed several sex- and region-dependent alterations in FNC implicating FNC as potential biomarker for PAE. Given that FNC is sensitive to neurological and psychiatric conditions in humans, here, we explore the use of previously acquired FNC data and machine learning methods to detect PAE among a sample of rodents exposed to moderate PAE and controls exposed to a saccharin solution.Materials & MethodsWe utilized previously acquired fMRI data from 48 adult rats 24 PAE (12 male 12 female) and 24 saccharin exposed (SAC) controls (12 male and 12 female) for classification. The entire data sample was utilized to perform binary classification (SAC or PAE) of FNC data with multiple support vector machine (SVM) kernels and out-of-sample cross-validation to evaluate classification performance.ResultsResults revealed accuracy rates of 62.5% for all samples, 58.3% for males, and 79.2% for females using a quadratic SVM kernel to classify moderate PAE from FNC data. In addition, brain networks localized to hippocampal and cortical regions contributed strongly to QSVM classifications.ConclusionOur results suggest overall modest classification performance of a QSVM to detect moderate PAE from FNC data gathered from adult rats, yet good performance among females. Further developments and refinement of the technique hold promise for the detection of PAE in earlier developmental time periods that potentially offer additional tools for the non-invasive detection of PAE from FNC data.IMPACT STATEMENTThe diagnosis of fetal alcohol spectrum disorders (FASDs) can be challenging in individuals who lack the hallmark facial dysmorphologies associated with heavy prenatal alcohol exposure (PAE). The absence of a diagnosis prevents individuals with PAE from receiving the treatment and services that improves quality of life outcomes. This research explores the use of preclinical functional network connectivity data and machine learning techniques as a novel and non-invasive means of detecting PAE. Our aim is to contribute basic science towards improving diagnostic strategies that can lead to securing timely and appropriate support for individuals with FASD and their caregivers.
Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses
Authors: Ramana Chilakamarti V. 
Published: August 2020

AbstractRespiratory virus infection is one of the leading causes of death in the world. Activation of the Jak-Stat pathway by Interferon-alpha/beta (IFN-α/β) in lung epithelial cells is critical for innate immunity to respiratory viruses. Genetic and biochemical studies have shown that transcriptional regulation by IFN-α/βrequired the formation of Interferon-stimulated gene factor-3 (ISGF-3) complex consisting of Stat1, Stat2, and Irf9 transcription factors. Furthermore, IFNα/βreceptor activates multiple signal transduction pathways in parallel to the Jak-Stat pathway and induces several transcription factors at mRNA levels resulting in the secondary and tertiary rounds of transcription. Transcriptional factor profiling in the transcriptome and RNA analysis revealed that Early growth response-1 (Egr-1) was rapidly induced by IFN-α/βand Toll-like receptor (TLR) ligands in multiple cell types. Studies in mutant cell lines lacking components of the ISGF-3 complex revealed that IFN-βinduction of Egr-1 was independent of Stat1, Stat2, or Irf9. Activation of the Mek/Erk-1/2 pathway was implicated in the rapid induction of Egr-1 by IFN-βin serum-starved mouse lung epithelial cells. Interrogation of multiple microarray datasets revealed that respiratory viruses including coronaviruses regulated Egr-1 expression in human lung cell lines. Furthermore, Egr-1 inducible genes including transcription factors, mediators of cell growth, and chemokines were differentially regulated in the human lung cell lines after coronavirus infection, and in the lung biopsies of COVID-19 patients. Rapid induction by interferons, TLR ligands, and respiratory viruses suggests a critical role for Egr-1 in antiviral response and inflammation with potential implications for human health and disease.
Designing Sub-20 nm Nanocarriers for Small Molecule Delivery: Interplay among Structural Geometry, Assembly Energetics, and Cargo Release Kinetics
Authors: Jung Benson T. , Lim Marc , Jung Katherine , Li Michael , Dong He , Dube Nikhil , Xu Ting 
Published: August 2020

AbstractBiological constraints in diseased tissues have motivated the need for small nanocarriers (10-30 nm) to achieve sufficient vascular extravasation and pervasive tumor penetration. This particle size limit is only an order of magnitude larger than small molecules, such that cargo loading is better described by co-assembly processes rather than simple encapsulation. Understanding the structural, kinetic, and energetic contributions of carrier-cargo co-assembly is thus critical to achieve molecular-level control and predictablein vivobehavior. These interconnected set of properties were systematically examined using sub-20 nm self-assembled nanocarriers known as three-helix micelles (3HM). Both hydrophobicity and the “geometric packing parameter” dictate small molecule compatibility with 3HM’s alkyl tail core. Planar obelisk-like apomorphine and doxorubicin (DOX) molecules intercalated well within the 3HM core and near the core-shell interface, forming an integral component to the co-assembly, as corroborated by small angle X-ray and neutron-scattering structural studies. DOX promoted crystalline alkyl tail ordering, which significantly increased (+63%) the activation energy of 3HM subunit exchange. Subsequently, 3HM-DOX displayed slow-release kinetics (t1/2=40 h) at physiological temperatures, with ~50x greater cargo preference for the micelle core as described by two drug partitioning coefficients (micellar core/shell Kp1~24, and shell/bulk solvent Kp2~2). The geometric and energetic insights between nanocarrier and their small molecule cargos developed here will aid in broader efforts to deconvolute the interconnected properties of carrier-drug co-assemblies, and to understand nanomedicine behavior throughout all the physical andin vivoprocesses they are intended to encounter.
Identification and characterization of phlorizin transporter fromArabidopsis thalianaand its application for phlorizin production inSaccharomyces cerevisiae
Authors: Belew Zeinu Mussa , Crocoll Christoph , Møller-Hansen Iben , Naesby Michael , Borodina Irina , Nour-Eldin Hussam Hassan 
Published: August 2020

AbstractBioengineering aimed at producing complex and valuable plant specialized metabolites in microbial hosts requires efficient uptake of precursor molecules and export of final products to alleviate toxicity and feedback inhibition. Plant genomes encode a vast repository of transporters of specialized metabolites that— due to lack of molecular knowledge—remains largely unexplored in bioengineering. Using phlorizin as a case study—an anti-diabetic and anti-cancerous flavonoid from apple—we demonstrate that brute-force functional screening of plant transporter libraries inXenopusoocytes is a viable approach to identify transporters for bioengineering. By screening 600Arabidopsistransporters, we identified and characterizedpurinepermease 8 (AtPUP8) as a bidirectional phlorizin transporter. Functional expression in the plasma membrane of a phlorizin-producing yeast strain increased phlorizin titer by more than 80 %. This study provides a generic approach for identifying plant exporters of specialized metabolites and demonstrates the potential of transport-engineering for improving yield in bioengineering approaches.
A fetal wave of human type-3 γδ T cells with restricted TCR diversity persists into adulthood
Authors: Tan Likai , Fichtner Alina Suzann , Bubke Anja , Odak Ivan , Schultze-Florey Christian , Koenecke Christian , Förster Reinhold , Jarek Michael , von Kaisenberg Constantin , Borchers Alina , Panzer Ulf , Krebs Christian , Ravens Sarina , Prinz Immo 
Published: August 2020

AbstractAccumulating evidence suggests that the human embryonic thymus produces distinct waves of innate effector γδ T cells. However, it is unclear whether this process comprises a dedicated subset of IL-17-producing γδ T (γδT17) cells, like reported in mice. Here we present a novel protocol for high-throughput paired γδ TCR-sequencing, which in combination with single-cell RNA-sequencing revealed a high heterogeneity of effector γδ T cell clusters. While immature γδ T cell clusters displayed mixed and diverse TCR, effector cell types in neonatal and adult blood segregated according to γδTCR usage. In adult samples, mature Vδ1+T cells segregated into exhausted PD-1hiand active PD-1lowclusters. Among Vγ9Vδ2+T cell subsets, we identified distinct PLZF-positive effector γδ T cell clusters with innate type-1 and type-3 T cell signatures that were already detectable in a public dataset of early embryonic thymus organogenesis. Together, this suggests that functionally distinct waves of human innate effector γδ T cells including CCR6+γδT17 cells develop in the early fetal thymus and persist into adulthood.
Alpha-1-antitrypsin and its variant-dependent role in COVID-19 pathogenesis
Authors: Stevens Christian S , Oguntuyo Kasopefoluwa Y , Kowdle Shreyas , Brambilla Luca , Haas Griffin , Gowlikar Aditya , Siddiquey Mohammed NA , Schilke Robert M , Woolard Matthew D , Zhang Hongbo , Acklin Joshua A , Ikegame Satoshi , Huang Chuan-Tien , Lim Jean K , Cross Robert W , Geisbert Thomas W , Ivanov Stanimir S , Kamil Jeremy P ,   the Alpha-1 Foundation, Lee Benhur 
Published: August 2020

ABSTRACTRationaleSARS-CoV-2 entry into host cells is facilitated by endogenous and exogenous proteases that proteolytically activate the spike glycoprotein and antiproteases inhibiting this process. Understanding the key actors in viral entry is crucial for advancing knowledge of virus tropism, pathogenesis, and potential therapeutic targets.ObjectivesWe aimed to investigate the role of naïve serum and alpha-1-antitrypsin (AAT) in inhibiting protease-mediated SARS-CoV-2 entry and explore the implications of AAT deficiency on susceptibility to different SARS-CoV-2 variants.FindingsOur study demonstrates that naïve serum exhibits significant inhibition of SARS-CoV-2 entry, with AAT identified as the major serum protease inhibitor potently restricting entry. Using pseudoparticles, replication-competent pseudoviruses, and authentic SARS-CoV-2, we show that AAT inhibition occurs at low concentrations compared with those in serum and bronchoalveolar tissues, suggesting physiological relevance. Furthermore, sera from subjects with an AAT-deficient genotype show reduced ability to inhibit entry of both Wuhan-Hu-1 (WT) and B.1.617.2 (Delta) but exhibit no difference in inhibiting B.1.1.529 (Omicron) entry.ConclusionsAAT may have a variant-dependent therapeutic potential against SARS-CoV-2. Our findings highlight the importance of further investigating the complex interplay between proteases, antiproteases, and spike glycoprotein activation in SARS-CoV-2 and other respiratory viruses to identify potential therapeutic targets and improve understanding of disease pathogenesis.
Contribution of resident and circulating precursors to tumor-infiltrating CD8+T cell populations in non-small cell lung cancer patients
Authors: Gueguen Paul , Metoikidou Christina , Dupic Thomas , Lawand Myriam , Goudot Christel , Baulande Sylvain , Lameiras Sonia , Lantz Olivier , Girard Nicolas , Seguin-Givelet Agathe , Lefevre Marine , Mora Thierry , Walczak Aleksandra M. , Waterfall Joshua J , Amigorena Sebastian 
Published: August 2020

AbstractTumor-infiltrating lymphocytes (TILs) in general, and CD8+TILs in particular, represent a favorable prognostic factor in non-small cell lung cancer (NSCLC). The tissue origin, regenerative capacities, and differentiation pathways of TIL subpopulations, however, remain poorly understood. Using a combination of single cell RNA and T cell receptor (TCR) sequencing, we investigate the functional organization of TIL populations in primary NSCLC. We identify two CD8+TIL subpopulations expressing memory-like gene modules: one is also present in blood (circulating precursors) and the other one in juxta-tumor tissue (tissue resident precursors). In tumors, these two precursor populations converge through a unique transitional state into terminally differentiated cells, often referred to as dysfunctional or exhausted. Differentiation is associated with TCR expansion, and transition from precursor to late differentiated states correlates with intratumor T cell cycling. These results provide a coherent working model for TIL origin, filiation and functional organization in primary NSCLC.
The immune response is a critical regulator of zebrafish retinal pigment epithelium regeneration
Authors: Leach Lyndsay L. , Hanovice Nicholas J. , George Stephanie M. , Gabriel Ana E. , Gross Jeffrey M. 
Published: August 2020

ABSTRACTLoss of the retinal pigment epithelium (RPE) due to dysfunction or disease can lead to blindness in humans. Harnessing the intrinsic ability of the RPE to self-repair is an attractive therapeutic strategy; however, mammalian RPE is limited in its regenerative capacity. Zebrafish possess tremendous intrinsic regenerative potential in ocular tissues, including the RPE, but little is known about the mechanisms that drive RPE regeneration. Here, utilizing zebrafish, we identified elements of the immune response as critical mediators of intrinsic RPE regeneration. Macrophages/microglia are responsive to RPE damage and are required for the timely progression of the regenerative response and our data highlight that inflammation post-RPE injury is also critical for normal RPE regeneration. To our knowledge, these data are the first to identify the molecular and cellular underpinnings of RPE regeneration in any system and hold significant potential for translational approaches aimed towards promoting a pro-regenerative environment in mammalian RPE.