bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of COVID-19 on Lipid Profile and its Correlation with Acute Phase Reactants
Authors: Malik Jahanzeb , Laique Talha , Ishaq Uzma , Ashraf Amna , Malik Asmara , Ali Mommana , Zaidi Syed Muhammad Jawad , Javaid Muhammad , Mehmood Asad 
Published: April 2021

AbstractBackground and ObjectiveCoronavirus disease 2019 (COVID-19) manifests as multiple clinical and pathological organ dysfunctions. It also disrupts metabolic profile due to the release of pro-inflammatory cytokines causing a systemic inflammation reaction. However, the development and correlation of dyslipidemia with acute phase reactants is unknown. This investigation was performed to assess the pathological alterations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein (HDL), triglycerides, and total cholesterol levels in COVID-19 patients.MethodsThis was a prospective study performed on real-world patients to assess serum levels of LDL-C, HDL, TG, TC on COVID-19 patients (mild: 319; moderate: 391; critical: 357) hospitalized at our center between April 2020 through January 2021. Age- and gender-matched controls who had their lipid profiles in the same period were included as the control group.ResultsLDL-C, HDL, TG, and TC levels were significantly lower in COVID-19 patients when compared with the control group (P < 0.001, 0.047, 0.045, < 0.001, respectively). All parameters decreased gradually with COVID-19 disease severity (LDL-C: median (IQR), mild: 98 (91,134); moderate: 97 (81,113); critical: 68 (68,83); HDL: mild: 45 (37,50); moderate: 46 (41,50); critical: 40 (37,46); TG: mild: 186 (150,245); moderate: 156 (109,198); critical: 111 (98,154); TC: mild: 224 (212,238); moderate: 212 (203,213); critical: 154 (125,187)). LDL-C, TC, and TG were inversely correlated with acute phase reactants (interleukin-6 (IL-6), Procalcitonin, C-reactive protein (CRP), and D-dimers). Logistic regression demonstrated lipid profile, thyroid profile, and acute phase reactants as predictors of severity of COVID-19 disease.ConclusionHypolipidemia develops in increasing frequency with severe COVID-19 disease. It inversely correlates with levels of acute-phase reactants, indicating SARS-COV-2 as the causative agent for alteration in lipid and thyroid levels.
Life without mismatch repair
Authors: Sanders Mathijs A. , Vöhringer Harald , Forster Victoria J. , Moore Luiza , Campbell Brittany B. , Hooks Yvette , Edwards Melissa , Bianchi Vanessa , Coorens Tim H. H. , Butler Timothy M. , Lee-Six Henry , Robinson Philip S. , Flensburg Christoffer , Bilardi Rebecca A. , Majewski Ian J. , Reschke Agnes , Cairney Elizabeth , Crooks Bruce , Lindhorst Scott , Stearns Duncan , Tomboc Patrick , McDermott Ultan , Stratton Michael R. , Shlien Adam , Gerstung Moritz , Tabori Uri , Campbell Peter J. 
Published: April 2021

AbstractMismatch repair (MMR) is a critical defence against mutation, but we lack quantification of its activity on different DNA lesions during human life. We performed whole-genome sequencing of normal and neoplastic tissues from individuals with constitutional MMR deficiency to establish the roles of MMR components, tissue type and disease state in somatic mutation rates. Mutational signatures varied extensively across genotypes, some coupled to leading-strand replication, some to lagging-strand replication and some independent of replication, implying that the various MMR components engage different forms of DNA damage. Loss ofMSH2orMSH6(MutSα), but notMLH1orPMS2(MutLα), caused 5-methylcytosine-dependent hypermutation, indicating that MutSα is the pivotal complex for repairing spontaneous deamination of methylated cytosines in humans. Neoplastic change altered the distribution of mutational signatures, particularly accelerating replication-coupled indel signatures. Each component of MMR repairs 1-10 lesions/day per normal human cell, and many thousands of additional events during neoplastic transformation.HighlightsMMR repairs 1-10 lesions/day in every normal cell and thousands more in tumor cellsMMR patterns and rates are shaped by genotype, tissue type and malignant transformationMSH2 and MSH6 are pivotal for repairing spontaneous deamination of methylated cytosineReplication indels and substitutions vary by leading versus lagging strand and genotype
Postnatal inflammation inApoe−/−mice is associated with immune training and atherosclerosis
Authors: Noye Ellesandra C. , Bekkering Siroon , Limawan Albert P. , Nguyen Maria U. , Widiasmoko Lisa K. , Lu Hui , Pepe Salvatore , Cheung Michael M. , Menheniott Trevelyan R. , Wallace Megan J , Moss Timothy J. , Burgner David P. , Short Kirsty R. 
Published: April 2021

AbstractBackground and aimsPreterm birth is associated with increased risk of cardiovascular disease (CVD). This may reflect a legacy of inflammatory exposures such as chorioamnionitis, that complicate pregnancies delivering preterm, or recurrent early-life infections, common in preterm infants. We previously reported that experimental chorioamnionitis followed by postnatal inflammation has additive and deleterious effects on atherosclerosis inApoe−/−mice. Here, we aimed to investigate whether innate immune training is a contributory inflammatory mechanism in this murine model of atherosclerosis.MethodsBone marrow-derived macrophages and peritoneal macrophages were isolated from 13 week-oldApoe−/−mice, previously exposed to prenatal intra-amniotic (experimental choriomanionitis) and/or repeated postnatal (peritoneal) lipopolysaccharide (LPS). Innate immune responses were assessed by cytokine responses following 24-hourex vivostimulation with toll-like receptor (TLR) agonists (LPS, Pam3Cys), and RPMI for 24 hours. Bone marrow progenitor populations were studied using flow cytometric analysis.ResultsFollowing postnatal LPS exposure, bone marrow-derived macrophages and peritoneal macrophages produced more pro-inflammatory cytokines following TLR stimulation than those from LPS unexposed mice, characteristic of a trained phenotype. Cytokine productionex vivocorrelated with atherosclerosis severityin vivo. Prenatal LPS did not affect cytokine production capacity. Combined prenatal and postnatal LPS exposure was associated with a reduction in common myeloid progenitor cells in the bone marrow.ConclusionsPostnatal inflammation results in a trained phenotype in atherosclerosis-prone mice that is not enhanced by prenatal inflammation. If analogous mechanisms occur in humans, then there may be novel early life opportunities to reduce CVD risk in infants with early life infections.
Palaeogenomic analysis of black rat (Rattus rattus) reveals multiple European introductions associated with human economic history
Authors: Yu He , Jamieson Alexandra , Hulme-Beaman Ardern , Conroy Chris J. , Knight Becky , Speller Camilla , Al-Jarah Hiba , Eager Heidi , Trinks Alexandra , Adikari Gamini , Baron Henriette , Böhlendorf-Arslan Beate , Bohingamuwa Wijerathne , Crowther Alison , Cucchi Thomas , Esser Kinie , Fleisher Jeffrey , Gidney Louisa , Gladilina Elena , Gol’din Pavel , Goodman Steven M. , Hamilton-Dyer Sheila , Helm Richard , Hillman Chris , Kallala Nabil , Kivikero Hanna , Kovács Zsófia E. , Karl Kunst Günther , Kyselý René , Linderholm Anna , Maraoui-Telmini Bouthéina , Morales-Muñiz Arturo , Nabais Mariana , O’Connor Terry , Oueslati Tarek , Quintana Morales Eréndira M. , Pasda Kerstin , Perera Jude , Perera Nimal , Radbauer Silvia , Ramon Joan , Rannamäe Eve , Sanmartí Grego Joan , Treasure Edward , Valenzuela-Lamas Silvia , van der Jagt Inge , Van Neer Wim , Vigne Jean-Denis , Walker Thomas , Wynne-Jones Stephanie , Zeiler Jørn , Dobney Keith , Boivin Nicole , Searle Jeremy B. , Krause-Kyora Ben , Krause Johannes , Larson Greger , Orton David 
Published: April 2021

AbstractThe distribution of the black rat (Rattus rattus) has been heavily influenced by its association with humans. The dispersal history of this non-native commensal rodent across Europe, however, remains poorly understood, and different introductions may have occurred during the Roman and medieval periods. Here, in order to reconstruct the population history of European black rats, we generated ade novogenome assembly of the black rat, 67 ancient black rat mitogenomes and 36 ancient nuclear genomes from sites spanning the 1st-17thcenturies CE in Europe and North Africa. Analyses of mitochondrial DNA confirm that black rats were introduced into the Mediterranean and Europe from Southwest Asia. Genomic analyses of the ancient rats reveal a population turnover in temperate Europe between the 6thand 10thcenturies CE, coincident with an archaeologically attested decline in the black rat population. The near disappearance and re-emergence of black rats in Europe may have been the result of the breakdown of the Roman Empire, the First Plague Pandemic, and/or post-Roman climatic cooling.
Repression of CHROMOMETHYLASE 3 Prevents Epigenetic Collateral Damage in Arabidopsis
Authors: Papareddy Ranjith K. , Páldi Katalin , Smolka Anna D. , Hüther Patrick , Becker Claude , Nodine Michael D. 
Published: April 2021

ABSTRACTDNA methylation has evolved to silence mutagenic transposable elements (TEs) while typically avoiding the targeting of endogenous genes. Mechanisms that prevent DNA methyltransferases from ectopically methylating genes are expected to be of prime importance during periods of dynamic cell cycle activities including plant embryogenesis. However, virtually nothing is known regarding how DNA methyltransferase activities are precisely regulated during embryogenesis to prevent the induction of potentially deleterious and mitotically stable genic epimutations. Here, we report that microRNA-mediated repression of CHROMOMETHYLASE 3 (CMT3) and the chromatin features that CMT3 prefers help prevent ectopic methylation of thousands of genes during embryogenesis that can persist for weeks afterwards. Moreover, CMT3-induced ectopic methylation of genes undergoing transcriptional activation can reduce their corresponding transcript levels. Therefore, the repression of CMT3 prevents epigenetic collateral damage on endogenous genes. We also provide a model that may help reconcile conflicting viewpoints regarding the functions of gene-body methylation that occurs in nearly all flowering plants.
Specific transcriptomic signatures and dual regulation of steroidogenesis between fetal and adult mouse Leydig cells
Authors: Sararols Pauline , Stévant Isabelle , Neirijnck Yasmine , Rebourcet Diane , Darbey Annalucia , Curley Michael K. , Kühne Françoise , Dermitzakis Emmanouil , Smith Lee B. , Nef Serge 
Published: April 2021

AbstractLeydig cells (LC) are the main testicular androgen-producing cells. In eutherian mammals, two types of LCs emerge successively during testicular development, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs). Both display significant differences in androgen production and regulation. Using bulk RNA sequencing, we compared the transcriptomes of both LC populations to characterise their specific transcriptional and functional features. Despite similar transcriptomic profiles, a quarter of the genes show significant variations in expression between FLCs and ALCs. Non-transcriptional events, such as alternative splicing was also observed, including a high rate of intron retention in FLCs compared to ALCs. The use of single-cell RNA sequencing data also allowed the identification of nine FLC-specific genes and 50 ALC-specific genes. Expression of the corticotropin-releasing hormone 1 (Crhr1) receptor and the ACTH receptor melanocortin type 2 receptor (Mc2r) specifically in FLCs suggests a dual regulation of steroidogenesis. The androstenedione synthesis by FLCs is stimulated by luteinizing hormone (LH), CRH and ACTH whereas the testosterone synthesis by ALCs is dependent exclusively on LH. Overall, our study provides a useful database to explore LC development and function.
Disruption of the surfactant protein A receptor SP-R210L(CD245α/MYO18Aα) alters respiratory function and iron sequestration in alveolar macrophages of aged mice
Authors: Yau Eric , Umstead Todd M , Abdulqadir Raz , Fino Kristin , Guan Zhiwei , Hu Sanmei , DiAngelo Susan , Hassan Kavitha , Bingaman Sarah S. , Atkins Hannah , Cooper Timothy K , Arnold Amy C. , Halstead E. Scott , Chroneos Zissis C. 
Published: April 2021

ABSTRACTPrevious studies demonstrated that the host defense collectins, surfactant protein A and complement component 1q, modulate tissue-dependent macrophage activation, pathogen clearance, and regulatory macrophage functions through the receptor SP-R210, which consists of two isoforms SP-R210Land SP-R210S. These isoforms are encoded by alternatively spliced mRNAs of theMyo18a MYO18Agene in mice and humans. The present study in conditional transgenic mice revealed novel age-related functions of the SP-R210Lisoform in modulating pulmonary mechanics, iron sequestration in alveolar macrophages (AMs), and life-long maintenance of the alveolar macrophage population. Our findings support the novel idea that SP-R210L-deficient AMs undergo bi-directional epigenetic adaptation that results in chronic dysregulation of broncho-alveolar function, immune homeostasis, and maintenance of oncotic balance at the airway-capillary interface. Disruption of SP-R210Lincreases the risk for development of severe interstitial lung disease during development and aging.
Mapping Transcription Factor-Nucleosome Dynamics from Plasma cfDNA
Authors: Rao Satyanarayan , Han Amy L. , Zukowski Alexis , Kopin Etana , Sartorius Carol A. , Kabos Peter , Ramachandran Srinivas 
Published: April 2021

AbstractCell-free DNA (cfDNA) contains a composite map of the epigenomes of its cells-of-origin. Tissue-specific transcription factor (TF) binding inferred from cfDNA could enable us to track disease states in humans in a minimally invasive manner. Here, by enriching for short cfDNA fragments, we directly map TF footprints at single binding sites from plasma. We show that the enrichment of TF footprints in plasma reflects the binding strength of the TF in cfDNA tissue-of-origin. Based on this principle, we were able to identify the subset of genome-wide binding sites for selected TFs that leave TF-specific footprints in plasma. These footprints enabled us to not only identify the tissue-of-origin of cfDNA but also map the chromatin structure around the factor-bound sites in their cells-of-origin. To ask if we can use these plasma TF footprints to map cancer states, we first defined pure tumor TF signatures in plasmain vivousing estrogen receptor-positive (ER+) breast cancer xenografts. We found that the tumor-specific cfDNA protections of ER-α could distinguish WT, ER-amplified, and ER-mutated xenografts. Further, tumor-specific cfDNA protections of ER-α and FOXA1 reflect TF-specific accessibility across human breast tumors, demonstrating our ability to capture tumor TF binding in plasma. We then scored TF binding in human plasma samples and identified specific binding sites whose plasma TF protections can identify the presence of cancer and specifically breast cancer. Thus, plasma TF footprints enable minimally invasive mapping of the regulatory landscape of cancer in humans.
Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation
Authors: Sarode Gaurav V. , Neier Kari , Shibata Noreene M. , Shen Yuanjun , Goncharov Dmitry A , Goncharova Elena A. , Mazi Tagreed A. , Joshi Nikhil , Settles Matthew L. , LaSalle Janine M. , Medici Valentina 
Published: April 2021

AbstractThe pathogenesis of Wilson disease (WD) is multi-factorial, involving hepatic and brain copper accumulation due to pathogenic variants affecting theATP7Bgene and downstream epigenetic and metabolic mechanisms. Prior DNA methylation investigations in human WD liver and blood and in a WD mouse model revealed an epigenetic signature of WD, including alterations in the histone deacetylase HDAC5. To test the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD, we investigated class IIa histone deacetylases (HDAC4 and HDAC5) and H3K9/H3K27 histone acetylation in the Jackson Laboratory toxic milk (tx-j) mouse model of WD compared to C3HeB/FeJ (C3H) control in response to 3 treatments: 60% kcal fat diet (HFD), D-penicillamine (PCA, copper chelator), and choline (methyl group donor). HDAC5 levels significantly increased in 9-week tx-j livers after 8 days of HFD compared to chow. In 24-week tx-j livers, HDAC4/5 levels were reduced 5- to 10-fold compared to C3H likely through mechanisms involving HDAC phosphorylation. HDAC4/5 levels were also affected by disease progression and accompanied by increased acetylation. PCA and choline partially restored HDAC4, HDAC5, H3K9ac, and H3K27ac levels to that of CH3 liver. Integrated RNA and chromatin immunoprecipitation sequencing analyses revealed genes regulating energy metabolism and cellular stress/development were, in turn, regulated by histone acetylation in tx-j mice compared to C3H, withPparαandPparγamong the most relevant targets. These results suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation, can regulate gene expression in key metabolic pathways in the pathogenesis of WD.Significance StatementWilson disease is considered a monogenic disease caused by pathogenic variants in the ATP7B copper transporter, resulting in hepatic and brain copper accumulation. Given the lack of genotype-phenotype correlation, evidence of epigenetic and metabolic mechanisms regulating phenotype in patients and in animal models could explain the high phenotype variability observed in WD. In this study, we identify class IIa histone deacetylases as players involved in the epigenetic regulation of key metabolic pathways that can affect WD severity as well as targets sensitive to dietary modulations, which is an important characteristic for designing effective and feasible therapies. Understanding the epigenetic mechanisms in WD pathogenesis contributes to a better understanding of the phenotypic variability in WD and other common liver conditions.
α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response
Authors: Delaidelli Alberto , Richner Mette , Jiang Lixiang , van der Laan Amelia , Christiansen Ida Bergholdt Jul , Ferreira Nelson , Nyengaard Jens R. , Vægter Christian B. , Jensen Poul H. , Mackenzie Ian R. , Sorensen Poul H. , Jan Asad 
Published: April 2021

ABSTRACTCircumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbolSNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleionpathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2) is recognized as ‘the master regulator of cellular anti-oxidant response’, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, Prnp-SNCA*Ala53Thr), which manifest widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.
Chlamydia coinfection inhibits HPV-induced safeguards of the cellular and genomic integrity in patient-derived ectocervical organoids
Authors: Koster Stefanie , Gurumurthy Rajendra Kumar , Berger Hilmar , Drabkina Marina , Mollenkopf Hans-Joachim , Goosmann Christian , Brinkmann Volker , Nagel Zachary , Mangler Mandy , Meyer Thomas F , Chumduri Cindrilla 
Published: April 2021

AbstractCervical mucosa is continually confronted by coinfections with pathogenic microbes. In addition to human papillomavirus, coinfections withChlamydia trachomatishave been associated with an increased risk of cervical cancer. However, the dynamics of coinfections, their impact on the epithelia, and their contribution to pathogenesis remain obscure. Using a novel human ectocervical squamous stratified epithelial organoids, we recapitulated the natural infections of the cervix by Chlamydia, HPV, and their coinfections. Towards this, we genetically manipulated the healthy organoids to mimic in vivo HPV persistence by introducing E6E7 oncogenes into the host genome. HPV persistent organoids show enhanced tissue regeneration, increased proliferation and differentiation of stem cells, and nuclear atypia resembling cervical intraepithelial neoplasia grade 1. We found that HPV interferes with normal Chlamydia development. Further, a unique transcriptional host response induced by Chlamydia and HPV leads to distinct reprogramming of host cell processes. Strikingly, in coinfections, Chlamydia impedes HPV-induced mechanisms that maintain cellular and genome integrity, including mismatch repair (MMR). Distinct post-translational proteasomal-degradation and E2F-mediated transcriptional regulation delineate the inverse regulation of MMR during coinfections. Our study employing organoids demonstrates the jeopardy of multiple sequential infection processes and the unique cellular microenvironment they create, accelerating neoplastic progression.
Use of extreme risk protection orders to reduce gun violence in Oregon
Authors: Zeoli April M. , Paruk Jennifer , Branas Charles C. , Carter Patrick M. , Cunningham Rebecca , Heinze Justin , Webster Daniel W. 
Published: April 2021

Research SummaryWe examined petition and respondent characteristics from extreme risk protection order (ERPO) cases in Oregon for the 15 months after implementation (n = 93). Most petitions were filed by law enforcement (65%) a were more likely to be granted than petitions filed by family/household members (p < 0.001). Most ERPO respondents were reported by petitioners to have histories of suicidality (73%) or interpersonal violence (75%), with over half of death threats, suicide threats, or suicide attempts with known timing occurring within 1 week of the petition being filed.Policy ImplicationsERPO petitions and orders are overwhelmingly being used as intended, that is, specifically for cases of imminent risk of harm to self or others. Greater dissemination of public information about ERPOs may increase their appropriate use and the proportion of high‐risk individuals and families who may benefit. Legal aid assistance for family or household members in filling out petitions is advisable.