bluuebunny/crossref_metadata_2025_split huggingface dataset:
Statin associated lower cancer risk and related mortality in patients with heart failure
Authors: Ren Qing-Wen , Yu Si-Yeung , Teng Tiew-Hwa Katherine , Li Xue , Cheung Ka-Shing , Wu Mei-Zhen , Li Hang-Long , Wong Pui-Fai , Tse Hung-Fat , Lam Carolyn S P , Yiu Kai-Hang 
Published: May 2021

Abstract

Aims
Patients with heart failure (HF) have an increased risk of incident cancer. Data relating to the association of statin use with cancer risk and cancer-related mortality among patients with HF are sparse.

Methods and results
Using a previously validated territory-wide clinical information registry, statin use was ascertained among all eligible patients with HF (n = 87 102) from 2003 to 2015. Inverse probability of treatment weighting was used to balance baseline covariates between statin nonusers (n = 50 926) with statin users (n = 36 176). Competing risk regression with Cox proportional-hazard models was performed to estimate the risk of cancer and cancer-related mortality associated with statin use. Of all eligible subjects, the mean age was 76.5 ± 12.8 years, and 47.8% was male. Over a median follow-up of 4.1 years (interquartile range: 1.6–6.8), 11 052 (12.7%) were diagnosed with cancer. Statin use (vs. none) was associated with a 16% lower risk of cancer incidence [multivariable adjusted subdistribution hazard ratio (SHR) = 0.84; 95% confidence interval (CI), 0.80–0.89]. This inverse association with risk of cancer was duration dependent; as compared with short-term statin use (3 months to &lt;2 years), the adjusted SHR was 0.99 (95% CI, 0.87–1.13) for 2 to &lt;4 years of use, 0.82 (95% CI, 0.70–0.97) for 4 to &lt;6 years of use, and 0.78 (95% CI, 0.65–0.93) for ≥6 years of use. Ten-year cancer-related mortality was 3.8% among statin users and 5.2% among nonusers (absolute risk difference, −1.4 percentage points [95% CI, −1.6% to −1.2%]; adjusted SHR = 0.74; 95% CI, 0.67–0.81).

Conclusion
Our study suggests that statin use is associated with a significantly lower risk of incident cancer and cancer-related mortality in HF, an association that appears to be duration dependent.
Age-related functional changes of intestinal flora in rats
Authors: Yang Yuping , Chen Tianlu , Zhang Xia , Wang Xiaoyan 
Published: May 2021

ABSTRACTIntestinal flora structure and function change with age and have been associated with a variety of aging-related diseases. Until now, how age affects the functions of gut bacteria has not been fully understood. We used 16S-rRNA-sequencing technology and PICRUSt2 analysis to predict the functions encoded by intestinal flora in male Wistar rats across lifespan. We found that the abundance of gut microbiota genes encoding the L-tryptophan, L-histidine, L-leucine, inositol and catechol degradation pathways as well as L-arginine, ectoine, flavin and ubiquinol synthesis pathways increased with age. Differential analysis of the associated genera revealed that Rhodococcus spp. were significantly abundant during middle-old aged stage. This genus contributed greatly to the L-tryptophan, catechol and inositol degradation pathways as well as ectoine and L-arginine biosynthesis pathways. We concluded that gut bacteria-encoded functions such as amino acid metabolism, B vitamin metabolism, aromatic compound metabolism and energy metabolism varied in an age-dependent manner, and Rhodococcus spp. were the most associated functional bacteria in middle-old aged rats. These may be closely associated with the physiological phenotype of the aging process, which offers new insights for evaluating the relationship between intestinal flora and aging.
DNA methylation profiling of a cnidarian-algal symbiosis using nanopore sequencing
Authors: Dimond James L , Nguyen Nhung , Roberts Steven B 
Published: May 2021

Abstract
Symbiosis with protists is common among cnidarians such as corals and sea anemones and is associated with homeostatic and phenotypic changes in the host that could have epigenetic underpinnings, such as methylation of CpG dinucleotides. We leveraged the sensitivity to base modifications of nanopore sequencing to probe the effect of symbiosis with the chlorophyte Elliptochloris marina on methylation in the sea anemone Anthopleura elegantissima. We first validated the approach by comparison of nanopore-derived methylation levels with CpG depletion analysis of a published transcriptome, finding that high methylation levels are associated with CpG depletion as expected. Next, using reads generated exclusively from aposymbiotic anemones, a largely complete draft genome comprising 243 Mb was assembled. Reads from aposymbiotic and symbiotic sea anemones were then mapped to this genome and assessed for methylation using the program Nanopolish, which detects signal disruptions from base modifications as they pass through the nanopore. Based on assessment of 452,841 CpGs for which there was adequate read coverage (approximately 8% of the CpGs in the genome), symbiosis with E. marina was, surprisingly, associated with only subtle changes in the host methylome. However, we did identify one extended genomic region with consistently higher methylation among symbiotic individuals. The region was associated with a DNA polymerase zeta that is noted for its role in translesion synthesis, which opens interesting questions about the biology of this symbiosis. Our study highlights the power and relative simplicity of nanopore sequencing for studies of nucleic acid base modifications in non-model species.
DNA templates with blocked long 3ʹ end single-stranded overhangs (BL3SSO) promote bona fide Cas9-stimulated homology-directed repair of long transgenes into endogenous gene loci
Authors: Bandyopadhyay Saptaparni , Douglass Joseph , Kapell Sebastian , Khan Nazimuddin , Feitosa-Suntheimer Fabiana , Klein Jenny A , Temple Jasmine , Brown-Culbertson Jayce , Tavares Alexander H , Saeed Mohsan , Lau Nelson C 
Published: May 2021

Abstract
Knock-in of large transgenes by Cas9-mediated homology-directed repair (HDR) is an extremely inefficient process. Although the use of single-stranded oligonucleotides (ssODN) as an HDR donor has improved the integration of smaller transgenes, they do not support efficient insertion of large DNA sequences. In an effort to gain insights into the mechanism(s) governing the HDR-mediated integration of larger transgenes and to improve the technology, we conducted knock-in experiments targeting the human EMX1 locus and applied rigorous genomic PCR analyses in the human HEK293 cell line. This exercise revealed an unexpected molecular complication arising from the transgene HDR being initiated at the single homology arm and the subsequent genomic integration of plasmid backbone sequences. To pivot around this problem, we devised a novel PCR-constructed template containing blocked long 3' single-stranded overhangs (BL3SSO) that greatly improved the efficiency of bona fide Cas9-stimulated HDR at the EMX1 locus. We further refined BL3SSO technology and successfully used it to insert GFP transgenes into two important interferon-stimulated genes (ISGs) loci, Viperin/RSAD2, and ISG15. This study demonstrates the utility of the BL3SSO platform for inserting long DNA sequences into both constitutive and inducible endogenous loci to generate novel human cell lines for the study of important biological processes.
Environmentally contingent control of Candida albicans cell wall integrity by transcriptional regulator Cup9
Authors: Ichikawa Yuichi , Bruno Vincent M , Woolford Carol A , Kim Hannah , Do Eunsoo , Brewer Grace C , Mitchell Aaron P 
Published: May 2021

Abstract
The fungal pathogen Candida albicans is surrounded by a cell wall that is the target of caspofungin and other echinocandin antifungals. Candida albicans can grow in several morphological forms, notably budding yeast and hyphae. Yeast and hyphal forms differ in cell wall composition, leading us to hypothesize that there may be distinct genes required for yeast and hyphal responses to caspofungin. Mutants in 27 genes reported previously to be caspofungin hypersensitive under yeast growth conditions were all caspofungin hypersensitive under hyphal growth conditions as well. However, a screen of mutants defective in transcription factor genes revealed that Cup9 is required for normal caspofungin tolerance under hyphal and not yeast growth conditions. In a hyphal-defective efg1Δ/Δ background, Cup9 is still required for normal caspofungin tolerance. This result argues that Cup9 function is related to growth conditions rather than cell morphology. RNA-seq conducted under hyphal growth conditions indicated that 361 genes were up-regulated and 145 genes were down-regulated in response to caspofungin treatment. Both classes of caspofungin-responsive genes were enriched for cell wall-related proteins, as expected for a response to disruption of cell wall integrity and biosynthesis. The cup9Δ/Δ mutant, treated with caspofungin, had reduced RNA levels of 40 caspofungin up-regulated genes, and had increased RNA levels of 8 caspofungin down-regulated genes, an indication that Cup9 has a narrow rather than global role in the cell wall integrity response. Five Cup9-activated surface-protein genes have roles in cell wall integrity, based on mutant analysis published previously (PGA31 and IFF11) or shown here (ORF19.3499, ORF19.851, or PGA28), and therefore may explain the hypersensitivity of the cup9Δ/Δmutant to caspofungin. Our findings define Cup9 as a new determinant of caspofungin susceptibility.
Parallel and population-specific gene regulatory evolution in cold-adapted fly populations
Authors: Huang Yuheng , Lack Justin B , Hoppel Grant T , Pool John E 
Published: May 2021

AbstractChanges in gene regulation at multiple levels may comprise an important share of the molecular changes underlying adaptive evolution in nature. However, few studies have assayed within- and between-population variation in gene regulatory traits at a transcriptomic scale, and therefore inferences about the characteristics of adaptive regulatory changes have been elusive. Here, we assess quantitative trait differentiation in gene expression levels and alternative splicing (intron usage) between three closely related pairs of natural populations of Drosophila melanogaster from contrasting thermal environments that reflect three separate instances of cold tolerance evolution. The cold-adapted populations were known to show population genetic evidence for parallel evolution at the SNP level, and here we find evidence for parallel expression evolution between them, with stronger parallelism at larval and adult stages than for pupae. We also implement a flexible method to estimate cis- vs trans-encoded contributions to expression or splicing differences at the adult stage. The apparent contributions of cis- vs trans-regulation to adaptive evolution vary substantially among population pairs. While two of three population pairs show a greater enrichment of cis-regulatory differences among adaptation candidates, trans-regulatory differences are more likely to be implicated in parallel expression changes between population pairs. Genes with significant cis-effects are enriched for signals of elevated genetic differentiation between cold- and warm-adapted populations, suggesting that they are potential targets of local adaptation. These findings expand our knowledge of adaptive gene regulatory evolution and our ability to make inferences about this important and widespread process.
Care, Dementia, and the Fourth Age in Erica Jong’s Later Work
Authors: Stončikaitė Ieva 
Published: May 2021

Abstract

Background and Objectives
This article addresses the representations of dementia and caregiving in the fourth age as depicted in Erica Jong’s later-life work. It shows how the experience of parental care leads to the discovery of new ways of human interaction and expressions of personhood.

Research Design and Methods
Framed within literary–cultural age studies, this article shows how humanities-based inquiry can illuminate important aspects of aging and care of the oldest old, which are significant and revealing, but often hidden under the dark shadow of dementia.

Results
Newly discovered ways of communication challenge the notion of the loss of agency as they demonstrate that the body itself has the power of creative and intentional capacities and self-expression.

Discussion and Implications
Care-related narratives offer new insights into aging, dementia, and subjectivity that can help pursue a better analysis of the “deep” old age, strengthen collective solidarity, and manage increasing ageism, especially pronounced during the coronavirus disease 2019 pandemic.
Modeling gap junction beta 2 gene-related deafness with human iPSC
Authors: Fukunaga Ichiro , Oe Yoko , Danzaki Keiko , Ohta Sayaka , Chen Cheng , Shirai Kyoko , Kawano Atsushi , Ikeda Katsuhisa , Kamiya Kazusaku 
Published: May 2021

AbstractThere are &gt;120 forms of non-syndromic deafness associated with identified genetic loci. In particular, mutation of the gap junction beta 2 gene (GJB2), which encodes connexin (CX)26 protein, is the most frequent cause of hereditary deafness worldwide. We previously described an induction method to develop functional CX26 gap junction-forming cells from mouse-induced pluripotent stem cells (iPSCs) and generated in vitro models for GJB2-related deafness. However, functional CX26 gap junction-forming cells derived from human iPSCs or embryonic stem cells (ESCs) have not yet been reported. In this study, we generated human iPSC-derived functional CX26 gap junction-forming cells (iCX26GJCs), which have the characteristics of cochlear supporting cells. These iCX26GJCs had gap junction plaque-like formations at cell–cell borders and co-expressed several markers that are expressed in cochlear supporting cells. Furthermore, we generated iCX26GJCs derived from iPSCs from two patients with the most common GJB2 mutation in Asia, and these cells reproduced the pathology of GJB2-related deafness. These in vitro models may be useful for establishing optimal therapies and drug screening for various mutations in GJB2-related deafness.
NovelLRRK2mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors
Authors: Cheung Mitchell , Kadariya Yuwaraj , Sementino Eleonora , Hall Michael J , Cozzi Ilaria , Ascoli Valeria , Ohar Jill A , Testa Joseph R 
Published: May 2021

AbstractThere is irrefutable evidence that germline BRCA1-associated protein 1 gene (BAP1) mutations contribute to malignant mesothelioma (MM) susceptibility. However, BAP1 mutations are not found in all cases with evidence of familial MM or in other high-risk cancer families affected by various cancers, including MM. The goal of this study was to use whole genome sequencing (WGS) to determine the frequency and types of germline gene variants occurring in 12 MM patients who were selected from a series of 141 asbestos-exposed MM patients with a family history of cancer but without a germline BAP1 mutation. WGS was also performed on two MM cases, a proband and sibling, from a previously reported family with multiple cases of MM without the inheritance of a predisposing BAP1 mutation. Altogether, germline DNA sequencing variants were identified in 21 cancer-related genes in 10 of the 13 probands. Germline indel, splice site and missense mutations and two large deletions were identified. Among the 13 MM index cases, 6 (46%) exhibited one or more predicted pathogenic mutations. Affected genes encode proteins involved in DNA repair (ATM, ATR, BRCA2, BRIP1, CHEK2, MLH3, MUTYH, POLE, POLE4, POLQ and XRCC1), chromatin modification (ARID1B, DNMT3A, JARID2 and SETD1B) or other cellular pathways: leucine-rich repeat kinase 2 gene (LRRK2) (two cases) and MSH4. Notably, somatic truncating mutation or deletions of LRRK2 were occasionally found in MMs in The Cancer Genome Atlas, and the expression of LRRK2 was undetectable or downregulated in a majority of primary MMs and MM cell lines we examined, implying that loss of LRRK2 expression is a newly recognized tumor suppressor alteration in MM.
High-altitude pulmonary edema is aggravated by risk loci and associated transcription factors in HIF-prolyl hydroxylases
Authors: Sharma Kavita , Mishra Aastha , Singh Himanshu N , Parashar Deepak , Alam Perwez , Thinlas Tashi , Mohammad Ghulam , Kukreti Ritushree , Syed Mansoor Ali , Pasha M A Qadar 
Published: May 2021

Abstract
High-altitude (HA, &gt;2500 m) hypoxic exposure evokes several physiological processes that may be abetted by differential genetic distribution in sojourners, who are susceptible to various HA disorders, such as high-altitude pulmonary edema (HAPE). The genetic variants in hypoxia-sensing genes influence the transcriptional output; however the functional role has not been investigated in HAPE. This study explored the two hypoxia-sensing genes, prolyl hydroxylase domain protein 2 (EGLN1) and factor inhibiting HIF-1α (HIF1AN) in HA adaptation and maladaptation in three well-characterized groups: highland natives, HAPE-free controls and HAPE-patients. The two genes were sequenced and subsequently validated through genotyping of significant single nucleotide polymorphisms (SNPs), haplotyping and multifactor dimensionality reduction. Three EGLN1 SNPs rs1538664, rs479200 and rs480902 and their haplotypes emerged significant in HAPE. Blood gene expression and protein levels also differed significantly (P &lt; 0.05) and correlated with clinical parameters and respective alleles. The RegulomeDB annotation exercises of the loci corroborated regulatory role. Allele-specific differential expression was evidenced by luciferase assay followed by electrophoretic mobility shift assay, liquid chromatography with tandem mass spectrometry and supershift assays, which confirmed allele-specific transcription factor (TF) binding of FUS RNA-binding protein (FUS) with rs1538664A, Rho GDP dissociation inhibitor 1 (ARHDGIA) with rs479200T and hypoxia upregulated protein 1 (HYOU1) with rs480902C. Docking simulation studies were in sync for the DNA-TF structural variations. There was strong networking among the TFs that revealed physiological consequences through relevant pathways. The two hydroxylases appear crucial in the regulation of hypoxia-inducible responses.
HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages Through the SIK/CRTC3 Pathway
Authors: Fu Yong , Ma Gailing , Zhang Yuqian , Wang Wenli , Shi Tongguo , Zhu Jie , Zhang Junfeng , Huang Zhen , Chen Jiangning 
Published: May 2021

Abstract

Background
Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that plays a pivotal role in maintaining mucosal immune homeostasis. As a novel synthetic inhibitor of salt-inducible kinases (SIKs), HG-9-91-01 can effectively enhance IL-10 secretion at the cellular level, but its in vivo immunoregulatory effects remain unclear. In this study, we investigated the effects and underlying mechanism of HG-9-91-01 in murine colitis models.

Methods
The anti-inflammatory effects of HG-9-91-01 were evaluated on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-, dextran sulfate sodium–induced colitis mice, and IL-10 knockout chronic colitis mice. The in vivo effector cell of HG-9-91-01 was identified by fluorescence-activated cell sorting and quantitative real-time polymerase chain reaction. The underlying mechanism of HG-9-91-01 was investigated via overexpressing SIKs in ANA-1 macrophages and TNBS colitis mice.

Results
Treatment with HG-9-91-01 showed favorable anticolitis effects in both TNBS- and DSS-treated mice through significantly promoting IL-10 expression in colonic macrophages but failed to protect against IL-10 KO murine colitis. Further study indicated that HG-9-91-01 markedly enhanced the nuclear level of cAMP response element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3), whereas treatment with lentiviruses encoding SIK protein markedly decreased the nuclear CRTC3 level in HG-9-91-01–treated ANA-1 macrophages. In addition, intracolonic administration with lentiviruses encoding SIK protein significantly decreased the nuclear CRTC3 level in the lamina propria mononuclear cells and ended the anti-inflammatory activities of HG-9-91-01.

Conclusions
We found that HG-9-91-01 promoted the IL-10 expression of colonic macrophages and exhibited its anticolitis activity through the SIK/CRTC3 axis, and thus it may represent a promising strategy for inflammatory bowel disease therapy.
The Impact of Alcohol in Inflammatory Bowel Diseases
Authors: White Bradley A , Ramos Guilherme Piovezani , Kane Sunanda 
Published: May 2021

AbstractSeveral environmental factors have been implicated in the pathogenesis of inflammatory bowel diseases (IBD); however, the evidence for alcohol is sparse, as is its implications on disease activity and overall management. Here, we examine the available evidence for the effect of alcohol on IBD, including its association with the development of IBD, role in exacerbations, and potential medication interactions. Several mechanisms have been demonstrated to mediate the effects of ethanol in the gastrointestinal tract. Alcohol has been shown to alter the gut microbiome, disrupt intestinal barrier, and increase intestinal permeability, directly and indirectly promoting immune activation. Conversely, specific alcoholic beverages, notably red wine, may have anti-inflammatory properties capable of assisting in disease control and affecting disease monitoring. Nonetheless, most alcohol-mediated effects seem to facilitate intestinal inflammation and consequently impact disease onset, recurrence, and symptom control. Furthermore, alcohol use interferes with the metabolism of several medications leading to increased side effect profiles or even loss of effect. Notably, mesalamine, azathioprine, methotrexate, and biologic medications can all be affected by concomitant alcohol intake via a variety of mechanisms.
Influenza Vaccines: Successes and Continuing Challenges
Authors: Becker Tanja , Elbahesh Husni , Reperant Leslie A , Rimmelzwaan Guus F , Osterhaus Albert D M E 
Published: May 2021

AbstractInfluenza vaccines have been available for over 80 years. They have contributed to significant reductions in influenza morbidity and mortality. However, there have been limitations in their effectiveness, in part due to the continuous antigenic evolution of seasonal influenza viruses, but also due to the predominant use of embryonated chicken eggs for their production. The latter furthermore limits their worldwide production timelines and scale. Therefore today, alternative approaches for their design and production are increasingly pursued, with already licensed quadrivalent seasonal influenza vaccines produced in cell cultures, including based on a baculovirus expression system. Next-generation influenza vaccines aim at inducing broader and longer-lasting immune responses to overcome seasonal influenza virus antigenic drift and to timely address the emergence of a new pandemic influenza virus. Tailored approaches target mechanisms to improve vaccine-induced immune responses in individuals with a weakened immune system, in particular older adults.