bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lower risks of new-onset acute pancreatitis and pancreatic cancer in sodium glucose cotransporter 2 (SGLT2) inhibitors compared to dipeptidyl peptidase-4 (DPP4) inhibitors: a propensity score-matched study with competing risk analysis
Authors: Chou Oscar Hou In , Zhou Jiandong , Mui Jonathan V , Satti Danish Iltaf , Lee Teddy Tai Loy , Lee Sharen , Dee Edward Christopher , Ng Kenrick , Zhang Qingpeng , Cheung Bernard Man Yung , Jing Fengshi , Tse Gary 
Published: May 2022

AbstractBackgroundDipeptidyl peptidase-4 inhibitors (DPP4I) may be associated with higher risks of acute pancreatitis and pancreatic cancer. This study compared the risks of acute pancreatitis and pancreatic cancer between sodium glucose cotransporter 2 inhibitors (SGLT2I) and DPP4I users.MethodsThis was a retrospective population-based cohort study of patients with type-2 diabetes mellitus on either SGLT2I or DPP4I between January 1st 2015 and December 31st 2020 in Hong Kong. The primary outcome was new-onset acute pancreatitis and pancreatic cancer. Propensity score matching (1:1 ratio) using the nearest neighbour search was performed. Univariable and multivariable Cox regressions were applied to identify significant predictors.ResultsThis cohort included 31609 T2DM patients (median age: 67.4 years old [SD: 12.5]; 53.36% males). 6479 patients (20.49%) used SGLT2I, and 25130 patients (70.50%) used DPP4I. After matching, the incidence of acute pancreatitis was significantly lower in SGLT2I users (incidence rate, IR: 0.6; 95% confidence interval, CI: 0.2-1.4) than in DPP4I (IR: 2.1; CI: 1.3-3.0). The incidence of pancreatic cancer was also lower among SGLT2I users (IR: 1.4; 95% CI: 0.7-2.6 vs. 3.6; 95% CI: 2.6-4.9). SGLT2I was associated with lower risks of acute pancreatitis (hazard ratio, HR: 0.11; 95% CI: 0.02-0.51; P=0.0017) and pancreatic cancer (HR: 0.22; 95% CI: 0.039-0.378; P=0.0003) after adjustments. The results were consistent in the competing risk models and the different matching approaches.ConclusionsSGLT2I may be associated with lower risks of new-onset acute pancreatitis and pancreatic cancer after matching and adjustments, underscoring the need for further evaluation in the prospective setting.Key messagesWhat is already known on this topicT2DM was associated with higher risks of pancreatic cancer. Meanwhile, second-line anti-diabetic drugs were suggested to reduce the risks of pancreatic cancer, although DPP4I was suggested to be associated with acute pancreatitis.What this study addsSGLT2I was associated with an 89% lower risk of acute pancreatitis and 78% lower risk of pancreatic cancer than DPP4I users.How this study might affect research, practice or policyThe findings of this study may influence the choice of second-line antidiabetic therapy in T2DM patients in terms of the pancreatic safety profile. This study may inspire more studies on the long-term cancer benefits of SGLT2I.
A pharmacoepidemiological study of myocarditis and pericarditis following mRNA COVID-19 vaccination in Europe
Authors: Tome Joana , Cowan Logan T. , Fung Isaac Chun-Hai 
Published: May 2022

ABSTRACTPurposeTo assess myocarditis and pericarditis reporting rate as adverse drug reactions (ADRs) for the messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccines authorized in Europe.MethodsData on myocarditis and pericarditis related to mRNA COVID-19 vaccines (period: January 1, 2021 - February 11, 2022) were collected from the EudraVigilance database and combined with the European Centre for Disease Prevention and Control’s (ECDC) vaccination tracker database. The reporting rate was expressed as 1 million individual vaccinated-days with a corresponding 95% confidence interval (CI), and an observed-to-expected (OE) analysis was performed to check if there was an excess risk for myocarditis or pericarditis following mRNA COVID-19 vaccination.ResultsThe reporting rate of myocarditis per 1 million individual vaccinated-days in the study period was 17.27 (95% CI, 16.34-18.26) for the CX-024414 vaccine and 8.44 (95% CI, 8.18-8.70) for TOZINAMERAN vaccine. The reporting rate for pericarditis per 1 million individual vaccinated-days in the study period was 9.76 (95% CI, 9.06-10.51) for the CX-024414 vaccine and 5.79 (95% CI, 5.56-6.01) for TOZINAMERAN vaccine. The OE analysis showed that both vaccines produced a myocarditis standardized morbidity ratio (SMR) greater than 1, with the CX-024414 vaccine having a greater SMR than TOZINAMERAN. Regarding TOZINAMERAN, SMR for pericarditis was greater than 1 when considering the lowest background incidence, but smaller than 1 when considering the highest background incidence.ConclusionsOur results suggest an excess risk of myocarditis following the first dose of mRNA COVID-19 vaccine, but the relationship between pericarditis and mRNA COVID-19 vaccine remains unclear.
Impact of the aryl hydrocarbon receptor on Aurora A kinase and the G2/M phase pathway in hematopoietic stem and progenitor cells
Authors: Franchini Anthony M. , Vaughan Keegan , Bhattacharya Soumyaroop , Singh Kameshwar , Gasiewicz Thomas A. , Lawrence B. Paige 
Published: May 2022

AbstractRecent evidence suggests that the environment-sensing transcription factor aryl hydrocarbon receptor (AHR) is an important regulator of hematopoiesis. Yet, the mechanisms and extent of AHR-mediated regulation within the most primitive hematopoietic cells, hematopoietic stem and progenitor cells (HSPCs), are poorly understood. Through a combination of transcriptomic and flow cytometric approaches, this study provides new insight into how the AHR influences HSPCs. Comparative analysis of intraphenotypic transcriptomes of hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells from AHR knockout (AHR KO) and wild-type (WT) mice revealed significant differences in gene expression patterns. Notable among these were differences in expression of cell cycle regulators, specifically an enrichment of G2/M checkpoint genes when Ahr was absent. This included the regulator Aurora A kinase (Aurka, AurA). Interrogation of AurA protein levels in HSPC subsets using flow cytometry, in combination with inducible AHR KO or in vivo AHR antagonism showed that attenuation of AHR increased levels of AurA in HSCs and lineage-biased MPP cells. Overall, these data highlight a potential novel mechanism by which AHR controls HSC homeostasis and HSPC differentiation. These findings advance the understanding of how AHR influences and regulates primitive hematopoiesis.Highlights (max 85 characters)AHR alters gene expression during HSC-MPP transition.Transcriptomic analysis shows AHR regulation of key G2/M phase regulatorsInducible AHR KO mice show increased AurA levels in HSPC populationsAcute antagonism of AHR increased AurA levels across multiple HSPC populations
Integrating proteomic data with metabolic modelling provides insight into key pathways ofBordetella pertussisbiofilms
Authors: Suyama Hiroki , Luu Laurence Don Wai , Zhong Ling , Raftery Mark J. , Lan Ruiting 
Published: May 2022

AbstractPertussis, commonly known as whooping cough is a severe respiratory disease caused by the bacterium,Bordetella pertussis. Despite widespread vaccination, pertussis resurgence has been observed globally. The development of the current acellular vaccine (ACV) has been based on planktonic studies. However, recent studies have shown thatB. pertussisreadily forms biofilms. A better understanding ofB. pertussisbiofilms is important for developing novel vaccines that can target all aspects ofB. pertussisinfection. This study compared the proteomic expression of biofilm and planktonicB. pertussiscells to identify key changes between the conditions. Major differences were identified in virulence factors including an upregulation of toxins (adenylate cyclase toxin and dermonecrotic toxin) and downregulation of pertactin and type III secretion system proteins in biofilm cells. To further dissect metabolic pathways that are altered during the biofilm lifestyle, the proteomic data was then incorporated into a genome scale metabolic model using the integrative metabolic analysis tool (iMAT). The analysis revealed that planktonic cells utilised the glyoxylate shunt while biofilm cells completed the full tricarboxylic acid cycle. Differences in processing aspartate, arginine and alanine were identified as well as unique export of valine out of biofilm cells which may have a role in inter-bacterial communication and regulation. Finally, increased polyhydroxybutyrate accumulation and superoxide dismutase activity in biofilm cells may contribute to increased persistence during infection. Taken together, this study modelled major proteomic and metabolic changes that occur in biofilm cells which helps lay the groundwork for further understandingB. pertussispathogenesis.
Drosophila insulator proteins exhibit in-vivo liquid-liquid phase separation properties
Authors: Amankwaa Bright , Schoborg Todd , Labrador Mariano 
Published: May 2022

AbstractMounting evidence implicates liquid-liquid phase separation (LLPS), the condensation of biomolecules into liquid-like droplets in the formation and dissolution of membraneless intracellular organelles (MLOs). Eukaryotic cells utilize MLOs or condensates for various biological processes, including emergency signaling, spatiotemporal control over steady-state biochemical reactions and heterochromatin formation. Insulator proteins function as architectural elements involved in establishing independent domains of transcriptional activity within eukaryotic genomes. In Drosophila, insulator proteins coalesce to form nuclear foci known as insulator bodies in response to osmotic stress and during apoptosis. However, the mechanism through which insulator proteins assemble into bodies and whether these bodies confer any genome function are yet to be fully investigated. Here, we identify signatures of liquid-liquid phase separation by insulator bodies, including high disorder tendency in insulator proteins, scaffold-client dependent assembly, extensive fusion behavior, sphericity, and sensitivity to 1,6-hexanediol. We also show that the cohesin subunit Rad21 is a component of insulator bodies adding to the known insulator proteins and the histone variant γH2Av constituents. Our data suggest a concerted role of cohesin and insulator proteins in insulator body formation and under physiological conditions. We propose a mechanism whereby these architectural proteins modulate 3D genome organization through LLPS.
Development of a Novel SARS-CoV-2 Immune Complex Vaccine Candidate (CRCx) with Broad Immune Responses: A Preclinical Trial in Animal Model
Authors: Salah Sherif , Mubarki Abdula , Zayed Khalid , Omar Khaled 
Published: May 2022

AbstractBackgroundThe ongoing pandemic of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a serious threat to global public health and imposes a severe burden on the entire human population. Faced with a virus that can mutate its structure while immunity is incapacitated, a need to develop a universal vaccine that can boost immunity to coronaviruses is highly needed.DesignFive formulations of two types (CRCx2 and CRCx3) of immune complexes with an immunogen adjuvant were evaluated in a mouse model as candidate SARS CoV-2 vaccines in a pretrial prior to clinical trials in humans. CRCx3 comprises 3 different formulas and CRCx2 comprises 2. Balb/c mice were vaccinated intraperitoneally on days 0/7 with a high or low dose of CRCx2 or on days 0/7/14 with a high, medium, or low dose of CRCx3 series, and their blood was sampled for serum antibody measurements. Mice were challenged with live virus after immunization with either vaccine to evaluate prophylaxis ability or treated with them after challenge to evaluate therapeutic ability on day 15. Immunological markers and histopathological studies as well as titration of neutralizing antibodies to the vaccines were evaluated and analyzed.ResultsCRCx 3 and CRCx 2 vaccine candidates induced elevated levels of positive neutralizing antibodies as well as a cellular immune response with safety, efficient productivity, and good genetic stability for vaccine manufacturing to provide protection against SARS-CoV-2 with relatively higher levels with the high dose CRCx2 candidate combination.ConclusionsHighly efficient protection and therapeutic effect against SARS-CoV-2 were obtained with a double-dose immunization schedule spaced at 7-day intervals using injections 0.25 of or 0.40 ml of CRCx2 vaccine formulations with a 25-mm needle. These results support further evaluation of CRCx in a clinical trial on humans.
SMALL NONCODING RNA CONTENTS OF RAT EPIDIDYMAL EXTRACELLULAR VESICLES INCLUDING A PUTATIVE NOVEL SMALL RNA
Authors: Gillette Ross , Waghwala Shyamal , Gore Andrea C. 
Published: May 2022

AbstractExtracellular vesicles (EVs) released from the epididymal epithelium (epididymosomes) impart functional competence on sperm as they transit the epididymis by merging with sperm and releasing a complex repertoire of molecules. The cargo of epididymosomes includes small noncoding RNAs (sncRNAs) that are modified by external factors such as stress, nutrition, and drug use. If incorporated into sperm, the EV sncRNA cargo can affect offspring and lead to heritable phenotypes. In the current study we characterized the RNA contents of EVs collected from the caput epididymis of adult male rats in order to fill a gap in knowledge in this species and to establish a sncRNA profile. Small RNAs of EVs were isolated from the caput portion of the epididymis of adult male rats, and sequenced on a NovaSeq 6000 on a SP flow cell in a single-end 50 bp configuration. The resulting reads were checked for quality, trimmed for adapter sequences, aligned to the unmasked rat genome (Rnor 6), and assigned an annotation designation. The majority of RNA reads aligned to either tRNA fragments (79.1%) or piRNA (18.1%) loci. Micro RNAs (miRNAs) accounted for a surprisingly small proportion of reads (0.18%). The third largest category of aligned reads (1.5%) was in intergenic space and not strictly associated with canonical sncRNA loci. In-depth investigation determined these latter reads (∼19 nt) aligned strictly within the boundaries of known CpG islands (CpGi), which have not previously been reported to express any form of sncRNA. These newly described “CpGi sRNAs” could not consistently be accounted for by overlaying features of any other annotation type (including rRNA and piRNA). The CpGi sRNAs have characteristics of RNA fragments that can associate with the Argonaute/PIWI family of proteins and therefore could have regulatory function via RNA induced silencing or de novo DNA methylation. We propose that CpGi sRNAs constitute a new family of sncRNA that may represent an important and unreported class of regulatory RNA in gametes.
Influence of amino acids and glucosinolates in three Brassicaceae vegetable plants on preference and performance of the green peach aphid: Myzus persicae
Authors: Ahmed Muhammad Afaq , Ban Ning , Hussain Sarfaraz , Batool Raufa , Liu Tong-Xian , Zhang Yong-Jun , Cao He-He 
Published: May 2022

AbstractThe green peach aphid, Myzus persicae (Sulzer) is a generalist pest of various host plants, whose feeding preference and growth performance mainly depends on the quantity and quality of nutrients and defensive metabolites in host plants. Here, we studied the preference and performance of M. persicae on three major Brassicaceae vegetables in China and measured nutrient (amino acids) and defensive (glucosinolates) metabolites in these plants. We found that M. persicae preferred and performed better on Chinese cabbage than cabbage and radish, which may be due to the relatively higher concentration of amino acids and lower levels of glucosinolates in their leaves. The glucosinolates level in cabbage leaves was ten times higher than the other two plants, while the amino acid concentration in radish was only half of the cabbage or Chinese cabbage. The higher concentration of glucosinolates in cabbage and lower levels of amino acids in radish may account for the poorer preference and growth of M. persicae on these two plants. These results suggest that both amino acids and glucosinolates in plants are important determinants of the preference and performance of M. persicae, which provide new knowledge for the cultivation and breeding of Brassicaceae vegetables.
Sucrose metabolism and candidate genes during catkin fibers development in poplar
Authors: Yang Xiong , Zhao Tianyun , Rao Pian , Yang Ning , Li Guolei , Jia Liming , An Xinmin , Chen Zhong 
Published: May 2022

AbstractPoplar is an important tree species for ecological protection, wood production, bioenergy and urban greening; it has been widely planted worldwide. However, the catkin fibers produced by female poplars can cause environmental pollution and safety hazards during spring. This study focused onPopulus tomentosa, and revealed the sucrose metabolism regulatory mechanism of catkin fibers development from morphological, physiological and molecular aspects. Paraffin section suggested that poplar catkin fibers were not seed hairs and produced from the epidermal cells of funicle and placenta. Sucrose degradation via invertase and sucrose synthase played the dominant role during poplar catkin fibers development. The expression patterns revealed that sucrose metabolism-related genes played important roles during catkin fibers development. Y1H analysis indicated that there was a potential interaction betweensucrose synthase 2 (PtoSUS2)/vacuolar invertase 3 (PtoVIN3)and MYB/ bHLH transcription factors in poplar. Finally, the two key genes,PtoSUS2andPtoVIN3, had roles inArabidopsistrichome density, indicating that sucrose metabolism is important in poplar catkin fibers development. This study is not only helpful for clarifying the mechanism of sucrose regulation during trichome development in perennial woody plants, but also establishes a foundation to solve poplar catkin fibers pollution through genetic engineering methods.HighlightSucrose degradation via invertase and sucrose synthase plays an important role in poplar catkin fibers development, andPtoSUS2andPtoVIN3are potential promising targets to solve poplar catkin fibers pollution.
Secretoglobin family 1D member 2 (SCGB1D2) protein inhibits growth of Borrelia burgdorferi and affects susceptibility to Lyme disease
Authors: Strausz Satu , Blacker Grace , Galloway Sarah , Hansen Paige , Jones Samuel E. , Sanders Erin , Sinnott-Armstrong Nasa , FinnGen  , Weissman Irving L. , Daly Mark , Aivelo Tuomas , Tal Michal Caspi , Ollila Hanna M. 
Published: May 2022

SUMMARYLyme disease is a tick-borne disease caused by bacteria of the genus Borrelia. The disease can initially manifest as an erythema migrans rash and, if able to evade the host immune defenses, can progress into a secondary stage chronic disease with debilitating physical or neurological manifestations1,2. The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Here we show a novel host defense mechanism against Lyme disease in humans. Using epidemiological and genetic data from FinnGen, we identify a common missense variant at the gene encoding for Secretoglobin family 1D member 2 (SCGB1D2) protein that increases the susceptibility for Lyme disease. The genetic variant changes proline at position 53 to leucine and is predicted as deleterious. Consequently, we validate the dysfunction of this protein variant using live Borrelia burgdorferi (Bb). Recombinant reference SCGB1D2 protein inhibits the growth of Bb twice as effectively as the recombinant SCGB1D2 P53L deleterious missense variant. Together, these data suggest that SCGB1D2 is a host defense factor present in the skin, sweat, and other secretions which protects against Bb infection. This finding provides a novel therapeutic avenue for drug development to prevent and treat Lyme disease.
Affinity-optimizing variants within the ZRS enhancer disrupt limb development
Authors: Lim Fabian , Ryan Genevieve E , Le Sophia H , Solvason Joe J , Steffen Paige , Farley Emma K 
Published: May 2022

SummaryAn emerging regulatory principle governing enhancers is the use of suboptimal affinity binding sites to encode tissue-specific gene expression. Here we investigate if optimizing single-nucleotide variants that violate this principle can disrupt tissue-specific gene expression and development. The ZRS enhancer mediates expression of Shh in the posterior of the developing limb buds and is critical for limb and digit development. We find that the ZRS contains suboptimal-affinity ETS binding sites. Two human mutations and a synthetic mutation that optimize the affinity of the ETS-A site from 0.15 to 0.25 relative binding affinity cause polydactyly with the same penetrance and severity. Further increasing the affinity of the ETS-A site results in more penetrant and severe phenotypes. The prevalent use of suboptimal affinity binding sites within enhancers to encode tissue-specificity creates a vulnerability within genomes whereby variants that optimize affinity, even subtly, can be pathogenic. This provides a generalizable approach to identify causal variants that underlie enhanceropathies.In BriefSubtle increases in low-affinity sites underlie human limb defects, while greater increases in affinity lead to more severe and penetrant phenotypes.HighlightsPrediction and validation of pathogenic enhancer variantsVery subtle increases in affinity of low-affinity sites are pathogenicPenetrance and severity of phenotype scales with increase in affinity
Effect of colours on sponsor recall
Authors: Toh Brendon , Leng Ho Keat , Phua Yi Xian Philip 
Published: May 2022

PurposeAs sports sponsorship is a common marketing tool among commercial organisations, there had been a large number of studies examining the effectiveness of sponsorship. The aim of this study is to examine whether colour affects sponsorship effectiveness on printed advertisements of sports events. This is an area that has received less research interest.Design/methodology/approachIn total, 85 participants were randomly assigned to a control group and three experimental groups. In each of the groups, the participants viewed an advertisement of a sports event on a computer linked to an eye tracker. In the control group, the logos of sponsors were in their original colours. In each of the three experimental groups, the logos were manipulated and featured greyscale, blue or red backgrounds.FindingsThe study found that sponsor recall and recognition rates were highest for the control group. Visual attention was also the highest in the control group.Research limitations/implicationsThe findings suggest that manipulating colours of the sponsors' logos can negatively affect attention and sponsorship effectiveness.Originality/valueWhile there exist studies that focus on the effects of colour in sponsorship, they are typically conducted with regard to physically attending the event itself. However, sponsorship involves other marketing collaterals such as printed advertisements on the event. In such mediums, colour contrast is also important in print advertisements as it affects readability and legibility. As such, the examination of effect of colour on such marketing collaterals provides additional empirical support to the phenomenon.