bluuebunny/crossref_metadata_2025_split huggingface dataset:
METTL3/N6‐methyladenosine/ miR‐21‐5p promotes obstructive renal fibrosis by regulating inflammation through SPRY1/ERK/NF‐κB pathway activation
Authors: Liu Erpeng , Lv Lei , Zhan Yonghao , Ma Yuan , Feng Jinjin , He Yulin , Wen Yibo , Zhang Yanping , Pu Qingsong , Ji Fengping , Yang Xinghuan , Wen Jian Guo 
Published: June 2021

AbstractRenal fibrosis induced by urinary tract obstruction is a common clinical occurrence; however, effective treatment is lacking, and a deeper understanding of the mechanism of renal fibrosis is needed. Previous studies have revealed that miR‐21 impacts liver and lung fibrosis progression by activating the SPRY1/ERK/NF‐kB signalling pathway. However, whether miR‐21 mediates obstructive renal fibrosis through the same signalling pathway has not been determined. Additionally, studies have shown that N6‐methyladenosine (m6A) modification‐dependent primary microRNA (pri‐microRNA) processing is essential for maturation of microRNAs, but its role in the maturation of miR‐21 in obstructive renal fibrosis has not yet been investigated in detail. To address these issues, we employed a mouse model of unilateral ureteral obstruction (UUO) in which the left ureters were ligated for 3, 7 and 14 days to simulate the fibrotic process. In vitro, human renal proximal tubular epithelial (HK‐2) cells were transfected with plasmids containing the corresponding sequence of METTL3, miR‐21‐5p mimic or miR‐21‐5p inhibitor. We found that the levels of miR‐21‐5p and m6A modification in the UUO model groups increased significantly, and as predicted, the SPRY1/ERK/NF‐kB pathway was activated by miR‐21‐5p, confirming that miR‐21‐5p plays an important role in obstructive renal fibrosis by enhancing inflammation. METTL3 was found to play a major catalytic role in m6A modification in UUO mice and drove obstructive renal fibrosis development by promoting miR‐21‐5p maturation. Our research is the first to demonstrate the role of the METTL3‐m6A‐miR‐21‐5p‐SPRY1/ERK/NF‐kB axis in obstructive renal fibrosis and provides a deeper understanding of renal fibrosis.
The Segond’s fracture and the anterolateral ligament
Authors: Ferretti Andrea , Monaco Edoardo , Redler Andrea 
Published: June 2021

AbstractThe study of Mullins et al. reasonably explains how the Segond's fracture is probably the most frequent avulsion fracture of the tibia plateau, but it does not challenge the hypothesis of the existence of a discrete ligament (the ALL) strong enough to sometimes pull out its bony insertion as a result of a forced internal rotation and of an ACL failure.
Hypertension genetics past, present and future applications
Authors: Olczak Kaya J. , Taylor‐Bateman Victoria , Nicholls Hannah L. , Traylor Matthew , Cabrera Claudia P. , Munroe Patricia B. 
Published: June 2021

AbstractEssential hypertension is a complex trait where the underlying aetiology is not completely understood. Left untreated it increases the risk of severe health complications including cardiovascular and renal disease. It is almost 15 years since the first genome‐wide association study for hypertension, and after a slow start there are now over 1000 blood pressure (BP) loci explaining ∼6% of the single nucleotide polymorphism‐based heritability. Success in discovery of hypertension genes has provided new pathological insights and drug discovery opportunities and translated to the development of BP genetic risk scores (GRSs), facilitating population disease risk stratification. Comparing highest and lowest risk groups shows differences of 12.9 mm Hg in systolic‐BP with significant differences in risk of hypertension, stroke, cardiovascular disease and myocardial infarction. GRSs are also being trialled in antihypertensive drug responses. Drug targets identified include NPR1, for which an agonist drug is currently in clinical trials. Identification of variants at the PHACTR1 locus provided insights into regulation of EDN1 in the endothelin pathway, which is aiding the development of endothelin receptor EDNRA antagonists. Drug re‐purposing opportunities, including SLC5A1 and canagliflozin (a type‐2 diabetes drug), are also being identified. In this review, we present key studies from the past, highlight current avenues of research and look to the future focusing on gene discovery, epigenetics, gene‐environment interactions, GRSs and drug discovery. We evaluate limitations affecting BP genetics, including ancestry bias and discuss streamlining of drug target discovery and applications for treating and preventing hypertension, which will contribute to tailored precision medicine for patients.
Shrub facilitation promotes advancing of the Fagus sylvatica treeline across the Apennines (Italy)
Authors: Bonanomi Giuliano , Mogavero Valentina , Rita Angelo , Zotti Maurizio , Saulino Luigi , Tesei Giulio , Allegrezza Marina , Saracino Antonio , Rossi Sergio , Allevato Emilia 
Published: June 2021

AbstractQuestionsElevational treelines are expected to shift upwards in response to warming climate. However, worldwide upward shifts of treelines are inconsistent because local scale factors can affect the response to temperature. In this study, we explore the hypothesis that in the Apennines, where the current altitudinal treeline position is largely depressed because of past human activity, shrubs act as nurse plants promoting the upward migration of Fagus sylvatica.LocationA 500–km‐long latitudinal gradient in the Apennines, Italy.MethodsWe selected, along this gradient, nine treeline sites with different elevations, rock substrates, and physiognomic types including Juniperus communis, Pinus mugo, Vaccinium myrtillus shrublands, and grasslands. Here, in 68 transects we collected and analysed spatially fine‐scale distribution data of F. sylvatica individuals in relation to both their age and their position, associated or not with shrubs.ResultsFagus sylvatica regeneration is rare in open secondary grasslands at 1,600–2,100 m a.s.l., highlighting a bottleneck in the regeneration phase of this species. On the contrary, we systematically observed a strong association between shrubs and F. sylvatica individuals. Compared with the adjacent grassland, F. sylvatica regeneration was 58.3 times higher under Pinus mugo, 131.5 timeshigher under Juniperus communis and 102.4 times higher under Vaccinium myrtillus. The age structure of F. sylvatica population indicates that, in the last 50 years, recruitment under shrubs is continuous, while in grassland it is episodic.ConclusionsAbove the current treeline of the Apennines, F. sylvatica individuals develop only in the presence of shrubs, which act as nurse species. Shrubs are a necessary condition for F. sylvatica re‐colonization of the high‐altitude open areas affected, in the last centuries, by intense human land use.
Assessment of bivalve carrying capacities and seeding densities in aquaculture areas of Jiaozhou Bay, China, using ecological modeling and the food balance
Authors: Liu Xuehai , Zhang Mingliang , Wang Zongling , Wang Bo 
Published: June 2021

AbstractThe increasing growth of the bivalve‐culture industry necessitates a scientific assessment of the carrying capacity (CC) of this aquaculture system, in order to ensure sustainability. Here, using a marine plankton ecological model and the food balance, bivalve CCs were estimated for aquaculture zones in Jiaozhou Bay (JZB), an important aquaculture center in China. The results indicated that CCs mainly depended on bivalve filtration rates, which were in turn regulated by temperature. The CCs of Manila clams, razor clams, and scallops were lowest in August–September, while the CCs of oysters and mussels were lowest in October. For all taxa, CCs were higher in areas with higher primary production. Further evaluation indicated that present cultures were saturated, with high mortality rates. To improve culture quality and efficiency, the seeding density of the Manila clam, the most widely farmed species in the JZB, should be reduced to ~700 individuals (ind.)/m2. We also recommend reducing the seeding densities of razor clams, oysters, and mussels to 345, 60, and 165 ind./m2, and reducing scallop seeding density to 280 ind./cage. Our methods and results provide a basis for further assessments of stocking capacities and the promotion of sustainable, healthy aquaculture in other bays.
Pseudouridines on Trypanosoma brucei mRNAs are developmentally regulated: Implications to mRNA stability and protein binding
Authors: Rajan K. Shanmugha , Adler Katerina , Madmoni Hava , Peleg‐Chen Dana , Cohen‐Chalamish Smadar , Doniger Tirza , Galili Beathrice , Gerber Doron , Unger Ron , Tschudi Christian , Michaeli Shulamit 
Published: June 2021

AbstractThe parasite Trypanosoma brucei cycles between an insect and a mammalian host and is the causative agent of sleeping sickness. Here, we performed high‐throughput mapping of pseudouridines (Ψs) on mRNA from two life stages of the parasite. The analysis revealed ~273 Ψs, including developmentally regulated Ψs that are guided by homologs of pseudouridine synthases (PUS1, 3, 5, and 7). Mutating the U that undergoes pseudouridylation in the 3′ UTR of valyl‐tRNA synthetase destabilized the mRNA level. To investigate the mechanism by which Ψ affects the stability of this mRNA, proteins that bind to the 3′ UTR were identified, including the RNA binding protein RBSR1. The binding of RBSR1 protein to the 3′ UTR was stronger when lacking Ψ compared to transcripts carrying the modification, suggesting that Ψ can inhibit the binding of proteins to their target and thus affect the stability of mRNAs. Consequently, Ψ modification on mRNA adds an additional level of regulation to the dominant post‐transcriptional control in these parasites.
Vacuolar transporter Mnr2 safeguards organellar integrity in aged cells
Authors: Reza Md. Hashim , Patkar Rajesh , Sanyal Kaustuv 
Published: June 2021

AbstractAging is associated with altered mitochondrial function, which is dependent on the magnesium (Mg+2) ion flux. The molecular mechanism underlying Mg+2 homeostasis, especially during aging has not been well understood. We previously demonstrated that the absence of a vacuolar ion transporter Mnr2 accelerates cell death in the older part of the colony in Magnaporthe oryzae presumably due to an altered Mg+2 homeostasis. Here, we show the localization of Mnr2 as dynamic puncta at the vacuolar membrane, especially in the older Magnaporthe cells. Such vacuolar Mnr2 puncta are often localized in close proximity with the filamentous mitochondria in the older cells. Further, we show loss of integrity of mitochondria and vacuoles in older mnr2∆ null cells. Remarkably, exogenously added Mg+2 restores the mitochondrial structure as well as improves the lifespan of mnr2∆ null cells. Taken together, we propose an ion transporter Mnr2‐based Mg+2 homeostasis as a means in preserving mitochondrial and vacuolar integrity and function in older M. oryzae cells.
SnRK1.1‐mediated resistance of Arabidopsis thaliana to clubroot disease is inhibited by the novel Plasmodiophora brassicae effector PBZF1
Authors: Chen Wang , Li Yan , Yan Ruibin , Ren Li , Liu Fan , Zeng Lingyi , Sun Shengnan , Yang Huihui , Chen Kunrong , Xu Li , Liu Lijiang , Fang Xiaoping , Liu Shengyi 
Published: June 2021

AbstractPlants have evolved a series of strategies to combat pathogen infection. Plant SnRK1 is probably involved in shifting carbon and energy use from growth‐associated processes to survival and defence upon pathogen attack, enhancing the resistance to many plant pathogens. The present study demonstrated that SnRK1.1 enhanced the resistance of Arabidopsis thaliana to clubroot disease caused by the plant‐pathogenic protozoan Plasmodiophora brassicae. Through a yeast two‐hybrid assay, glutathione S‐transferase pull‐down assay, and bimolecular fluorescence complementation assay, a P. brassicae RxLR effector, PBZF1, was shown to interact with SnRK1.1. Further expression level analysis of SnRK1.1‐regulated genes showed that PBZF1 inhibited the biological function of SnRK1.1 as indicated by the disequilibration of the expression level of SnRK1.1‐regulated genes in heterogeneous PBZF1‐expressing A. thaliana. Moreover, heterogeneous expression of PBZF1 in A. thaliana promoted plant susceptibility to clubroot disease. In addition, PBZF1 was found to be P. brassicae‐specific and conserved. This gene was significantly highly expressed in resting spores. Taken together, our results provide new insights into how the plant‐pathogenic protist P. brassicae employs an effector to overcome plant resistance, and they offer new insights into the genetic improvement of plant resistance against clubroot disease.
G protein‐coupled receptor kinases are associated with Alzheimer's disease pathology
Authors: Guimarães Thais Rafael , Swanson Eric , Kofler Julia , Thathiah Amantha 
Published: June 2021

AbstractAimAlzheimer's disease (AD) is characterised by extracellular deposition of amyloid‐β (Aβ) in amyloid plaques and intracellular aggregation and accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs). Although several kinases have been identified to contribute to the pathological phosphorylation of tau, kinase‐targeted therapies for AD have not been successful in clinical trials. Critically, the kinases responsible for numerous identified tau phosphorylation sites remain unknown. G protein‐coupled receptor (GPCR) kinases (GRKs) have recently been implicated in phosphorylation of non‐GPCR substrates, for example, tubulin and α‐synuclein, and in neurological disorders, including schizophrenia and Parkinson's disease. Accordingly, we investigated the involvement of GRKs in the pathophysiology of AD.MethodsWe performed a comprehensive immunohistochemical and biochemical analysis of the ubiquitously expressed GRKs, namely, GRK2, 3, 5 and 6, in postmortem human brain tissue of control subjects and AD patients.ResultsGRKs display unique cell‐type‐specific expression patterns in neurons, astrocytes and microglia. Levels of GRKs 2, 5 and 6 are specifically decreased in the CA1 region of the AD hippocampus. Biochemical evidence indicates that the GRKs differentially associate with total, soluble and insoluble pools of tau in the AD brain. Complementary immunohistochemical studies indicate that the GRKs differentially colocalise with total tau, phosphorylated tau and NFTs. Notably, GRKs 3 and 5 also colocalise with amyloid plaques.ConclusionThese studies establish a link between GRKs and the pathological phosphorylation and accumulation of tau and amyloid pathology in AD brains and suggest a novel role for these kinases in regulation of the pathological hallmarks of AD.
Blinded review of hippocampal neuropathology in sudden unexplained death in childhood reveals inconsistent observations and similarities to explained paediatric deaths
Authors: Leitner Dominique F. , McGuone Declan , William Christopher , Faustin Arline , Askenazi Manor , Snuderl Matija , Guzzetta Melissa , Jarrell Heather S. , Maloney Katherine , Reichard Ross , Smith Colin , Weedn Victor , Wisniewski Thomas , Gould Laura , Devinsky Orrin 
Published: June 2021

AbstractAimsHippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls.MethodsHippocampal haematoxylin and eosin (H&E) slides (n = 67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by nine blinded reviewers: three board‐certified forensic pathologists, three neuropathologists and three dual‐certified neuropathologists/forensic pathologists.ResultsAmong nine reviewers, about 50% of hippocampal sections were rated as abnormal (52.5% SUDC, 53.0% controls), with no difference by cause of death (COD) (p = 0.16) or febrile seizure history (p = 0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' κ = 0.014, p = 0.47). Within reviewer groups, there were no findings more frequent in SUDC compared with controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD (p = 0.41).ConclusionsThe lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal maldevelopment associated with sudden death (HMASD). These findings underscore a need for larger studies to standardise evaluation of hippocampal findings, identifying the range of normal variation and changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.
Maternal serum 25‐hydroxyvitamin D levels and infant atopic dermatitis: A prospective cohort study
Authors: Tian Youping , Ye Ying , Zhang Yi , Dou Limin , Dou Yalan , Zhao Piaoping , Jiang Yuan , Gao Xiaohua , Zhang Xiaohua , Huang Jun , Xiao Liping , Wang Liuhui , Yan Weili 
Published: June 2021

AbstractBackgroundMaternal vitamin D status during pregnancy has been linked with the risk of atopic dermatitis (AD) in children, while the results were inconsistent. The objective of this study was to assess the potential association.MethodsSerum 25‐hydroxyvitamin D (25(OH)D) levels were measured in pregnant women from the birth cohort MKFOAD. Infant AD was diagnosed according to Williams' criteria. Multivariate logistic regression model was used to examine the association of maternal serum 25(OH)D levels in the first, second, and third trimester of gestation with the risk of infant AD at first year of age.ResultsIn total, 121 (26.5%) of 456 infants developed AD prior to 1 year of age. In general, higher maternal serum 25(OH)D levels throughout pregnancy were associated with increased risks of AD in infants prior to 1 year of age in multivariate logistic regression models, with borderline statistical significance in the first (per ln unit increase: adjusted OR = 1.93, 95% CI: 0.96, 3.88) and second (per ln unit increase: adjusted OR = 1.72, 95% CI: 0.93, 3.19) trimester. Multivariate logistic regression models using categorical variables of maternal 25(OH)D levels by tertiles showed similar results: Infants born to mothers with serum 25(OH)D levels in the highest tertile had higher risk of AD than those with 25(OH)D in the lowest tertile.ConclusionsThe present study found some evidence supporting that higher maternal 25(OH)D levels during pregnancy increased the risk of infant AD. However, the clinical implication of the findings should be limited for those with blood levels over the recommendations.
Faith Entails Belief: Three Avenues of Defense Against the Argument from Doubt
Authors: Mugg Joshua 
Published: June 2021

AbstractDoxasticism is the view that propositional faith entails belief. A common criticism of doxasticism is that faith seems compatible with doubt in a way that belief is not. Thus, it seems possible to have faith without belief, and several non‐doxasticist accounts of faith are motivated inter alia by the need to account for this type of doubt. I provide three avenues of response: (1) favored cases of faith without belief beg the question by stipulating faith‐that‐p‐without‐belief‐that‐p, or if the non‐doxasticist provides evidence that there is faith without belief, this evidence points to either (2) no‐faith‐that‐p‐because‐disbelief‐that‐p or (3) faith‐that‐p‐with‐belief‐that‐p.
High ambient temperature and child emergency and hospital visits in New York City
Authors: Niu Li , Herrera Maria Teresa , Girma Blean , Liu Bian , Schinasi Leah , Clougherty Jane E. , Sheffield Perry E. 
Published: June 2021

AbstractBackgroundEmerging literature has documented heat‐related impacts on child health, yet few studies have evaluated the effects of heat among children of different age groups and comparing emergency department (ED) and hospitalisation risks.ObjectivesTo examine the differing associations between high ambient temperatures and risk of ED visits and hospitalisations among children by age group in New York City (NYC).MethodsWe used New York Statewide Planning and Research Cooperative System (SPARCS) data on children aged 0–18 years admitted to NYC EDs (n = 2,252,550) and hospitals (n = 228,006) during the warm months (May‐September) between 2005 and 2011. Using a time‐stratified, case‐crossover design, we estimated the risk of ED visits and hospitalisations associated with daily maximum temperature (Tmax) for children of all ages and by age group.ResultsThe average Tmax over the study period was 80.3°F (range 50°, 104°F). Tmax conferred the greatest risk of ED visits for children aged 0–4, with a 6‐day cumulative excess risk of 2.4% (95% confidence interval [CI] 1.7, 3.0) per 13°F (ie interquartile range) increase in temperature. Children and adolescents 5–12 years (0.8%, 95% CI 0.1, 1.6) and 13–18 years (1.4%, 95% CI 0.6, 2.3) are also sensitive to heat. For hospitalisations, only adolescents 13–18 years had increased heat‐related risk, with a cumulative excess risk of 7.9% (95% CI 2.0, 14.2) per 13°F increase in Tmax over 85°F.ConclusionsThis urban study in NYC reinforces that young children are particularly vulnerable to effects of heat, but also demonstrates the sensitivity of older children and adolescents as well. These findings underscore the importance of focussing on children and adolescents in targeting heat illness prevention and emergency response activities, especially as global temperatures continue to rise.
Contemporary Concise Review 2020: Asthma
Authors: Wang Gang , McDonald Vanessa M. 
Published: June 2021

SUMMARY OF KEY POINTS
Bushfires and coronavirus 2019 (COVID‐19) were dominate features of 2020.
Patients with asthma were significantly affected by the 2019/2020 bushfire season with an increased burden compared to the general population.
Patients with controlled asthma do not appear to be at higher risk of severe COVID‐19 infection or death than the general population.
Personalized medicine is proposed as the next era for asthma management, with treatable traits as a strategy to implement personalized medicine into practice.
Patient engagement in personalized medicine strategies is important and needs to be further explored.
Oral corticosteroid (OCS) use in asthma is common and contributes a major burden. OCS stewardship is recommended.
Biologic therapies reduce exacerbations of severe asthma and biomarkers can be used to predict treatment responders.
Epithelia at mucosal and cutaneous surfaces are components in asthma pathogenesis, through airway immunity and inflammation.
Dysregulation of resident microbial communities in the lung, gut and skin microbiome is relevant to asthma pathogenesis, but there are still many unknowns in this field.