bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide association and multi-omic analyses reveal new mechanisms for Heart Failure
Authors: Arvanitis Marios , Zhang Yanxiao , Wang Wei , Auton Adam ,   23andMe Research Team, Keramati Ali , Chi Neil C. , Ren Bing , Post Wendy S. , Battle Alexis 
Published: September 2019

AbstractHeart failure is a major medical and economic burden in the healthcare system affecting over 23 million people worldwide. Although recent pedigree studies estimate heart failure heritability around 26%, genome-wide association studies (GWAS) have had limited success in explaining disease pathogenesis. We conducted the largest meta-analysis of heart failure GWAS to-date and replicated our findings in a comparable sized cohort to identify one known and two novel variants associated with heart failure. Leveraging heart failure sub-phenotyping and fine-mapping, we reveal a putative causal variant found in a cardiac muscle specific regulatory region that binds to the ACTN2 cardiac sarcolemmal gene and affects left ventricular adverse remodeling and clinical heart failure in response to different initial cardiac muscle insults. Via genetic correlation, we show evidence of broadly shared heritability between heart failure and multiple musculoskeletal traits. Our findings extend our understanding of biological mechanisms underlying heart failure.
Bi-directional effects between loneliness and substance use: Evidence from a Mendelian randomisation study
Authors: Greenstone Harriet S R , Wootton Robyn E , Abdellaoui Abdel , Denys Damiaan , Verweij Karin J H , Munafò Marcus R , Treur Jorien L 
Published: September 2019

AbstractAimsLoneliness and social isolation are associated with cigarette smoking and problematic alcohol use. Observational evidence suggests these associations arise because loneliness increases substance use, however there is potential for reverse causation (problematic drinking causing damage to social networks, leading to loneliness). With conventional epidemiological methods, controlling for (residual) confounding and reverse causality is difficult. In this study, we apply Mendelian randomisation (MR) to assess bi-directional causal effects between loneliness on the one hand and smoking behaviour and alcohol (ab)use on the other.DesignWe applied bi-directional MR using summary-level data of the largest available genome-wide association studies of loneliness (n=511,280), smoking (initiation (n=249,171), cigarettes-per-day (n=249,171) and cessation (n=143,852)), alcoholic drinks-per-week (n=226,223) and alcohol dependence (n=46,568), using independent samples. For each relationship, we selected genetic variants predictive of the exposure variable as instruments and tested their association with the outcome variable. Effect estimates for individual variants were combined with inverse-variance weighted regression (gene-outcome/gene-exposure association) and the robustness of these findings was assessed with five different sensitivity methods.FindingsThere was weak evidence of increased loneliness leading to higher likelihood of initiating smoking and smoking more cigarettes, and a lower likelihood of quitting smoking. Additionally, there was evidence that initiating smoking increases loneliness. We found no evidence of a causal effect between loneliness and alcohol (ab)use.ConclusionsWe report tentative evidence for causal, bidirectional, increasing effects between loneliness and cigarette smoking. These findings improve our understanding of the interrelatedness of smoking and loneliness, however, replication with better powered genetic instruments is recommended.
Plasminogenuria is associated with podocyte injury, edema, and kidney dysfunction in incident glomerular disease
Authors: Egerman Marc A. , Wong Jenny S. , Runxia Tian , Mosoyan Gohar , Chauhan Kinsuk , El Salem Fadi , Meliambro Kristin , Li Hong , Azeloglu Evren , Coca Steven , Campbell Kirk N. , Raij Leopoldo 
Published: September 2019

ABSTRACTUrinary plasminogen/plasmin, or plasmin(ogen)uria, has been demonstrated in proteinuric patients and exposure of cultured podocytes to plasminogen results in injury via oxidative stress pathways. A causative role for plasmin(ogen) as a “second hit” in kidney disease progression has yet to be demonstratedin vivo, and the association between plasmin(ogen)uria and kidney function in glomerular diseases remains unclear. We performed comparative studies in a puromycin aminonucleoside (PAN) nephropathy rat model treated with amiloride, an inhibitor of plasminogen activation, and measured changes in plasmin(ogen)uria and urinary endothelin-1 (ET1). In a glomerular disease biorepository cohort (n=128), we measured time-of-biopsy albuminuria, proteinuria, and plasmin(ogen)uria for correlations with renal outcomes. Increased glomerular plasmin(ogen) was found in PAN rats and FSGS patients. PAN nephropathy was associated with increases in plasmin(ogen)uria, proteinuria, and urinary ET1. Amiloride was protective against PAN-induced glomerular injury, reducing urinary ET1 and oxidative stress. In patients, we found associations between plasmin(ogen)uria and edema status as well as eGFR. Our study demonstrates a role for plasmin(ogen)-induced podocyte injury in the PAN nephropathy model, with amiloride having podocyte-protective properties. In one of largest glomerular disease cohorts to study plasminogen, we validated previous findings while suggesting a potentially novel relationship between plasmin(ogen)uria and eGFR. Together, these findings suggest a role for plasmin(ogen) in mediating glomerular injury and as a viable targetable biomarker for podocyte-sparing treatments.TRANSLATIONAL STATEMENTProteinuria is associated with CKD progression, and increased cardiovascular morbidity and mortality. The underlying mechanisms of podocyte injury, the hallmark of proteinuric kidney disease, are poorly understood with limited, non-specific therapeutic options. This study adds to the evidence that plasmin(ogen) in the urine of proteinuric patients is associated with podocyte injury, edema, and impaired renal function. Previously published results from us and others, taken together with our current rodent model and human data, suggest that urinary plasmin(ogen) is a potential targetable biomarker. Efforts to decrease plasmin(ogen)-mediated podocyte injury could be part of a novel therapeutic strategy for glomerular disease.
Does Pecs II Block Reduce the Incidence of Post Mastectomy Pain Syndrome (PMPS)? A Cross Sectional Study
Authors: Varma Vimal , Yeoh Chih N. , Lee Choon Y. , Azidin Azrin M. 
Published: September 2019

ABSTRACTBackground and ObjectivesPost mastectomy pain syndrome (PMPS) is a chronic pain condition that develops after breast cancer surgery. The objective of this study was to determine if Pecs II block administered prior to general anesthesia (GA) reduced the incidence of PMPS after mastectomy and axillary clearance (MAC) when compared with conventional analgesic therapy.MethodsThis cross sectional study compared incidence and severity of PMPS in 288 women who underwent unilateral MAC. Questionnaire survey was done via personal and telephone interview with 145 patients who received conventional analgesic therapy versus 143 patients who received Pecs II block. Outcomes assessed included incidence, severity and chronic pain symptom and sign score of PMPS.ResultsWe found a significantly lower incidence of PMPS in patients who received Pecs II block compared with conventional analgesic therapy [49.7% vs. 63.4%, OR 0.57 (0.36-0.91), P = 0.018], which was a 22% relative risk reduction (RR 0.78). Severity of PMPS in Pecs II group was also significantly reduced as shown by lower static and dynamic pain scores at operative site (P < 0.001). Furthermore, Pecs II group reported significantly lower Chronic Pain Symptom and Sign Score (P = 0.002) compared to conventional group.ConclusionsPecs II block prior to MAC significantly reduced the incidence of PMPS, severity of chronic pain at operative site and number of chronic pain symptoms and signs related to PMPS.This study is registered under National Medical Research Register. NMRR ID: 17-2627-38056
Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance
Authors: Bi Mingjun , Zhang Zhao , Xue Pengya , Hernandez Karen , Wang Hu , Fu Xiaoyong , De Angelis Carmine , Gao Zhen , Ruan Jianhua , Jin Victor X. , Wang Qianben , Marangoni Elisabetta , Huang Tim Hui-Ming , Chen Lizhen , Glass Christopher K. , Li Wei , Schiff Rachel , Liu Zhijie 
Published: September 2019

ABSTRACTAcquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ERα and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems including culture and xenograft models of MCF7 and T47D lines support a coordinate role of GATA3 and AP1 in enhancer reprogramming that promotes phenotypic plasticity and endocrine resistance. Collectively, our study implicates that changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression.
A reversible KO model reveals therapeutic potentials of defective Tregs
Authors: Li Yongqin , Chi Tian 
Published: September 2019

ABSTRACTTregs must be activated to suppress immune responses, but the transcriptional program controlling Treg activation remains incompletely understood. We previously found that Treg-specific deletion of the chromatin remodeling factor Brg1 impairs Treg activation and causes fatal autoimmunity in mice. Here, using a method that allows gene KO to be reversed in a Tamoxifen-dependent manner, we addressed whether reinstating Brg1 expression in the defective Tregs in the sick mice could restore Treg function, and if so, whether such Tregs could stop and resolve the fatal inflammation. We found that reexpressing Brg1 unexpectedly converted the defective Tregs into highly potent “SuperTregs”, which effectively rescued the dying mice. Remarkably, Brg1 reexpression in as little as 8% of the Tregs sufficed for the rescue in some cases. Brg1-deleted Tregs in the inflamed mice experienced excessive cytokine stimulation, became hyperactivated upon Brg1 reexpression and then deactivated as the inflammation subsided, suggesting that BRG1 acted in conjunction with inflammation to induce and maintain the SuperTreg phenotype. These data illustrate the power of reversible KO models in uncovering gene functions, and suggest a novel therapeutic strategy for IPEX(-related) disorders that exploits the defective Tregs and the inflammatory environment preexisting within the patients.
Single-cell profiling and SCOPE-seq reveal the lineage dynamics of adult neurogenesis and NOTUM as a key V-SVZ regulator
Authors: Mizrak Dogukan , Bayin N. Sumru , Yuan Jinzhou , Liu Zhouzerui , Suciu Radu , Niphakis Micah J. , Ngo Nhi , Lum Kenneth M. , Cravatt Benjamin F. , Joyner Alexandra L. , Sims Peter A. 
Published: September 2019

SUMMARYNeural stem cells (NSCs) and their progeny reside in specialized niches in the adult mammalian brain where they generate new neurons and glia throughout life. Adult NSCs of the ventricular-subventricular zone (V-SVZ) are prone to rapid exhaustion; thus timely, context-dependent neurogenesis demands adaptive signaling among the vast number of neighboring progenitors nestled between the ventricular surface and nearby blood vessels. To dissect adult neuronal lineage progression and regulation, we profiled >56,000 V-SVZ and olfactory bulb (OB) cells by single-cell RNA-sequencing (scRNA-seq). Our analyses revealed the diversity of V-SVZ-derived OB neurons, the temporal dynamics of lineage progression, and a key intermediate NSC population enriched for expression of Notum, which encodes a secreted WNT antagonist. Single Cell Optical Phenotyping and Expression (SCOPE-seq), a technology linking live cell imaging with scRNA-seq, uncovered dynamic control of cell size concomitant with NSC differentiation with Notum+ NSCs at a critical size poised for cell division, and a preference of NOTUM surface binding to neuronal precursors with active WNT signaling. Finally, in vivo pharmacological inhibition of NOTUM significantly expanded neuronal precursor pools in the V-SVZ. Our findings highlight a critical regulatory state during NSC activation marked by NOTUM, a secreted enzyme that ensures efficient neurogenesis by preventing WNT signaling activation in NSC progeny.
Gene-diet interactions: dietary rescue of metabolic defects inspen-depleted Drosophila
Authors: Gillette Claire M. , Hazegh Kelsey E. , Nemkov Travis , Stefanoni Davide , D’Alessandro Angelo , Taliaferro J. Matthew , Reis Tânia 
Published: September 2019

ABSTRACTObesity and its co-morbidities are a growing health epidemic. Interactions between genetic background and the environment and behavior (i.e. diet) greatly influence organismal energy balance. Previously, we described obesogenic mutations in the geneSplit ends(Spen) inDrosophila melanogaster, and roles for Spen in fat storage and metabolic state. In Spen-deficient storage cells lipid catabolism is impaired, accompanied by a compensatory increase in glycolytic flux and protein catabolism. Here we investigate gene-diet interactions to determine if diets supplemented with specific macronutrients can rescue metabolic dysfunction in Spen-depleted animals. We show that a high-yeast diet partially rescues adiposity and developmental defects. High sugar partially improves developmental timing as well as adult longevity. Gene-diet interactions were heavily influenced by developmental-stage-specific organismal needs: extra yeast provides benefits early in development (larval stages) but becomes detrimental in adulthood. High sugar confers benefits at both larval and adult stages, with the caveat of increased adiposity. A high-fat diet is detrimental according to all tested criteria, regardless of genotype. Whereas Spen depletion influenced phenotypic responses to supplemented diets, diet was the dominant factor in directing the whole-organism steady-state metabolome. Obesity is a complex disease of genetic, environmental, and behavioral inputs. Our results show that diet customization can ameloriate metabolic dysfunction underpinned by a genetic factor.
A20 is an immune tolerance factor that can determine islet transplant outcomes
Authors: Zammit Nathan W. , Walters Stacey N. , Seeberger Karen L. , Korbutt Gregory S. , Grey Shane T. 
Published: September 2019

AbstractIslet transplantation can restore lost glycemic control in type 1 diabetes subjects, but is restricted in its clinical application by limiting supplies of islets and the need for heavy immune suppression to prevent rejection.TNFAIP3, encoding the ubiquitin editing enzyme A20, regulates the activation of immune cells by raising NF-κB signalling thresholds. Here we show that increasing A20 expression in allogeneic islet grafts resulted in permanent survival for ~45 % of recipients, and >80% survival when combined with subtherapeutic rapamycin. Allograft survival was dependent upon regulatory T cells, was antigen-specific and grafts showed reduced expression of inflammatory factors, but increased TGFβ and IL-10. By analysing islets expressing an A20 coding mutation (I325N) that cripples A20’s OTU ubiquitin editing domain, we found that A20 regulates intra-graft RIPK1 levels to modulate NF-κB signalling. Transplantation of I325N islets resulted in increased NF-κB signalling, graft hyper-inflammation and acute allograft rejection. Neonatal porcine islets (NPI) represent a clinical alternative islet source but are readily rejected. However, forced A20 expression reduced NPI inflammation and increased their function after transplantation. Therapeutic administration of A20 raises NF-κB signalling thresholds and promotes islet allogeneic survival. Clinically this would allow for reduced immunosuppression supporting the use of alternate islet sources.
Arginine-enriched mixed-charge domains provide cohesion for nuclear speckle condensation
Authors: Greig Jamie A. , Nguyen Tu Anh , Lee Michelle , Holehouse Alex S. , Posey Ammon E. , Pappu Rohit V. , Jedd Gregory 
Published: September 2019

AbstractLow-complexity protein domains promote the formation of various biomolecular condensates. However, in many cases, the precise sequence features governing condensate formation and identity remain unclear. Here, we investigate the role of intrinsically disordered mixed-charge domains (MCDs) in nuclear speckle condensation. Proteins composed exclusively of arginine/aspartic-acid dipeptide repeats undergo length-dependent condensation and speckle incorporation. Substituting arginine with lysine in synthetic and natural speckle-associated MCDs abolishes these activities, identifying a key role for multivalent contacts through arginine’s guanidinium ion. MCDs can synergise with a speckle-associated RNA recognition motif to promote speckle specificity and residence. MCD behaviour is tuneable through net-charge: increasing negative charge abolishes condensation and speckle incorporation. By contrast, increasing positive charge through arginine leads to enhanced condensation, speckle enlargement, decreased splicing factor mobility, and defective mRNA export. Together, these results identify key sequence determinants of MCD-promoted speckle condensation, and link the speckle’s dynamic material properties with function in mRNA processing.
Motor behaviour selectively inhibits hair cells activated by forward motion in the lateral line of Zebrafish
Authors: Pichler Paul , Lagnado Leon 
Published: September 2019

SummaryHow do sensory systems disambiguate events in the external world from signals generated by the motor behaviour of the animal? One strategy is to suppress the sensory input whenever the motor system is active, but the cellular mechanisms remain unclear. We investigated how motor behaviour modulates signals transmitted by the lateral line of zebrafish, which senses pressure changes around the body of the animal. Activation of motor neurons during fictive swimming caused co-activation of efferent fibers and suppression of synaptic transmission from the primary mechanoreceptors, the hair cells. In some hair cells, a single motor spike inhibited glutamate release by about 50% and block was often complete within 50-100 ms of the start of swimming. All hair cells polarized to be activated by posterior deflections, as would occur during forward swimming, were suppressed by >90%, while only half of those polarized in the anterior direction were inhibited and by an average of just 45%. The selective inhibition of hair cells activated during motor behaviour provides a mechanism for the suppression of self-generated signals while maintaining sensitivity to stimuli originating in the external world.
A new kinetic method for measuring agonist efficacy and ligand bias using high resolution biosensors and a kinetic data analysis framework
Authors: Hoare Sam R.J. , Tewson Paul H. , Quinn Anne Marie , Hughes Thomas E. 
Published: September 2019

ABSTRACTThe kinetics/dynamics of signaling are of increasing value for G-protein-coupled receptor therapeutic development, including spatiotemporal signaling and the kinetic context of biased agonism. Effective application of signaling kinetics to developing new therapeutics requires reliable kinetic assays and an analysis framework to extract kinetic pharmacological parameters. Here we describe a platform for measuring arrestin recruitment kinetics to GPCRs using a high quantum yield, genetically encoded fluorescent biosensor, and a new analysis framework to quantify the recruitment kinetics. The sensor enabled high temporal resolution measurement of arrestin recruitment to the angiotensin AT1and vasopressin V2receptors. The analysis quantified the initial rate of arrestin signaling (kτ), a biologically-meaningful kinetic drug efficacy parameter, by fitting time course data using routine curve-fitting methods. Biased agonism was assessed by comparingkτvalues for arrestin recruitment with those for Gq signaling via the AT1receptor. Thekτratio values were in good agreement with bias estimates from existing methods. This platform potentially improves and simplifies assessment of biased agonism because the same assay modality is used to compare pathways (potentially in the same cells), the analysis method is parsimonious and intuitive, and kinetic context is factored into the bias measurement.
The financial health of Australian universities: policy implications in a changing environment
Authors: Irvine Helen , Ryan Christine 
Published: September 2019

Purpose
In the context of the Australian Government’s attempts to impose budget austerity measures on publicly funded universities in its higher education sector, the purpose of this paper is to assess the sector’s financial health.

Design/methodology/approach
The multi-dimensional study is based on seven years of government financial data from all 39 publicly funded Australian universities, supplemented by information from universities’ annual reports. Using a financial health model that reflects vulnerability, viability and resilience, the authors examine sector data using a suite of metrics. The authors analyse differences between those universities in the Top 10 and Bottom 10 by revenue, as a window into the financial health of the sector at large.

Findings
While mostly financially viable, the sector shows signs of financial vulnerability, particularly in the areas of expense control and financial sustainability. Possibly in response to an uncertain funding environment, universities are managing long-term liquidity by growing reserves. Debt represents largely untapped potential for universities, while differences between the Top 10 and Bottom 10 universities were most evident in the area of revenue diversity, a strong predictor of financial viability.

Research limitations/implications
Focussing on a specific set of financial metrics limits the scope of the study, but highlights further research possibilities. These include more detailed statistical analysis of data, financial case studies of individual universities and the implications of revenue diversification on academic standards.

Originality/value
The paper contributes to higher education literature, providing empirical evidence of universities’ finances. It highlights the importance of universities’ financial resilience in an uncertain funding environment.