bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intensive Blood Pressure Treatment Goals: Evidence for Cardiovascular Protection From Observational Studies and Clinical Trials
Authors: Whelton Paul K , Bundy Joshua D , Carey Robert M 
Published: April 2022

Abstract
Epidemiologic studies have consistently identified a strong, progressive relationship between blood pressure (BP) and cardiovascular disease (CVD) events, in a range of systolic BP (SBP) from as low as 90 mm Hg to as high as 180 mm Hg. Clinical trials have demonstrated greater prevention of CVD with more compared with less intensive antihypertensive drug treatment. Meta-analyses of randomized controlled trials provide strong evidence for more intensive antihypertensive drug therapy down to an SBP of 130 mm Hg, and to an SBP 120–124 mm Hg in the meta-analysis with the greatest statistical power. In the Systolic Blood Pressure Intervention Trial (SPRINT) randomization to an SBP treatment goal of &lt;120 mm Hg compared with &lt;140 mm Hg in persons with high CVD risk not only reduced the rate of CVD but also all-cause mortality. These benefits were noted in all of the prestated subgroups of interest, including those ≥65 years of age at baseline. In addition, cognitive impairment was less common in those randomized to the intensive compared with standard treatment. Most clinical practice guidelines recommend an SBP treatment target &lt;130 mm Hg in adults with a high risk of CVD, which is the norm for many patients seen in clinical practice, especially those who are older, have diabetes mellitus, or chronic kidney disease.
Interspecific morphological variation in Juglandoideae resting bud organization: a winter’s tale?
Authors: Schoonderwoerd Kristel M , Friedman William E 
Published: April 2022

AbstractBackground and AimsDormant resting buds are frequently regarded as static units, with protective cataphylls on the outside and embryonic foliage leaves on the inside. How the presence of cataphylls influences the dynamic, cyclical, annually repeating sequence of leaf forms that a resting bud gives rise to has rarely been interrogated. To examine the connection between dormant structure and growing-season development, we compare the complete seasonal heteroblastic sequence of leaf forms of six species of temperate Juglandaceae with distinctly different vegetative resting bud structures. These include buds with cataphylls; buds without cataphylls; and buds with caducous cataphylls that are lost before the onset of winter.MethodsIn a common garden setting over a 7-month growing season, the dimensions of 2249 individual vegetative metamers were tracked from first exposure to abscission along the shoots of saplings and mature trees. The timing of metamer initiation within terminal buds was investigated using micro-CT scanning. Character state transitions of resting bud types were estimated using a phylogenetic tree of Juglandaceae.Key ResultsThe presence of cataphylls within a heteroblastic sequence is associated with a single cohort of foliage leaves that flush and abscise synchronously. This growing pattern is highly determinate, with next year’s terminal-bud cataphylls already initiated before spring leaf out. In contrast, in sequences without cataphylls, shorter-lived foliage leaves appear and abscise in a staggered fashion. Despite these differences in leaf demography, all examined heteroblastic sequences produce a series of small, caducous leaf forms that precede terminal bud set.ConclusionsThe ubiquity of caducous leaf forms in Juglandoideae may point to the importance of shoot tip protection far beyond the dormant season. In addition, the presence or absence of cataphylls in resting buds is indicative of distinct shoot ontogenetic patterns, and functional strategies, in summer.
Mining hidden knowledge: embedding models of cause–effect relationships curated from the biomedical literature
Authors: Krämer Andreas , Green Jeff , Billaud Jean-Noël , Pasare Nicoleta Andreea , Jones Martin , Tugendreich Stuart 
Published: April 2022

Abstract

Motivation
We explore the use of literature-curated signed causal gene expression and gene–function relationships to construct unsupervised embeddings of genes, biological functions and diseases. Our goal is to prioritize and predict activating and inhibiting functional associations of genes and to discover hidden relationships between functions. As an application, we are particularly interested in the automatic construction of networks that capture relevant biology in a given disease context.

Results
We evaluated several unsupervised gene embedding models leveraging literature-curated signed causal gene expression findings. Using linear regression, we show that, based on these gene embeddings, gene–function relationships can be predicted with about 95% precision for the highest scoring genes. Function embedding vectors, derived from parameters of the linear regression model, allow inference of relationships between different functions or diseases. We show for several diseases that gene and function embeddings can be used to recover key drivers of pathogenesis, as well as underlying cellular and physiological processes. These results are presented as disease-centric networks of genes and functions. To illustrate the applicability of our approach to other machine learning tasks, we also computed embeddings for drug molecules, which were then tested using a simple neural network to predict drug–disease associations.

Availability and implementation
Python implementations of the gene and function embedding algorithms operating on a subset of our literature-curated content as well as other code used for this paper are made available as part of the Supplementary data.

Supplementary information
Supplementary data are available at Bioinformatics Advances online.
Prediction of RNA–protein interactions using a nucleotide language model
Authors: Yamada Keisuke , Hamada Michiaki 
Published: April 2022

Abstract

Motivation
The accumulation of sequencing data has enabled researchers to predict the interactions between RNA sequences and RNA-binding proteins (RBPs) using novel machine learning techniques. However, existing models are often difficult to interpret and require additional information to sequences. Bidirectional encoder representations from transformer (BERT) is a language-based deep learning model that is highly interpretable. Therefore, a model based on BERT architecture can potentially overcome such limitations.

Results
Here, we propose BERT-RBP as a model to predict RNA–RBP interactions by adapting the BERT architecture pretrained on a human reference genome. Our model outperformed state-of-the-art prediction models using the eCLIP-seq data of 154 RBPs. The detailed analysis further revealed that BERT-RBP could recognize both the transcript region type and RNA secondary structure only based on sequence information. Overall, the results provide insights into the fine-tuning mechanism of BERT in biological contexts and provide evidence of the applicability of the model to other RNA-related problems.

Availability and implementation
Python source codes are freely available at https://github.com/kkyamada/bert-rbp. The datasets underlying this article were derived from sources in the public domain: [RBPsuite (http://www.csbio.sjtu.edu.cn/bioinf/RBPsuite/), Ensembl Biomart (http://asia.ensembl.org/biomart/martview/)].

Supplementary information
Supplementary data are available at Bioinformatics Advances online.
Semaglutide for treatment of obesity in hemodialysis patients waiting for a kidney transplant: new hope?
Authors: Touzot Maxime , Ureña-Torres Pablo , Dupuy Olivier 
Published: April 2022

ABSTRACT
Obesity limits the access to kidney transplantation and increases the risk of complications and mortality posttransplantation. Usual noninvasive measures, including lifestyle changes and dietary education, do not provide long-term and consistent body weight reduction. In many cases, only bariatric surgery allows patients to significantly reduce body weight. We here report two cases of obese hemodialysis (HD) patients who were successfully treated with off-labeled semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA). The first patient had a body mass index (BMI) of 45.7 kg/m2 despite a history of partial gastrectomy. The second patient had a history of type 2 diabetes mellitus and a BMI of 36.5 kg/m2. Both patients started semaglutide at the maximal subcutaneous dose of 1 mg/week, which was clinically well tolerated. During the 9-month follow-up, body weight loss ranged from 6.5 to 9.0 kg, ∼1 kg/month. GLP-1RAs, such as semaglutide or liraglutide, could be a novel pharmacological alternative to bariatric surgeries for these HD patients.
A mitochondrial long-chain fatty acid oxidation defect leads to transfer RNA uncharging and activation of the integrated stress response in the mouse heart
Authors: Ranea-Robles Pablo , Pavlova Natalya N , Bender Aaron , Pereyra Andrea S , Ellis Jessica M , Stauffer Brandon , Yu Chunli , Thompson Craig B , Argmann Carmen , Puchowicz Michelle , Houten Sander M 
Published: April 2022

Abstract

Aims
Cardiomyopathy and arrhythmias can be severe presentations in patients with inherited defects of mitochondrial long-chain fatty acid β-oxidation (FAO). The pathophysiological mechanisms that underlie these cardiac abnormalities remain largely unknown. We investigated the molecular adaptations to a FAO deficiency in the heart using the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse model.

Methods and results
We observed enrichment of amino acid metabolic pathways and of ATF4 target genes among the upregulated genes in the LCAD KO heart transcriptome. We also found a prominent activation of the eIF2α/ATF4 axis at the protein level that was independent of the feeding status, in addition to a reduction of cardiac protein synthesis during a short period of food withdrawal. These findings are consistent with an activation of the integrated stress response (ISR) in the LCAD KO mouse heart. Notably, charging of several transfer RNAs (tRNAs), such as tRNAGln was decreased in LCAD KO hearts, reflecting a reduced availability of cardiac amino acids, in particular, glutamine. We replicated the activation of the ISR in the hearts of mice with muscle-specific deletion of carnitine palmitoyltransferase 2.

Conclusions
Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact cardiac metabolic signalling, in particular the ISR. These results may serve as a foundation for investigating the role of the ISR in the cardiac pathology associated with long-chain FAO defects.
Translational Perspective: The heart relies mainly on mitochondrial fatty acid β-oxidation (FAO) for its high energy requirements. The heart disease observed in patients with a genetic defect in this pathway highlights the importance of FAO for cardiac health. We show that the consequences of a FAO defect extend beyond cardiac energy homeostasis and include amino acid metabolism and associated signalling pathways such as the integrated stress response.
Frequent premature atrial contractions as a signalling marker of atrial cardiomyopathy, incident atrial fibrillation, and stroke
Authors: Farinha José Maria , Gupta Dhiraj , Lip Gregory Y H 
Published: April 2022

AbstractPremature atrial contractions are a common cardiac phenomenon. Although previously considered a benign electrocardiographic finding, they have now been associated with a higher risk of incident atrial fibrillation (AF) and other adverse outcomes such as stroke and all-cause mortality. Since premature atrial contractions can be associated with these adverse clinical outcomes independently of AF occurrence, different explanations have being proposed. The concept of atrial cardiomyopathy, where AF would be an epiphenomenon outside the causal pathway between premature atrial contractions and stroke has received traction recently. This concept suggests that structural, functional, and biochemical changes in the atria lead to arrhythmia occurrence and thromboembolic events. Some consensus about diagnosis and treatment of this condition have been published, but this is based on scarce evidence, highlighting the need for a clear definition of excessive premature atrial contractions and for prospective studies regarding antiarrhythmic therapies, anticoagulation or molecular targets in this group of patients.
Markups and Financial Shocks
Authors: Meinen Philipp , Soares Ana Cristina 
Published: April 2022

Abstract
This paper analyses the impact of financial frictions on markup adjustments at the firm level. We use a rich panel data set that matches information on banking relationships with firm-level data. By relying on insights from recent contributions in the literature, we obtain exogenous credit supply shifters and markups that are both firm specific and time varying. We uncover new findings at this level. In particular, firms more exposed to liquidity risks tend to raise markups in response to negative bank-loan supply shocks, while less exposed firms generally reduce them. Further empirical analyses suggest that our findings are mostly consistent with models featuring a sticky customer base, where financially constrained firms have an incentive to raise markups in order to sustain liquidity without losing too many customers. Our results have important economic implications regarding the cyclicality of the aggregate markup.
Hidden Costs of Fire Exclusion in Longleaf Pine Forests Linked to Duff And Carbon Management
Authors: Susaeta Andres , Fill Jennifer , Crandall Raelene , Varner J Morgan 
Published: April 2022

AbstractThe reintroduction of fire to long-unburned pine ecosystems is a silvicultural tool to restore their ecological and economic value. However, if prescribed fire is used after long periods of fire exclusion, high amounts of duff consumed during fire can result in tree stress and mortality. Prescribed burning with a focus on managing duff has therefore been recommended for mitigating negative impacts on overstory trees when fire is reintroduced. We modeled the economic outcomes of different forest management scenarios related to burning for duff management in even-aged longleaf pine stands. We considered five management scenarios in which we varied prescribed fire use, thinnings, mortality rates, and salvage logging. Our findings indicate that burning for duff management without and with thinnings can be considered the most economically viable strategy ($1593/ha–$966/ha).
Reduction in leaf size at higher altitudes across 39 broad-leaved herbaceous species on the northeastern Qinghai-Tibetan Plateau
Authors: Ke Xinran , Kang Huixing , Tang Yanhong 
Published: April 2022

Abstract
Leaf size varies conspicuously within and among species under different environments. However, it is unclear how leaf size would change with elevation, whether there is a general elevational pattern, and what determines the altitudinal variation of leaf size. We thus aimed to address these questions by focusing on the broad-leaved herbaceous species at high altitudes on the northeastern Qinghai-Tibetan Plateau. We measured the leaf size, leaf length, leaf width and leaf mass per area for 39 broad-leaved herbaceous species inhabited in the open areas along two mountain slopes from 3200 to 4400 m at the Lenglongling and the Daban Mountain, the northeastern Qinghai-Tibetan Plateau. We analyzed the altitudinal patterns in leaf size in relation to leaf inclination and leaf surface features, and applied a leaf energy balance model to discuss the underlying mechanisms. Leaf size decreased significantly at higher altitudes. The altitudinal reduction of leaf size was mainly attributed to the reduction of leaf length, and differed in different species, and in leaves with different inclination and leaf surface features. A leaf energy balance model with local environmental measurements demonstrates that leaf temperature tracks air temperature more closely in small than in large leaves, and that the leaf-size impact is stronger at higher latitudes. Based on the observational findings, we propose that the distribution upper-limit for broad-leaved herbaceous species would be at an elevation of about 5400 m on the northeastern Qinghai-Tibetan Plateau.
The importance of ecotype diversity on duckweed growth with and without salt stress
Authors: van Moorsel Sofia J 
Published: April 2022

Abstract
The pollution of freshwater ecosystems is threatening freshwater plant species diversity worldwide. Freshwater plants, such as the common duckweed (Lemna minor), are potentially sensitive to novel stressful environments. To test if ecotype diversity could increase resistance to stressful environments, I used seven L. minor populations and measured their growth rates with and without moderate salt stress across an ecotype diversity gradient. The L. minor populations were grown over 5 months in 92 experimental mesocosms, either in ecotype monocultures or in polyculture with either one or three conspecific ecotypes (23 unique compositions). After growing the duckweed in unperturbed conditions (phase 1), the cultures were subjected to moderate salt stress (50 mmol/L NaCl) for several weeks (phase 2). The experiment was conducted in the presence of the natural epimicrobial community associated with the different ecotypes. In phase 2, a subset of these algae added an unintentional second stressor to the experiment. The ecotypes differed in their growth rates, the fastest growing at twice the rate of others. The diversity context further shaped the ecotype growth rates. Ecotype polycultures showed higher abundances towards the end of the experiment, thus over time, as the environment deteriorated, ecotype diversity gained in importance. These findings show that within-species variation in growth rates can translate to a positive effect of ecotype diversity on population abundance. Exposure of L. minor to moderate salt levels did not significantly impact growth rates, although the effect may have been masked by reduced algal stress in the saline environments.
Machine-learning of complex evolutionary signals improves classification of SNVs
Authors: Labes Sapir , Stupp Doron , Wagner Naama , Bloch Idit , Lotem Michal , L. Lahad Ephrat , Polak Paz , Pupko Tal , Tabach Yuval 
Published: April 2022

AbstractConservation is a strong predictor for the pathogenicity of single-nucleotide variants (SNVs). However, some positions that present complex conservation patterns across vertebrates stray from this paradigm. Here, we analyzed the association between complex conservation patterns and the pathogenicity of SNVs in the 115 disease-genes that had sufficient variant data. We show that conservation is not a one-rule-fits-all solution since its accuracy highly depends on the analyzed set of species and genes. For example, pairwise comparisons between the human and 99 vertebrate species showed that species differ in their ability to predict the clinical outcomes of variants among different genes using conservation. Furthermore, certain genes were less amenable for conservation-based variant prediction, while others demonstrated species that optimize prediction. These insights led to developing EvoDiagnostics, which uses the conservation against each species as a feature within a random-forest machine-learning classification algorithm. EvoDiagnostics outperformed traditional conservation algorithms, deep-learning based methods and most ensemble tools in every prediction-task, highlighting the strength of optimizing conservation analysis per-species and per-gene. Overall, we suggest a new and a more biologically relevant approach for analyzing conservation, which improves prediction of variant pathogenicity.
High unmet treatment needs in patients with chronic kidney disease and type 2 diabetes: real-world evidence from a US claims database
Authors: Fried Linda , Schmedt Niklas , Folkerts Kerstin , Bowrin Kevin , Raad Hanaya , Batech Michael , Kovesdy Csaba 
Published: April 2022

AbstractBackgroundChronic kidney disease (CKD), a serious complication of type 2 diabetes (T2D) increases the comorbid risk of cardiovascular disease (CVD) and end-stage kidney disease(ESKD). Treatment guidelines recommend renin–angiotensin blockade and antihyperglycemic treatment with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2is) as first-line treatment. We evaluated treatment initiation and discontinuation overall and in subgroups of T2D patients with incident CKD (incident cohort) and rates of clinical and economic outcomes in patients with T2D and any CKD (prevalent cohort).MethodsIn this retrospective study of administrative claims in the USA between 1 January 2007 and 31 March 2019, we evaluated the proportion of patients with concomitant, newly initiated and discontinued use of antihypertensive [angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blockers (ARBs), steroidal mineralocorticoid receptor antagonists (sMRAs)] and antidiabetic [SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), insulin and sulfonylureas] medications, rates of clinical outcomes per 1000 person-years and mean total healthcare costs.ResultsWe identified 63 127 and 326 763 patients in the incident and prevalent CKD cohorts, respectively. Low initiation and high discontinuation rates were observed with 17.8% and 56.0% for ACEi/ARBs, 1.3% and 66.0% for sMRAs, 2.5% and 65.0% for SGLT2is, 3.7% and 66.8% for DPP4is, 2.31% and 69.0% for GLP-1 RAs, 4% and 75.7% for insulin and 5.5% and 56.9% for sulfonylureas. Similar results were seen by subgroups. Rates of clinical outcomes ranged from 35.07 per 1000 person-years for all-cause mortality to 104.19 for ESKD, with rates of hospitalization ranging from 36.61 for kidney hospitalizations to 283.14 for all-cause hospitalizations. Among patients with comorbidities, higher clinical and economic outcomes were found.ConclusionOur results highlight high unmet needs of CKD and T2D, particularly subgroups of patients with multimorbid CVD, high-risk CKD (low estimated glomerular filtration rate or high urinary albumin:creatinine ratio) or rapidly progressing CKD. Low initiation and high discontinuation of recommended treatments suggest that adherence to guidelines for halting CKD progression is suboptimal. These high-risk patients may benefit from further treatment options to improve morbidity and mortality and reduce the economic burden.
Barriers to Worldwide Access for Paxlovid, a New Treatment for COVID-19
Authors: Pepperrell Toby , Ellis Leah , Wang Junzheng , Hill Andrew 
Published: April 2022

Abstract
Pfizer and the Medicines Patent Pool (MPP) have reached a voluntary licensing agreement for Paxlovid (nirmatrelvir+ritonavir), a novel antiviral for coronavirus disease 2019 (COVID-19) taken orally in the first 5 days from symptom onset. The Pfizer-MPP deal enables 95 low- and middle-income countries (L/MICs) to access affordable biosimilars. Generics are delayed awaiting bioequivalence testing and may be ineffective in L/MICs with reduced testing capacity, which comprise only 10% of global diagnoses. Thirty-nine percent of diagnoses originate in MICs forced to pay high prices due to exclusion from the Pfizer-MPP deal. The cost-effectiveness of Paxlovid could be limited compared with the creation of sustainable vaccine infrastructure in these nations, delaying socioeconomic pandemic recovery. Furthermore, Paxlovid may not be cost-effective in vaccinated populations, and concerns remain over ritonavir drug interactions with COVID-19 comorbidity medications. We call for expanded coverage by the Paxlovid-MPP deal and greater access to testing.