bluuebunny/crossref_metadata_2025_split huggingface dataset:
CircNet 2.0: an updated database for exploring circular RNA regulatory networks in cancers
Authors: Chen Yigang , Yao Lantian , Tang Yun , Jhong Jhih-Hua , Wan Jingting , Chang Jingyue , Cui Shidong , Luo Yijun , Cai Xiaoxuan , Li Wenshuo , Chen Qi , Huang Hsi-Yuan , Wang Zhuo , Chen Weiming , Chang Tzu-Hao , Wei Fengxiang , Lee Tzong-Yi , Huang Hsien-Da 
Published: October 2021

Abstract
Circular RNAs (circRNAs), which are single-stranded RNA molecules that have individually formed into a covalently closed continuous loop, act as sponges of microRNAs to regulate transcription and translation. CircRNAs are important molecules in the field of cancer diagnosis, as growing evidence suggests that they are closely related to pathological cancer features. Therefore, they have high potential for clinical use as novel cancer biomarkers. In this article, we present our updates to CircNet (version 2.0), into which circRNAs from circAtlas and MiOncoCirc, and novel circRNAs from The Cancer Genome Atlas database have been integrated. In total, 2732 samples from 37 types of cancers were integrated into CircNet 2.0 and analyzed using several of the most reliable circRNA detection algorithms. Furthermore, target miRNAs were predicted from the full-length circRNA sequence using three reliable tools (PITA, miRanda and TargetScan). Additionally, 384 897 experimentally verified miRNA–target interactions from miRTarBase were integrated into our database to facilitate the construction of high-quality circRNA–miRNA–gene regulatory networks. These improvements, along with the user-friendly interactive web interface for data presentation, search, and visualization, showcase the updated CircNet database as a powerful, experimentally validated resource, for providing strong data support in the biomedical fields. CircNet 2.0 is currently accessible at https://awi.cuhk.edu.cn/∼CircNet.
miRTarBase update 2022: an informative resource for experimentally validated miRNA–target interactions
Authors: Huang Hsi-Yuan , Lin Yang-Chi-Dung , Cui Shidong , Huang Yixian , Tang Yun , Xu Jiatong , Bao Jiayang , Li Yulin , Wen Jia , Zuo Huali , Wang Weijuan , Li Jing , Ni Jie , Ruan Yini , Li Liping , Chen Yidan , Xie Yueyang , Zhu Zihao , Cai Xiaoxuan , Chen Xinyi , Yao Lantian , Chen Yigang , Luo Yijun , LuXu Shupeng , Luo Mengqi , Chiu Chih-Min , Ma Kun , Zhu Lizhe , Cheng Gui-Juan , Bai Chen , Chiang Ying-Chih , Wang Liping , Wei Fengxiang , Lee Tzong-Yi , Huang Hsien-Da 
Published: October 2021

AbstractMicroRNAs (miRNAs) are noncoding RNAs with 18–26 nucleotides; they pair with target mRNAs to regulate gene expression and produce significant changes in various physiological and pathological processes. In recent years, the interaction between miRNAs and their target genes has become one of the mainstream directions for drug development. As a large-scale biological database that mainly provides miRNA–target interactions (MTIs) verified by biological experiments, miRTarBase has undergone five revisions and enhancements. The database has accumulated &gt;2 200 449 verified MTIs from 13 389 manually curated articles and CLIP-seq data. An optimized scoring system is adopted to enhance this update’s critical recognition of MTI-related articles and corresponding disease information. In addition, single-nucleotide polymorphisms and disease-related variants related to the binding efficiency of miRNA and target were characterized in miRNAs and gene 3′ untranslated regions. miRNA expression profiles across extracellular vesicles, blood and different tissues, including exosomal miRNAs and tissue-specific miRNAs, were integrated to explore miRNA functions and biomarkers. For the user interface, we have classified attributes, including RNA expression, specific interaction, protein expression and biological function, for various validation experiments related to the role of miRNA. We also used seed sequence information to evaluate the binding sites of miRNA. In summary, these enhancements render miRTarBase as one of the most research-amicable MTI databases that contain comprehensive and experimentally verified annotations. The newly updated version of miRTarBase is now available at https://miRTarBase.cuhk.edu.cn/.
7′,5′-alpha-bicyclo-DNA: new chemistry for oligonucleotide exon splicing modulation therapy
Authors: Evéquoz Damien , Verhaart Ingrid E C , van de Vijver Davy , Renner Wolfgang , Aartsma-Rus Annemieke , Leumann Christian J 
Published: October 2021

Abstract
Antisense oligonucleotides are small pieces of modified DNA or RNA, which offer therapeutic potential for many diseases. We report on the synthesis of 7′,5′-α-bc-DNA phosphoramidite building blocks, bearing the A, G, T and MeC nucleobases. Solid-phase synthesis was performed to construct five oligodeoxyribonucleotides containing modified thymidine residues, as well as five fully modified oligonucleotides. Incorporations of the modification inside natural duplexes resulted in strong destabilizing effects. However, fully modified strands formed very stable duplexes with parallel RNA complements. In its own series, 7′,5′-α-bc-DNA formed duplexes with a surprising high thermal stability. CD spectroscopy and extensive molecular modeling indicated the adoption by the homo-duplex of a ladder-like structure, while hetero-duplexes with DNA or RNA still form helical structure. The biological properties of this new modification were investigated in animal models for Duchenne muscular dystrophy and spinal muscular atrophy, where exon splicing modulation can restore production of functional proteins. It was found that the 7′,5′-α-bc-DNA scaffold confers a high biostability and a good exon splicing modulation activity in vitro and in vivo.
Disruption of Hydrogen Gas Synthesis Enhances the Cellular Levels of NAD(P)H, Glycogen, Poly(3-hydroxybutyrate) and Photosynthetic Pigments Under Specific Nutrient Condition(s) in Cyanobacterium Synechocystis sp. PCC 6803
Authors: Sukkasam Nannaphat , Incharoensakdi Aran , Monshupanee Tanakarn 
Published: October 2021

Abstract
In photoautotrophic Synechocystis sp. PCC 6803, NADPH is generated from photosynthesis and utilized in various metabolism, including the biosynthesis of glyceraldehyde 3-phosphate (the upstream substrate for carbon metabolism), poly(3-hydroxybutyrate) (PHB), photosynthetic pigments, and hydrogen gas (H2). Redirecting NADPH flow from one biosynthesis pathway to another has yet to be studied. Synechocystis’s H2 synthesis, one of the pathways consuming NAD(P)H, was disrupted by the inactivation of hoxY and hoxH genes encoding the two catalytic subunits of hydrogenase. Such inactivation with a complete disruption of H2 synthesis led to 1.4-, 1.9-, and 2.1-fold increased cellular NAD(P)H levels when cells were cultured in normal medium (BG11), the medium without nitrate (-N), and the medium without phosphate (-P), respectively. After 49–52 d of cultivation in BG11 (when the nitrogen source in the media was depleted), the cells with disrupted H2 synthesis had 1.3-fold increased glycogen level compared to wild type of 83–85% (w/w dry weight), the highest level reported for cyanobacterial glycogen. The increased glycogen content observed by transmission electron microscopy was correlated with the increased levels of glucose 6-phosphate and glucose 1-phosphate, the two substrates in glycogen synthesis. Disrupted H2 synthesis also enhanced PHB accumulation up to 1.4-fold under -P and 1.6-fold under -N and increased levels of photosynthetic pigments (chlorophyll a, phycocyanin, and allophycocyanin) by 1.3- to 1.5-fold under BG11. Thus, disrupted H2 synthesis increased levels of NAD(P)H, which may be utilized for the biosynthesis of glycogen, PHB, and pigments. This strategy might be applicable for enhancing other biosynthetic pathways that utilize NAD(P)H.
The influence of spring warming and food chain length on plankton phenology in subtropical shallow lakes: a mesocosm study
Authors: He Hu , Ning Xiaoyu , Chen Kunquan , Li Qisheng , Han Yanqing , Huang Xiaolong , Li Kuanyi , Liu Zhengwen , Jeppesen Erik 
Published: October 2021

Abstract
Numerous studies have shown that warming advances spring phenology in various ecosystems. However, few studies explicitly consider the effect of food web structure, e.g. food chain length (FCL), and most studies have focused on temperate systems. We investigated the effect of vernal warming on the spring phenology of a key herbivore, Daphnia galeata (hereafter Daphnia), and its prey, phytoplankton, in subtropical shallow aquatic mesocosms in the presence and absence of the planktivorous fish Aristichthys nobilis, simulating food chains with two or three trophic levels. The warming effect on the timing of the spring phytoplankton peak varied with the FCL. Warming led to the disappearance of the phytoplankton peak in the 2-level systems but resulted in an extensive, delayed phytoplankton peak in the 3-level systems. Irrespective of the FCL, warming did not significantly advance the timing of the Daphnia peak, although Daphnia recruited earlier under warm conditions. Both warming and FCL significantly reduced the size of the Daphnia peak. Our study suggests that spring warming affects the plankton spring phenology in subtropical shallow lakes, but the response patterns depend on the food web structure.
Using continuous directed evolution to improve enzymes for plant applications
Authors: García-García Jorge D , Van Gelder Kristen , Joshi Jaya , Bathe Ulschan , Leong Bryan J , Bruner Steven D , Liu Chang C , Hanson Andrew D 
Published: October 2021

Abstract
Continuous directed evolution of enzymes and other proteins in microbial hosts is capable of outperforming classical directed evolution by executing hypermutation and selection concurrently in vivo, at scale, with minimal manual input. Provided that a target enzyme’s activity can be coupled to growth of the host cells, the activity can be improved simply by selecting for growth. Like all directed evolution, the continuous version requires no prior mechanistic knowledge of the target. Continuous directed evolution is thus a powerful way to modify plant or non-plant enzymes for use in plant metabolic research and engineering. Here, we first describe the basic features of the yeast (Saccharomyces cerevisiae) OrthoRep system for continuous directed evolution and compare it briefly with other systems. We then give a step-by-step account of three ways in which OrthoRep can be deployed to evolve primary metabolic enzymes, using a THI4 thiazole synthase as an example and illustrating the mutational outcomes obtained. We close by outlining applications of OrthoRep that serve growing demands (i) to change the characteristics of plant enzymes destined for return to plants, and (ii) to adapt (“plantize”) enzymes from prokaryotes—especially exotic prokaryotes—to function well in mild, plant-like conditions.
Trade Finance and the Durability of the Dollar
Authors: Chahrour Ryan , Valchev Rosen 
Published: October 2021

Abstract
We propose a model in which the emergence of a single dominant currency is driven by the need to finance international trade. The model generates multiple stable steady states, each characterized by a different dominant asset, consistent with the historical durability of real-world currency regimes. The persistence of regimes is caused by a positive interaction between the returns to saving in an asset and the use of that asset for financing trade. A calibrated version of the model shows that the welfare gains of dominance are substantial, but accrue primarily during the transition to dominance. We perform several counterfactual experiments to assess potential threats to the dollar’s continued dominance.
Comomentum: Inferring Arbitrage Activity from Return Correlations
Authors: Lou Dong , Polk Christopher 
Published: October 2021

Abstract
We propose a novel measure of arbitrage activity to examine whether arbitrageurs can have a destabilizing effect on the stock market. We focus on stock price momentum, a classic example of a positive-feedback strategy that our theory predicts can be destabilizing. Our measure, dubbed comomentum, is the high-frequency abnormal return correlation among stocks on which a typical momentum strategy would speculate. When comomentum is low, momentum strategies are stabilizing, reflecting an underreaction phenomenon that arbitrageurs correct. When comomentum is high, the returns on momentum stocks strongly revert, reflecting prior overreaction from crowded momentum trading that pushes prices away from fundamentals.
Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
Development and validation of a prognostic model for leflunomide discontinuation with abnormal blood tests during long-term treatment: cohort study using data from the Clinical Practice Research Datalink Gold and Aurum
Authors: Nakafero Georgina , Grainge Matthew J , Card Tim , Taal Maarten W , Aithal Guruprasad P , Zhang Weiya , Doherty Michael , Fox Christopher P , Mallen Christian D , Abhishek Abhishek 
Published: October 2021

Abstract

Objective
To develop and validate a prognostic model for LEF discontinuation with abnormal blood test results.

Methods
Data from the Clinical Practice Research Datalink Gold and Aurum were used for model development and external validation, respectively. Participants prescribed LEF between 1 January 2007 and 31 December 2019 were followed up from 6 months after the first general practitioner prescription to the earliest of date of outcome, death, 5 year follow-up or 31 December 2019. Candidate prognostic factors were ascertained using theory and data-driven approaches. Penalized Cox regression was performed to develop the risk equation, followed by internal validation using 500 bootstraps to correct for optimism. Multiple imputation was applied to handle missing data. Model performance was assessed in terms of calibration and discrimination.

Results
Data for 1487 and 2329 participants contributing 3140 and 5246 person-years follow-up were included in the development and validation cohorts, respectively. Thirteen candidate predictors were included in the model. Epilepsy and either cytopenia or elevated liver enzymes during the first 6 months of shared-care LEF prescription were strong predictors of drug discontinuation with a hazard ratio of 4.39 (95% CI 1.74, 11.06) and 3.06 (2.15, 4.35), respectively. The unadjusted and optimism-adjusted calibration slope in development data was 1.00 (95% CI 0.75, 1.25) and 0.72 (95% CI 0.47, 0.97), respectively. The calibration slope in validation data was 0.91 (95% CI 0.74, 1.07). The model showed prognostic separation with an optimism-adjusted Royston D statistic of 0.73 (95% CI 0.44, 1.02).

Conclusion
We have developed and externally validated an easy-to-use prognostic model that may be used to risk stratify monitoring for LEF toxicity and to make informed choices about risks when choosing treatments.
Post-COVID conditions—What practitioners need to know
Authors: Waterbury Susan 
Published: October 2021

Abstract:
Up to 80% of patients have symptoms lasting 4-12 weeks or longer post infection with COVID-19. Persistent symptoms can be diverse and may include myalgia, insomnia, mobility issues, hair loss, loss of smell/taste, shortness of breath, chest pain, fatigue, cognitive impairment, and depression. More evidence will be forthcoming regarding long-term COVID-19 sequelae.
Best Practice Guidelines for Assessment and Management of Osteoporosis in Adult Patients Undergoing Elective Spinal Reconstruction
Authors: Sardar Zeeshan M. , Coury Josephine R. , Cerpa Meghan , DeWald Christopher J. , Ames Christopher P. , Shuhart Christopher , Watkins Colleen , Polly David W. , Dirschl Douglas R. , Klineberg Eric O. , Dimar John R. , Krohn Kelly D. , Kebaish Khaled M. , Tosi Laura L. , Kelly Michael , Lane Nancy E. , Binkley Neil C. , Berven Sigurd H. , Lee Nathan J. , Anderson Paul , Angevine Peter D. , Lehman Ronald A. , Lenke Lawrence G. 
Published: October 2021

Study Design.
Expert consensus study.

Objective.
This expert panel was created to establish best practice guidelines to identify and treat patients with poor bone health prior to elective spinal reconstruction.

Summary of Background Data.
Currently, no guidelines exist for the management of osteoporosis and osteopenia in patients undergoing spinal reconstructive surgery. Untreated osteoporosis in spine reconstruction surgery is associated with higher complications and worse outcomes.

Methods.
A multidisciplinary panel with 18 experts was assembled including orthopedic and neurological surgeons, endocrinologists, and rheumatologists. Surveys and discussions regarding the current literature were held according to Delphi method until a final set of guidelines was created with over 70% consensus.

Results.
Panelists agreed that bone health should be considered in every patient prior to elective spinal reconstruction. All patients above 65 and those under 65 with particular risk factors (chronic glucocorticoid use, high fracture risk or previous fracture, limited mobility, and eight other key factors) should have a formal bone health evaluation prior to undergoing surgery. DXA scans of the hip are preferable due to their wide availability. Opportunistic CT Hounsfield Units of the vertebrae can be useful in identifying poor bone health. In the absence of contraindications, anabolic agents are considered first line therapy due to their bone building properties as compared with antiresorptive medications. Medications should be administered preoperatively for at least 2 months and postoperatively for minimum 8 months.

Conclusion.
Based on the consensus of a multidisciplinary panel of experts, we propose best practice guidelines for assessment and treatment of poor bone health prior to elective spinal reconstructive surgery. Patients above age 65 and those with particular risk factors under 65 should undergo formal bone health evaluation. We also established guidelines on perioperative optimization, utility of various diagnostic modalities, and the optimal medical management of bone health in this population.

Level of Evidence: 5
Mental Health and Developmental Disorder Diagnoses of Foster and Nonfoster Children Enrolled in Medicaid
Authors: Keefe Rachael J. , Cummings Angela D. L. , Greeley Christopher S. , Van Horne Bethanie S. 
Published: October 2021

ABSTRACT:

Objective:
This study used Medicaid claims to compare the prevalence of mental health disorders (MHDs) and developmental disorders (DDs) between foster and nonfoster youth.

Methods:
Medicaid claims data were used to identify MHDs and DDs. Diagnosis codes were categorized into 16 MHD and 8 DD groups. Children were enrolled in their respective Medicaid plan for at least 30 days and had at least 1 health care encounter generating a claim. Prevalence was compared between children in foster care and children not in foster care overall and by age group. Logistic regression was used to compare the odds of having an MHD or DD diagnosis.

Results:
Of the 8706 children in foster care, 20.1% had an MHD compared with 9.7% of the 392,815 nonfoster children. Overall, the 5 most prevalent MHD and DD conditions among foster youth were attention-deficit/hyperactivity disorder (ADHD) (11.0%), miscellaneous (9.3%), bipolar disorders (5.6%), communication disorders (5.4%), and depressive disorders (5.1%). The 5 most prevalent conditions among children not in foster care were ADHD (6.1%); communication disorders (3.0%); disruptive, impulse control, and conduct disorders (2.7%); specific learning disorders (2.5%); and trauma and stressor-related disorders (2.4%). Anxiety was significantly higher among nonfoster children. The prevalence of the most common conditions by age group is reported. Overall, children in foster care had 2.5 and 2.3 times higher odds of having an MHD or DD diagnosis, respectively.

Conclusion:
Children in foster care had significantly higher rates of mental health and DD diagnoses compared with children not in foster care.
Cardioprotective Effects of Glucagon-like Peptide-1 (9-36) Against Oxidative Injury in H9c2 Cardiomyoblasts: Potential Role of the PI3K/Akt/NOS Pathway
Authors: Nuamnaichati Narawat , Parichatikanond Warisara , Mangmool Supachoke 
Published: October 2021

Abstract:
Glucagon-like peptide (GLP)-1(7-36), a major active form of GLP-1 hormone, is rapidly cleaved by dipeptidyl peptidase-4 to generate a truncated metabolite, GLP-1(9-36) which has a low affinity for GLP-1 receptor (GLP-1R). GLP-1(7-36) has been shown to have protective effects on cardiovascular system through GLP-1R-dependent pathway. Nevertheless, the cardioprotective effects of GLP-1(9-36) have not fully understood. The present study investigated the effects of GLP-1(9-36), including its underlying mechanisms against oxidative stress and apoptosis in H9c2 cells. Here, we reported that GLP-1(9-36) protects H9c2 cardiomyoblasts from hydrogen peroxide (H2O2)-induced oxidative stress by promoting the synthesis of antioxidant enzymes, glutathione peroxidase-1, catalase, and heme oxygenase-1. In addition, treatment with GLP-1(9-36) suppressed H2O2-induced apoptosis by attenuating caspase-3 activity and upregulating antiapoptotic proteins, Bcl-2 and Bcl-xL. These protective effects of GLP-1(9-36) are attenuated by blockade of PI3K-mediated Akt phosphorylation and prevention of nitric oxide synthase-induced nitric oxide production. Thus, GLP-1(9-36) represents the potential therapeutic target for prevention of oxidative stress and apoptosis in the heart via PI3K/Akt/nitric oxide synthase signaling pathway.
Lipoprotein(a) and Cardiovascular Disease: A Missing Link for Premature Atherosclerotic Heart Disease and/or Residual Risk
Authors: Melita Helen , Manolis Antonis A. , Manolis Theodora A. , Manolis Antonis S. 
Published: October 2021

Abstract:
Lipoprotein(a) or lipoprotein “little a” [Lp(a)] is an under-recognized causal risk factor for cardiovascular (CV) disease (CVD), including coronary atherosclerosis, aortic valvular stenosis, ischemic stroke, heart failure, and peripheral arterial disease. Elevated plasma Lp(a) (≥50 mg/dL or ≥100 nmol/L) is commonly encountered in almost 1 in 5 individuals and confers a higher CV risk compared with those with normal Lp(a) levels, although such normal levels have not been generally agreed upon. Elevated Lp(a) is considered a cause of premature and accelerated atherosclerotic CVD. Thus, in patients with a positive family or personal history of premature coronary artery disease (CAD), Lp(a) should be measured. However, elevated Lp(a) may confer increased risk for incident CAD even in the absence of a family history of CAD, and even in those who have guideline-lowered LDL cholesterol (<70 mg/dL) and continue to have a persisting CV residual risk. Thus, measurement of Lp(a) will have a significant clinical impact on the assessment of atherosclerotic CVD risk, and will assume a more important role in managing patients with CVD with the advent and clinical application of specific Lp(a)-lowering therapies. Conventional therapeutic approaches like lifestyle modification and statin therapy remain ineffective at lowering Lp(a). Newer treatment modalities, such as gene silencing via RNA interference with use of antisense oligonucleotide(s) or small interfering RNA molecules targeting Lp(a), seem very promising. These issues are herein reviewed, accumulated data are scrutinized, meta-analyses and current guidelines are tabulated, and Lp(a)-related CVDs and newer therapeutic modalities are pictorially illustrated.