bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comprehensive assessment of cell type-specific differential expression methods in bulk data
Authors: Meng Guanqun , Tang Wen , Huang Emina , Li Ziyi , Feng Hao 
Published: December 2022

Abstract
Accounting for cell type compositions has been very successful at analyzing high-throughput data from heterogeneous tissues. Differential gene expression analysis at cell type level is becoming increasingly popular, yielding biomarker discovery in a finer granularity within a particular cell type. Although several computational methods have been developed to identify cell type-specific differentially expressed genes (csDEG) from RNA-seq data, a systematic evaluation is yet to be performed. Here, we thoroughly benchmark six recently published methods: CellDMC, CARseq, TOAST, LRCDE, CeDAR and TCA, together with two classical methods, csSAM and DESeq2, for a comprehensive comparison. We aim to systematically evaluate the performance of popular csDEG detection methods and provide guidance to researchers. In simulation studies, we benchmark available methods under various scenarios of baseline expression levels, sample sizes, cell type compositions, expression level alterations, technical noises and biological dispersions. Real data analyses of three large datasets on inflammatory bowel disease, lung cancer and autism provide evaluation in both the gene level and the pathway level. We find that csDEG calling is strongly affected by effect size, baseline expression level and cell type compositions. Results imply that csDEG discovery is a challenging task itself, with room to improvements on handling low signal-to-noise ratio and low expression genes.
libRoadRunner 2.0: a high performance SBML simulation and analysis library
Authors: Welsh Ciaran , Xu Jin , Smith Lucian , König Matthias , Choi Kiri , Sauro Herbert M 
Published: December 2022

Abstract

Motivation
This article presents libRoadRunner 2.0, an extensible, high-performance, cross-platform, open-source software library for the simulation and analysis of models expressed using the systems biology markup language (SBML).

Results
libRoadRunner is a self-contained library, able to run either as a component inside other tools via its C++, C and Python APIs, or interactively through its Python or Julia interface. libRoadRunner uses a custom just-in-time (JIT) compiler built on the widely used LLVM JIT compiler framework. It compiles SBML-specified models directly into native machine code for a large variety of processors, making it fast enough to simulate extremely large models or repeated runs in reasonable timeframes. libRoadRunner is flexible, supporting the bulk of the SBML specification (except for delay and non-linear algebraic equations) as well as several SBML extensions such as hierarchical composition and probability distributions. It offers multiple deterministic and stochastic integrators, as well as tools for steady-state, sensitivity, stability and structural analyses.

Availability and implementation
libRoadRunner binary distributions for Windows, Mac OS and Linux, Julia and Python bindings, source code and documentation are all available at https://github.com/sys-bio/roadrunner, and Python bindings are also available via pip. The source code can be compiled for the supported systems as well as in principle any system supported by LLVM-13, such as ARM-based computers like the Raspberry Pi. The library is licensed under the Apache License Version 2.0.
CanMethdb: a database for genome-wide DNA methylation annotation in cancers
Authors: Zhao Jianmei , Qian Fengcui , Li Xuecang , Yu Zhengmin , Zhu Jiang , Yu Rui , Zhao Yue , Ding Ke , Li Yanyu , Yang Yongsan , Pan Qi , Chen Jiaxin , Song Chao , Wang Qiuyu , Zhang Jian , Wang Guohua , Li Chunquan 
Published: December 2022

Abstract

Motivation
DNA methylation within gene body and promoters in cancer cells is well documented. An increasing number of studies showed that cytosine–phosphate–guanine (CpG) sites falling within other regulatory elements could also regulate target gene activation, mainly by affecting transcription factors (TFs) binding in human cancers. This led to the urgent need for comprehensively and effectively collecting distinct cis-regulatory elements and TF-binding sites (TFBS) to annotate DNA methylation regulation.

Results
We developed a database (CanMethdb, http://meth.liclab.net/CanMethdb/) that focused on the upstream and downstream annotations for CpG–genes in cancers. This included upstream cis-regulatory elements, especially those involving distal regions to genes, and TFBS annotations for the CpGs and downstream functional annotations for the target genes, computed through integrating abundant DNA methylation and gene expression profiles in diverse cancers. Users could inquire CpG–target gene pairs for a cancer type through inputting a genomic region, a CpG, a gene name, or select hypo/hypermethylated CpG sets. The current version of CanMethdb documented a total of 38 986 060 CpG–target gene pairs (with 6 769 130 unique pairs), involving 385 217 CpGs and 18 044 target genes, abundant cis-regulatory elements and TFs for 33 TCGA cancer types. CanMethdb might help biologists perform in-depth studies of target gene regulations based on DNA methylations in cancer.

Availability and implementation
The main program is available at https://github.com/chunquanlipathway/CanMethdb.

Supplementary information
Supplementary data are available at Bioinformatics online.
Twelve-year neurocognitive decline in HIV is associated with comorbidities, not age: a CHARTER study
Authors: Heaton Robert K , Ellis Ronald J , Tang Bin , Marra Christina M , Rubin Leah H , Clifford David B , McCutchan J Allen , Gelman Benjamin B , Morgello Susan , Franklin Donald R , Letendre Scott L 
Published: December 2022

Abstract
Modern antiretroviral therapy (ART) has increased longevity of people with HIV and shifted the age distribution of the HIV pandemic upward toward that of the general population. This positive development has also led to concerns about premature and/or accelerated neurocognitive and physical ageing due to the combined effects of chronic HIV, accumulating comorbidities, adverse effects or possible toxicities of ART and biological ageing. Here we present results of comprehensive assessments over 12 years of 402 people with HIV in the CNS HIV ART Effects Research (CHARTER) programme, who at follow-up were composed of younger (&lt;60 years) and older (≥60 years) subgroups.
Over the 12 years, ART use and viral suppression increased in both subgroups as did systemic and psychiatric comorbidities; participants in both subgroups also evidenced neurocognitive decline beyond what is expected in typical ageing. Contrary to expectations, all these adverse effects were comparable in the younger and older CHARTER subgroups, and unrelated to chronological age. Neurocognitive decline was unrelated to HIV disease or treatment characteristics but was significantly predicted by the presence of comorbid conditions, specifically diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression and lifetime history of cannabis use disorder. These results are not consistent with premature or accelerated neurocognitive ageing due to HIV itself but suggest important indirect effects of multiple, potentially treatable comorbidities that are more common among people with HIV than in the general population.
Good medical management of HIV disease did not prevent these adverse outcomes, and increased attention to a range of comorbid conditions in people with HIV may be warranted in their care.
The reproduction of canonical silences: re-reading Habermas in the context of slavery and the slave trade
Authors: Willems Wendy 
Published: December 2022

AbstractRecent discussions on “decolonizing” knowledge production have often foregrounded the importance of centering “marginal” perspectives, which is crucial but insufficient as it risks leaving the canon untouched. Jürgen Habermas’ book on the bourgeois public sphere is one of the most frequently cited and debated canonical texts in media and communication studies. Drawing on the case of London’s coffee houses and newspapers, this article argues for a critical re-engagement with canonical thinkers. It examines what the emergence of a bourgeois public sphere in 17th- and 18th-century England looks like if we re-read it within the context of slavery and the slave trade. The article demonstrates that race does not simply provide another “prism” to examine the bourgeois public sphere but instead enables and is constitutive of it. The reproduction of canonical silences through the continued circulation of influential texts has implications for how we conceptualize racialized publics in contemporary times.
Quantification of Remimazolam Besylate (CNS7056B) and Its Metabolite (CNS7054X) by LC–MS/MS in Human Plasma Using Midazolam-d4 Maleate as Internal Standard
Authors: Schmidt Stefanie , Krajinovic Ljubica , Mertens Christian , Schramm Lisa , Schüttler Jürgen , Fechner Jörg 
Published: December 2022

Abstract
A new assay was developed to measure the concentration of remimazolam besylate (CNS7056B) and its major carboxylic acid metabolite (CNS7054X) in human plasma. For this new assay method, midazolam-d4 maleate was used as an internal standard. After setting up a previously described assay method, using CNS7056-d4 and CNS7054-d4 as internal standards, analytical results of both methods were compared. For the new analytical method, ultra-high-performance liquid chromatography (UHPLC) with tandem mass spectrometry was applied. A purification method, using solid phase extraction, was developed and validated. The chromatographic separation of the analytes was achieved with a mobile phase gradient using a Water Acquity™ UHPLC-System. The Kinetex™ biphenyl 50 × 2.1 mm UHPLC column was used with a particle diameter of 1.7 μm (Phenomenex, Germany). A measuring range of 0.6–2,000 ng/mL for CNS7056B and of 6–20,000 ng/mL for CNS7054X could be achieved with this new assay. The lower limit of quantification was 0.6 ng/mL for CNS7056B and 6 ng/mL for CNS7054X. The assay was validated according to US Food and Drug Administration guidelines. The new method showed an accuracy of 96.9–110.4% and a precision of 2.1–6.7% for both analytes.
Efficacy and Safety of Ensitrelvir in Patients With Mild-to-Moderate Coronavirus Disease 2019: The Phase 2b Part of a Randomized, Placebo-Controlled, Phase 2/3 Study
Authors: Mukae Hiroshi , Yotsuyanagi Hiroshi , Ohmagari Norio , Doi Yohei , Sakaguchi Hiroki , Sonoyama Takuhiro , Ichihashi Genki , Sanaki Takao , Baba Keiko , Tsuge Yuko , Uehara Takeki 
Published: December 2022

AbstractBackgroundThis phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during the Omicron epidemic.MethodsPatients were randomized (1:1:1) to orally receive ensitrelvir fumaric acid 125 mg (375 mg on day 1) or 250 mg (750 mg on day 1) or placebo once daily for 5 days. The co-primary endpoints were the change from baseline in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) titer on day 4 and time-weighted average change from baseline up to 120 hours in the total score of predefined 12 COVID-19 symptoms. Safety was assessed through adverse events.ResultsA total of 341 patients (ensitrelvir 125-mg group: 114; ensitrelvir 250-mg group: 116; and placebo group: 111; male: 53.5–64.9%; mean age: 35.3–37.3 years) were included in the efficacy analyses. The change from baseline in SARS-CoV-2 titer on day 4 was significantly greater with both ensitrelvir doses than with placebo (differences from placebo: −0.41 log10 50% tissue-culture infectious dose/mL; P &lt; .0001 for both). The total score of the 12 COVID-19 symptoms did not show a significant difference between the ensitrelvir groups and placebo group. The time-weighted average change from baseline up to 120 hours was significantly greater with ensitrelvir versus placebo in several subtotal scores, including acute symptoms and respiratory symptoms. Most adverse events were mild in severity.ConclusionsEnsitrelvir treatment demonstrated a favorable antiviral efficacy and potential clinical benefit with an acceptable safety profile.Clinical Trials RegistrationJapan Registry of Clinical Trials: jRCT2031210350 (https://jrct.niph.go.jp/en-latest-detail/jRCT2031210350)
Chromosome-scaleAmaranthus tricolorgenome provides insights into the evolution of the genusAmaranthusand the mechanism of betalain biosynthesis
Authors: Wang Hengchao , Xu Dong , Wang Sen , Wang Anqi , Lei Lihong , Jiang Fan , Yang Boyuan , Yuan Lihua , Chen Rong , Zhang Yan , Fan Wei 
Published: December 2022

AbstractAmaranthus tricolor is a vegetable and ornamental amaranth, with high lysine, dietary fibre and squalene content. The red cultivar of A. tricolor possesses a high concentration of betalains, which has been used as natural food colorants. Here, we constructed the genome of A. tricolor, the first reference genome for the subgenus Albersia, combining PacBio HiFi, Nanopore ultra-long and Hi–C data. The contig N50 size was 906 kb, and 99.58% of contig sequence was anchored to the 17 chromosomes, totalling 520 Mb. We annotated 27,813 protein-coding genes with an average 1.3 kb coding sequence and 5.3 exons. We inferred that A. tricolor underwent a whole-genome duplication (WGD) and that the WGD shared by amaranths occurred in the last common ancestor of subfamily Amaranthoideae. Moreover, we comprehensively identified candidate genes in betalain biosynthesis pathway. Among them, DODAα1 and CYP76ADα1, located in one topologically associated domain (TAD) of an active (A) compartment on chromosome 16, were more highly expressed in red leaves than in green leaves, and DODAα1 might be the rate-limiting enzyme gene in betalains biosynthesis. This study presents new genome resources and enriches our understanding of amaranth evolution, betalains production, facilitating molecular breeding improvements and the understanding of C4 plants evolution.
AI-AIF: artificial intelligence-based arterial input function for quantitative stress perfusion cardiac magnetic resonance
Authors: Scannell Cian M , Alskaf Ebraham , Sharrack Noor , Razavi Reza , Ourselin Sebastien , Young Alistair A , Plein Sven , Chiribiri Amedeo 
Published: December 2022

Abstract

Aims
One of the major challenges in the quantification of myocardial blood flow (MBF) from stress perfusion cardiac magnetic resonance (CMR) is the estimation of the arterial input function (AIF). This is due to the non-linear relationship between the concentration of gadolinium and the MR signal, which leads to signal saturation. In this work, we show that a deep learning model can be trained to predict the unsaturated AIF from standard images, using the reference dual-sequence acquisition AIFs (DS-AIFs) for training.

Methods and results
A 1D U-Net was trained, to take the saturated AIF from the standard images as input and predict the unsaturated AIF, using the data from 201 patients from centre 1 and a test set comprised of both an independent cohort of consecutive patients from centre 1 and an external cohort of patients from centre 2 (n = 44). Fully-automated MBF was compared between the DS-AIF and AI-AIF methods using the Mann–Whitney U test and Bland–Altman analysis. There was no statistical difference between the MBF quantified with the DS-AIF [2.77 mL/min/g (1.08)] and predicted with the AI-AIF (2.79 mL/min/g (1.08), P = 0.33. Bland–Altman analysis shows minimal bias between the DS-AIF and AI-AIF methods for quantitative MBF (bias of −0.11 mL/min/g). Additionally, the MBF diagnosis classification of the AI-AIF matched the DS-AIF in 669/704 (95%) of myocardial segments.

Conclusion
Quantification of stress perfusion CMR is feasible with a single-sequence acquisition and a single contrast injection using an AI-based correction of the AIF.
Illegal: The SolarWinds Hack under International Law
Authors: Coco Antonio , Dias Talita , van Benthem Tsvetelina 
Published: December 2022

Abstract
In late 2020, news surfaced about one of the most extensive attacks on an information technology (IT) supply chain to date. Hackers exploited a vulnerability in the update system of Orion, a network-monitoring and management software developed by the company SolarWinds. Malicious code embedded in Orion updates created a backdoor into the systems used by numerous private and public entities. This backdoor was then used to insert additional malware into affected systems – in particular, spyware to exfiltrate confidential or sensitive data. Considering both the importance of preserving the integrity of IT supply chains and the diverse risks of harm that attacks such as the SolarWinds hack give rise to, this article examines this cyber operation according to the relevant rules of international law – notably those on sovereignty, non-intervention, general due diligence duties and international human rights law. It concludes that the operation may have been illegal on multiple fronts.
Acute, periprocedural and longterm antithrombotic therapy in older adults
Authors: Andreotti Felicita , Geisler Tobias , Collet Jean-Philippe , Gigante Bruna , Gorog Diana A , Halvorsen Sigrun , Lip Gregory Y H , Morais Joao , Navarese Eliano Pio , Patrono Carlo , Rocca Bianca , Rubboli Andrea , Sibbing Dirk , Storey Robert F , Verheugt Freek W A , Vilahur Gemma 
Published: December 2022

Abstract
The first international guidance on antithrombotic therapy in the elderly came from the European Society of Cardiology Working Group on Thrombosis in 2015. This same group has updated its previous report on antiplatelet and anticoagulant drugs for older patients with acute or chronic coronary syndromes, atrial fibrillation, or undergoing surgery or procedures typical of the elderly (transcatheter aortic valve implantation and left atrial appendage closure). The aim is to provide a succinct but comprehensive tool for readers to understand the bases of antithrombotic therapy in older patients, despite the complexities of comorbidities, comedications and uncertain ischaemic- vs. bleeding-risk balance. Fourteen updated consensus statements integrate recent trial data and other evidence, with a focus on high bleeding risk. Guideline recommendations, when present, are highlighted, as well as gaps in evidence. Key consensus points include efforts to improve medical adherence through deprescribing and polypill use; adoption of universal risk definitions for bleeding, myocardial infarction, stroke and cause-specific death; multiple bleeding-avoidance strategies, ranging from gastroprotection with aspirin use to selection of antithrombotic-drug composition, dosing and duration tailored to multiple variables (setting, history, overall risk, age, weight, renal function, comedications, procedures) that need special consideration when managing older adults.
Acute ischaemic stroke: recent advances in reperfusion treatment
Authors: Widimsky Petr , Snyder Kenneth , Sulzenko Jakub , Hopkins Leo Nelson , Stetkarova Ivana 
Published: December 2022

Abstract
During the last 5–7 years, tremendous progress was achieved in the reperfusion treatment of acute ischaemic stroke during its first few hours from symptom onset. This review summarizes the latest evidence from randomized clinical trials and prospective registries with a focus on endovascular treatment using stent retrievers, aspiration catheters, thrombolytics, and (in selected patients) carotid stenting. Novel approaches in prehospital (mobile interventional stroke teams) and early hospital (direct transfer to angiography) management are described, and future perspectives (‘all-in-one’ laboratories with angiography and computed tomography integrated) are discussed. There is reasonable chance for patients with moderate-to-severe acute ischaemic stroke to survive without permanent sequelae when the large-vessel occlusion is removed by means of modern pharmaco-mechanic approach. Catheter thrombectomy is now the golden standard of acute stroke treatment. The role of cardiologists in stroke is expanding from diagnostic help (to reveal the cause of stroke) to acute therapy in those regions where such up-to-date Class I. A treatment is not yet available.
Dual antiplatelet therapy duration after percutaneous coronary intervention in high bleeding risk: a meta-analysis of randomized trials
Authors: Costa Francesco , Montalto Claudio , Branca Mattia , Hong Sung-Jin , Watanabe Hirotoshi , Franzone Anna , Vranckx Pascal , Hahn Joo-Yong , Gwon Hyeon-Cheol , Feres Fausto , Jang Yangsoo , De Luca Giuseppe , Kedhi Elvin , Cao Davide , Steg Philippe Gabriel , Bhatt Deepak L , Stone Gregg W , Micari Antonio , Windecker Stephan , Kimura Takeshi , Hong Myeong-Ki , Mehran Roxana , Valgimigli Marco 
Published: December 2022

AbstractAimsThe optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in patients at high bleeding risk (HBR) is still debated. The current study, using the totality of existing evidence, evaluated the impact of an abbreviated DAPT regimen in HBR patients.Methods and resultsA systematic review and meta-analysis was performed to search randomized clinical trials comparing abbreviated [i.e. very-short (1 month) or short (3 months)] with standard (≥6 months) DAPT in HBR patients without indication for oral anticoagulation. A total of 11 trials, including 9006 HBR patients, were included. Abbreviated DAPT reduced major or clinically relevant non-major bleeding [risk ratio (RR): 0.76, 95% confidence interval (CI): 0.61–0.94; I2 = 28%], major bleeding (RR: 0.80, 95% CI: 0.64–0.99, I2 = 0%), and cardiovascular mortality (RR: 0.79, 95% CI: 0.65–0.95, I2 = 0%) compared with standard DAPT. No difference in all-cause mortality, major adverse cardiovascular events, myocardial infarction, or stent thrombosis was observed. Results were consistent, irrespective of HBR definition and clinical presentation.ConclusionIn HBR patients undergoing PCI, a 1- or 3-month abbreviated DAPT regimen was associated with lower bleeding and cardiovascular mortality, without increasing ischaemic events, compared with a ≥6-month DAPT regimen.Study registrationPROSPERO registration number CRD42021284004
Economic, ethical, and environmental sustainability of cardiac imaging
Authors: Picano Eugenio 
Published: December 2022

Abstract
Current cardiology guidelines assign a class of recommendation 1 for the diagnosis of chest pain to five imaging techniques based on either anatomic (coronary computed tomography angiography) or functional approaches, such as stress single-photon emission tomography, stress positron emission tomography, stress cardiovascular magnetic resonance, and stress echocardiography. The choice is left to the prescribing physician, based on local availability and expertise. However, the five techniques differ substantially in their cost, applicability based on patient characteristics, long-term risk, and environmental impact. The average European immediate cost ranges from 50 to 1000 euros. The radiation exposure ranges from 0 to 500 chest x-rays. The environmental footprint ranges from 3 to 300 kg of carbon dioxide emissions equivalent. The ethical code of the World Medical Association 2021 recommends the responsible use of healthcare money by doctors, with the minimization of potential damage to patients and the environment. The Euratom law 2013/directive 59 reinforces the justification principle and the optimization principle for medical radiation exposures, with the legal responsibility of both the referrer and the practitioner. A small cost, a minimal long-term risk, and a modest carbon emission per examination multiplied by billions of tests per year become an unaffordable economic burden in the short-term, significant population damage to public health over the years, and impacts on climate change in decades. The cardiology community may wish to adopt a more sustainable practice with affordable, radiation-optimized, and carbon-neutral practices for the benefit of patients, physicians, payers, and the planet.