bluuebunny/crossref_metadata_2025_split huggingface dataset:
A double-blinded, placebo-controlled randomized trial evaluating the efficacy and safety of Zhigancao Tang granules for treating HFpEF: study protocol for a randomized controlled trial
Authors: Zhang Na , Zhao Yingli , Liu Yu , Tang Nuo , Zheng Wang , Mao Meijiao , Liu Qingcheng , Shen Lin , Deng Bing 
Published: April 2021

Abstract
Background
Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by diastolic dysfunction. Despite the increasing incidence of HFpEF, there is no available therapy that reduces the mortality rate of HFpEF. Zhigancao Tang has been used traditionally for the treatment of cardiovascular diseases in China. The use of traditional Chinese medicine (TCM) is associated with improvements in clinical syndromes and quality of life of patients. A randomized clinical trial should be conducted to provide clear evidence regarding the efficacy and safety of Zhigancao Tang granules for the treatment of HFpEF.

Methods
A randomized, double-blinded, placebo-controlled clinical trial was proposed. A total of 122 patients with HFpEF will be randomly assigned to receive Zhigancao Tang granules or placebo for 12 weeks. The primary outcome measure is cardiac function. The secondary outcomes include measurement of the integral TCM syndrome score, echocardiography, 6-min walk test, N-terminal-pro hormone B-type natriuretic peptide level, atrial natriuretic peptide level, Minnesota Living with Heart Failure scale, and Lee’s scale. The outcome measures will be evaluated at baseline, 4 weeks, and 12 weeks. Adverse events will be evaluated from baseline till the 12-week follow-up period.

Discussion
The results of this trial will demonstrate whether Zhigancao Tang granules are effective and safe for treating HFpEF.

Trial registration
ClinicalTrials.gov NCT04317339. Registered on 23 March 2020.
Effect of acupotomy in knee osteoarthritis patients: study protocol for a randomized controlled trial
Authors: Xu Danghan , Lee Minghui , Huang Cihui , Wei Jia , Zhou Mengxue , Yao Taotao , Lu Jingjing , Zhao Wenjing , Xu Nuo , Huang Ruina , He Jun , Zheng Liang 
Published: April 2021

AbstractBackgroundSymptomatic knee osteoarthritis (KOA) is common in China. Pharmacological therapy is not the first recommendation because of its safety issues. Nonpharmacological therapy, such as lifestyle adjustments, weight loss, muscle strengthening, and aerobic exercise programs, is strongly recommended for KOA. However, these approaches may fail due to poor patient compliance. There is a lack of high-quality randomized controlled trials of acupotomy, an effective treatment for KOA. This study was designed to investigate the efficacy of acupotomy in patients with KOA.MethodsA total of 136 patients will be enrolled at the First Affiliated Hospital of Guangzhou University of Chinese Medicine and assigned to the acupotomy group or sham acupotomy group according to the block randomization scheme. Patients in the acupotomy group will receive 2 sessions of acupotomy for 2 weeks (once a week). Patients in the sham group will receive 2 sessions of sham stimulation for 2 weeks (once a week). All patients will use indomethacin cream externally. The primary outcome will be the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the secondary outcomes will be the visual analog scale (VAS) score, plantar pressure distribution test result, X-ray examination findings, musculoskeletal ultrasound findings, maximum knee circumference, joint mobility, and quality of life. Measurements will be taken at baseline, 1 week after the end of treatment, and at the 3- and 6-month follow-ups.DiscussionTo the best of our knowledge, this will be the first single-blind, sham-controlled study of acupotomy. The outcome assessors will also be blinded. The aim of this work is to demonstrate the efficacy of acupotomy in treating KOA.Trial registrationChinese Clinical Trial RegistryChiCTR2000033047. Registered on 18 May 2020.
ATP and NADPH engineering of Escherichia coli to improve the production of 4-hydroxyphenylacetic acid using CRISPRi
Authors: Shen Yu-Ping , Liao Yu-Ling , Lu Qian , He Xin , Yan Zhi-Bo , Liu Jian-Zhong 
Published: April 2021

Abstract
Background
4-Hydroxyphenylacetic acid (4HPAA) is an important raw material for the synthesis of drugs, pesticides and biochemicals. Microbial biotechnology would be an attractive approach for 4HPAA production, and cofactors play an important role in biosynthesis.

Results
We developed a novel strategy called cofactor engineering based on clustered regularly interspaced short palindromic repeat interference (CRISPRi) screening (CECRiS) for improving NADPH and/or ATP availability, enhancing the production of 4HPAA. All NADPH-consuming and ATP-consuming enzyme-encoding genes of E. coli were repressed through CRISPRi. After CRISPRi screening, 6 NADPH-consuming and 19 ATP-consuming enzyme-encoding genes were identified. The deletion of the NADPH-consuming enzyme-encoding gene yahK and the ATP-consuming enzyme-encoding gene fecE increased the production of 4HPAA from 6.32 to 7.76 g/L. Automatically downregulating the expression of the pabA gene using the Esa-PesaS quorum-sensing-repressing system further improved the production of 4HPAA. The final strain E. coli 4HPAA-∆yfp produced 28.57 g/L of 4HPAA with a yield of 27.64% (mol/mol) in 2-L bioreactor fed-batch fermentations. The titer and yield are the highest values to date.

Conclusion
This CECRiS strategy will be useful in engineering microorganisms for the high-level production of bioproducts.
Insecticide resistance status in Anopheles gambiae (s.l.) in coastal Kenya
Authors: Munywoki Daniel N. , Kokwaro Elizabeth D. , Mwangangi Joseph M. , Muturi Ephantus J. , Mbogo Charles M. 
Published: April 2021

Abstract
Background
The rapid and widespread evolution of insecticide resistance has emerged as one of the major challenges facing malaria control programs in sub-Saharan Africa. Understanding the insecticide resistance status of mosquito populations and the underlying mechanisms of insecticide resistance can inform the development of effective and site-specific strategies for resistance prevention and management. The aim of this study was to investigate the insecticide resistance status of Anopheles gambiae (s.l.) mosquitoes from coastal Kenya.

Methods
Anopheles gambiae (s.l.) larvae sampled from eight study sites were reared to adulthood in the insectary, and 3- to 5-day-old non-blood-fed females were tested for susceptibility to permethrin, deltamethrin, dichlorodiphenyltrichloroethane (DDT), fenitrothion and bendiocarb using the standard World Health Organization protocol. PCR amplification of rDNA intergenic spacers was used to identify sibling species of the An. gambiae complex. The An. gambiae (s.l.) females were further genotyped for the presence of the L1014S and L1014F knockdown resistance (kdr) mutations by real-time PCR.

Results
Anopheles arabiensis was the dominant species, accounting for 95.2% of the total collection, followed by An. gambiae (s.s.), accounting for 4.8%. Anopheles gambiae (s.l.) mosquitoes were resistant to deltamethrin, permethrin and fenitrothion but not to bendiocarb and DDT. The L1014S kdr point mutation was detected only in An. gambiae (s.s.), at a low allelic frequency of 3.33%, and the 1014F kdr mutation was not detected in either An. gambiae (s.s.) or An. arabiensis.

Conclusion
The findings of this study demonstrate phenotypic resistance to pyrethroids and organophosphates and a low level of the L1014S kdr point mutation that may partly be responsible for resistance to pyrethroids. This knowledge may inform the development of insecticide resistance management strategies along the Kenyan Coast.

Graphical Abstract
Urine proteomics for profiling of mouse toxoplasmosis using liquid chromatography tandem mass spectrometry analysis
Authors: Cui Lin-Lin , Zhou Chun-Xue , Han Bing , Wang Sha-Sha , Li Si-Ying , Xie Shi-Chen , Zhou Dong-Hui 
Published: April 2021

Abstract
Background
Toxoplasma gondii is an obligate intracellular parasite that causes toxoplasmosis. Urine is an easily obtained clinical sample that has been widely applied for diagnostic purposes. However, changes in the urinary proteome during T. gondii infection have never been investigated.

Methods
Twenty four-hour urine samples were obtained from BALB/c mice with acute infection [11 days post infection (DPI)], mice with chronic infection (35 DPI) and healthy controls, and were analyzed using a label-free liquid chromatography tandem mass spectrometry analysis.

Results
We identified a total of 13,414 peptides on 1802 proteins, of which 169 and 47 proteins were significantly differentially expressed at acute and chronic infection phases, respectively. Clustering analysis revealed obvious differences in proteome profiles among all groups. Gene ontology analysis showed that a large number of differentially expressed proteins (DEPs) detected in acute infection were associated with biological binding activity and single-organism processes. KEGG pathway enrichment analysis showed that the majority of these DEPs were involved in disease-related and metabolic pathways.

Conclusions
Our findings revealed global reprogramming of the urine proteome following T.gondii infection, and data obtained in this study will enhance our understanding of the host responses to T. gondii infection and lead to the identification of new diagnostic biomarkers.

Graphical Abstract
Impacts of ivermectin mass drug administration for onchocerciasis on mosquito populations of Ogun state, Nigeria
Authors: Omitola Olaitan Olamide , Umunnakwe Cynthia Uchechukwu , Bayegun Adedotun Ayodeji , Anifowose Samuel Akinjide , Mogaji Hammed Oladeji , Oluwole Akinola Stephen , Odoemene Simon Nnayere , Awolola Taiwo Sam , Osipitan Adebola Adedoyin , Sam-Wobo Sammy Olufemi , Ekpo Uwem Friday 
Published: April 2021

Abstract
Background
The impact of single-dose mass drug administration (MDA) of ivermectin for onchocerciasis on mosquito populations was investigated in Ogun State, Nigeria.

Methods
Indoor and outdoor collection of mosquitoes was carried out in two intervention (IC) and two control communities (CC) at three different periods: pre-MDA (baseline), 2–3 days after MDA and 13–14 days after MDA. The density and parity rate of female Anopheles and Culex mosquitoes were determined and compared. Environmental and climatic data of study locations were obtained to perform generalized linear model analysis.

Results
A total of 1399 female mosquitoes were collected, including 1227 Anopheles and 172 Culex mosquitoes. There was a similar magnitude of reduction in the indoor density of Anopheles by 29% in the IC and CC 2–3 days post-MDA but the reduction in indoor parity rate was significantly higher (p = 0.021) in the IC, reducing by more than 50%. In the IC, observation of a significant reduction at 2–3 days post-MDA was consistent for both the indoor density (1.43 to 1.02) and indoor parity rate (95.35% to 44.26%) of Anopheles mosquitoes. The indoor parity rate of Anopheles remained significantly reduced (75.86%) 13–14 post-MDA. On the other hand, the indoor density of Culex increased from 0.07 to 0.10 at 2–3 days post-MDA while the indoor parity rate of Culex did not change. The outdoor density of Anopheles in the IC increased (p = 0.394) from 0.58 to 0.90 at 2–3 days post-MDA; a similar observation was consistent for the outdoor density (2.83 to 3.90) and outdoor parity rate (70.59% to 97.44%) of Culex, while the outdoor parity rate of Anopheles reduced from 85.71 to 66.67% at 2–3 days post-MDA. A generalized linear model showed that ivermectin MDA significantly caused a reduction in both the indoor density (p < 0.001) and indoor parity rate (p = 0.003) of Anopheles in the IC.

Conclusion
Ivermectin MDA resulted in the reduction of both the survival and density of Anopheles mosquitoes. This has strong implications for malaria transmission, which depends strongly on vector survival.

Graphical abstract
Transcriptomic profiling of three-dimensional cholangiocyte spheroids long term exposed to repetitive Clonorchis sinensis excretory-secretory products
Authors: Kim Jung-Woong , Yi Junyeong , Park Jinhong , Jeong Ji Hoon , Kim Jinho , Won Jihee , Chung Seok , Kim Tong-Soo , Pak Jhang Ho 
Published: April 2021

Abstract
Background
Biliary tract infection with the carcinogenic human liver fluke, Clonorchis sinensis, provokes chronic inflammation, epithelial hyperplasia, periductal fibrosis, and even cholangiocarcinoma. Complications are proportional to the intensity and duration of the infection. In addition to mechanical irritation of the biliary epithelia from worms, their excretory-secretory products (ESPs) cause chemical irritation, which leads to inflammation, proliferation, and free radical generation.

Methods
A three-dimensional in vitro cholangiocyte spheroid culture model was established, followed by ESP treatment. This allowed us to examine the intrinsic pathological mechanisms of clonorchiasis via the imitation of prolonged and repetitive in vivo infection.

Results
Microarray and RNA-Seq analysis revealed that ESP-treated cholangiocyte H69 spheroids displayed global changes in gene expression compared to untreated spheroids. In ESP-treated H69 spheroids, 185 and 63 probes were found to be significantly upregulated and downregulated, respectively, corresponding to 209 genes (p < 0.01, fold change > 2). RNA-Seq was performed for the validation of the microarray results, and the gene expression patterns in both transcriptome platforms were well matched for 209 significant genes. Gene ontology analysis demonstrated that differentially expressed genes were mainly classified into immune system processes, the extracellular region, and the extracellular matrix. Among the upregulated genes, four genes (XAF1, TRIM22, CXCL10, and BST2) were selected for confirmation using quantitative RT-PCR, resulting in 100% similar expression patterns in microarray and RNA-Seq.

Conclusions
These findings broaden our understanding of the pathological pathways of liver fluke-associated hepatobiliary disorders and suggest a novel therapeutic strategy for this infectious cancer.

Graphical Abstract
Co-infection of hepatitis E virus and Plasmodium falciparum malaria: A genuine risk in sub-Saharan Africa
Authors: Sahra Syeda , Jahangir Abdullah , Iqbal Qasim Zafar , Mobarakai Neville , Glaser Allison , Jahangir Ahmad 
Published: April 2021

Abstract
Background
There is a high prevalence of malaria and viral hepatitis in South Africa. Co-infection with Plasmodium malaria (leading to cerebral malaria) and hepatitis E virus (HEV) is a rare phenomenon.

Case presentation
A 33-year-old African American male with no past medical history developed altered mental status on his return from Ivory Coast. His blood tests were significant for renal and liver failure and a high Plasmodium parasite burden of 33% on the blood smear. Interestingly, he also had a positive result for hepatitis E IgM. The patient was effectively treated with aggressive hydration and intravenous (IV) artesunate.

Conclusion
Our report is the first to our knowledge in the cerebral malaria literature on a patient with hepatitis E co-infection. This exciting case emphasizes the importance of considering all kinds of endemic infectious diseases when evaluating sick returning travelers presenting to the emergency department.
IFN-γ and TNF-α drive a CXCL10+ CCL2+ macrophage phenotype expanded in severe COVID-19 lungs and inflammatory diseases with tissue inflammation
Authors:   Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, Zhang Fan , Mears Joseph R. , Shakib Lorien , Beynor Jessica I. , Shanaj Sara , Korsunsky Ilya , Nathan Aparna , Donlin Laura T. , Raychaudhuri Soumya 
Published: April 2021

Abstract
Background
Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies.

Methods
To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-β) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF.

Results
We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α.

Conclusions
Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.
Prevalence of abnormal and borderline electrocardiogram changes in 13, 079 Chinese amateur marathon runners
Authors: Wen Xu , Huang Yu-min , Shen Tong-Hui , Gong Ying-Lan , Dong Rui-qing , Xia Ling , Xie Tian-sheng 
Published: April 2021

Abstract
Background
The 12-lead electrocardiogram (ECG) has been adopted as an important component of preparticipation cardiovascular screening. However, there are still controversies in the screening and few studies with a large sample size have reported the results of ECGs of marathon runners. Therefore, the purpose of this study was to assess the prevalence of normal, borderline, and abnormal ECG changes in marathon runners.

Methods
The 12-lead ECG data of 13,079 amateur marathon runners between the ages of 18 and 35 years were included for analysis. The prevalence of ECG abnormalities among different gender groups was compared with chi-square tests.

Results
In terms of training-related changes, sinus bradycardia, sinus arrhythmia, and left ventricular high voltage were found in approximately 15, 5, and 3.28% of the participants, respectively. The incidence of right axis deviation in the marathon runners was 1.78%, which was slightly higher than the incidence of left axis deviation (0.88%). No more than 0.1% of the amateur marathon runners exhibited ST-segment depression, T wave inversion (TWI), premature ventricular contraction, pathologic Q waves, and prolonged QT interval.

Conclusions
Training-related ECG changes, including sinus bradycardia, sinus arrhythmia, and left ventricular high voltage, were common in amateur marathon runners. Most abnormal ECG changes, including ST-segment depression, TWI, premature ventricular contraction, pathologic Q waves, and prolonged QT interval, were infrequently found in amateur marathon runners. The data also suggested Chinese amateur marathon runners may have a relatively lower prevalence of ECG abnormalities than black and white runners.
Choroid plexus carcinoma in an adolescent male: a case report
Authors: Jameel Patel Zeeshan , Varma Ashish , Kumari Pooja , Vagha Keta , Vagha Jayant , Damke Sachin 
Published: April 2021

Abstract
Introduction/background
Although central nervous system tumors are the most common etiology of malignancies in the pediatric age group, choroid plexus carcinomas are rare, with an annual incidence rate of 0.10 per 100,000 children.

Case presentation
We report the case of an adolescent male belonging to central India who had presented with a history of persistent headache, projectile vomiting, neck stiffness, and an episode of generalized tonic-clonic seizure. Neurological examination was suggestive of a space-occupying lesion. Further neuroimaging was suggestive of a large left-sided choroid plexus carcinoma, later confirmed on pathological examination. Gross total resection was achieved and followed by radiation therapy. His recovery was satisfactory without any major events despite suffering from such a malignancy with a poor prognosis.

Conclusion
In the absence of a global consensus on choroid plexus carcinoma management, our patient underwent a successful gross total resection and received postoperative radiotherapy. He made a satisfactory recovery with a further plan to review with gadolinium-enhanced neuroimaging at a later date. We conclude that, when possible, achieving gross total resection is of utmost importance.
An ensemble of the iCluster method to analyze longitudinal lncRNA expression data for psoriasis patients
Authors: Tian Suyan , Wang Chi 
Published: April 2021

Abstract
Background
Psoriasis is an immune-mediated, inflammatory disorder of the skin with chronic inflammation and hyper-proliferation of the epidermis. Since psoriasis has genetic components and the diseased tissue of psoriasis is very easily accessible, it is natural to use high-throughput technologies to characterize psoriasis and thus seek targeted therapies. Transcriptional profiles change correspondingly after an intervention. Unlike cross-sectional gene expression data, longitudinal gene expression data can capture the dynamic changes and thus facilitate causal inference.

Methods
Using the iCluster method as a building block, an ensemble method was proposed and applied to a longitudinal gene expression dataset for psoriasis, with the objective of identifying key lncRNAs that can discriminate the responders from the non-responders to two immune treatments of psoriasis.

Results
Using support vector machine models, the leave-one-out predictive accuracy of the 20-lncRNA signature identified by this ensemble was estimated as 80%, which outperforms several competing methods. Furthermore, pathway enrichment analysis was performed on the target mRNAs of the identified lncRNAs. Of the enriched GO terms or KEGG pathways, proteasome, and protein deubiquitination is included. The ubiquitination-proteasome system is regarded as a key player in psoriasis, and a proteasome inhibitor to target ubiquitination pathway holds promises for treating psoriasis.

Conclusions
An integrative method such as iCluster for multiple data integration can be adopted directly to analyze longitudinal gene expression data, which offers more promising options for longitudinal big data analysis. A comprehensive evaluation and validation of the resulting 20-lncRNA signature is highly desirable.