bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140
Authors: Ghiboub Mohammed , Koster Jan , Craggs Peter D. , Li Yim Andrew Y. F. , Shillings Anthony , Hutchinson Sue , Bingham Ryan P. , Gatfield Kelly , Hageman Ishtu L. , Yao Gang , O’Keefe Heather P. , Coffin Aaron , Patel Amish , Sloan Lisa A. , Mitchell Darren J. , Hayhow Thomas G. , Lunven Laurent , Watson Robert J. , Blunt Christopher E. , Harrison Lee A. , Bruton Gordon , Kumar Umesh , Hamer Natalie , Spaull John R. , Zwijnenburg Danny A. , Welting Olaf , Hakvoort Theodorus B. M. , te Velde Anje A. , van Limbergen Johan , Henneman Peter , Prinjha Rab K. , de Winther Menno P. J. , Harker Nicola R. , Tough David F. , de Jonge Wouter J. 
Published: August 2022

Abstract
Background
SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation.

Results
We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14+ macrophages isolated from CD intestinal mucosa.

Conclusions
This study identifies SP140 as a druggable epigenetic therapeutic target for CD.
Time-resolved trajectory of glucose lowering medications and cardiovascular outcomes in type 2 diabetes: a recurrent neural network analysis
Authors: Longato Enrico , Di Camillo Barbara , Sparacino Giovanni , Avogaro Angelo , Fadini Gian Paolo 
Published: August 2022

Abstract
Aim
Treatment algorithms define lines of glucose lowering medications (GLM) for the management of type 2 diabetes (T2D), but whether therapeutic trajectories are associated with major adverse cardiovascular events (MACE) is unclear. We explored whether the temporal resolution of GLM usage discriminates patients who experienced a 4P-MACE (heart failure, myocardial infarction, stroke, death for all causes).

Methods
We used an administrative database (Veneto region, North-East Italy, 2011–2018) and implemented recurrent neural networks (RNN) with outcome-specific attention maps. The model input included age, sex, diabetes duration, and a matrix of GLM pattern before the 4P-MACE or censoring. Model output was discrimination, reported as area under receiver characteristic curve (AUROC). Attention maps were produced to show medications whose time-resolved trajectories were the most important for discrimination.

Results
The analysis was conducted on 147,135 patients for training and model selection and on 10,000 patients for validation. Collected data spanned a period of ~ 6 years. The RNN model efficiently discriminated temporal patterns of GLM ending in a 4P-MACE vs. those ending in an event-free censoring with an AUROC of 0.911 (95% C.I. 0.904–0.919). This excellent performance was significantly better than that of other models not incorporating time-resolved GLM trajectories: (i) a logistic regression on the bag-of-words encoding all GLM ever taken by the patient (AUROC 0.754; 95% C.I. 0.743–0.765); (ii) a model including the sequence of GLM without temporal relationships (AUROC 0.749; 95% C.I. 0.737–0.761); (iii) a RNN model with the same construction rules but including a time-inverted or randomised order of GLM. Attention maps identified the time-resolved pattern of most common first-line (metformin), second-line (sulphonylureas) GLM, and insulin (glargine) as those determining discrimination capacity.

Conclusions
The time-resolved pattern of GLM use identified patients with subsequent cardiovascular events better than the mere list or sequence of prescribed GLM. Thus, a patient’s therapeutic trajectory could determine disease outcomes.
Circular RNA circFIRRE drives osteosarcoma progression and metastasis through tumorigenic-angiogenic coupling
Authors: Yu Lingfeng , Zhu Hao , Wang Zhen , Huang Jianhao , Zhu Yan , Fan Gentao , Wang Yicun , Chen Xi , Zhou Guangxin 
Published: August 2022

Abstract
Background
Disappointing clinical efficacy of standard treatment has been proven in refractory metastatic osteosarcoma, and the emerging anti-angiogenic regimens are still in the infantile stage. Thus, there is an urgent need to develop novel therapeutic approach for osteosarcoma lung metastasis.

Methods
circFIRRE was selected from RNA-sequencing of 4 matched osteosarcoma and adjacent samples. The expression of circFIRRE was verified in clinical osteosarcoma samples and cell lines via quantitative real-time polymerase chain reaction (RT-qPCR). The effect of circFIRRE was investigated in cell lines in vitro models, ex vivo models and in vivo xenograft tumor models, including proliferation, invasion, migration, metastasis and angiogenesis. Signaling regulatory mechanism was evaluated by RT-qPCR, Western blot, RNA pull-down and dual-luciferase reporter assays.

Results
In this article, a novel circular RNA, circFIRRE (hsa_circ_0001944) was screened out and identified from RNA-sequencing, and was upregulated in both osteosarcoma cell lines and tissues. Clinically, aberrantly upregulated circFIRRE portended higher metastatic risk and worse prognosis in osteosarcoma patients. Functionally, in vitro, ex vivo and in vivo experiments demonstrated that circFIRRE could drive primary osteosarcoma progression and lung metastasis by inducing both tumor cells and blood vessels, we call as “tumorigenic-angiogenic coupling”. Mechanistically, upregulated circFIRRE was induced by transcription factor YY1, and partially boosted the mRNA and protein level of LUZP1 by sponging miR-486-3p and miR-1225-5p.

Conclusions
We identified circFIRRE as a master regulator in the tumorigenesis and angiogenesis of osteosarcoma, which could be purposed as a novel prognostic biomarker and therapeutic target for refractory osteosarcoma.
Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA
Authors: Zhou Li , Jiang Jingwen , Huang Zhao , Jin Ping , Peng Liyuan , Luo Maochao , Zhang Zhe , Chen Yan , Xie Na , Gao Wei , Nice Edouard C. , Li Jing-Quan , Chen Hai-Ning , Huang Canhua 
Published: August 2022

AbstractBackgroundHypoxia, a typical hallmark of solid tumors, exhibits an essential role in the progression of colorectal cancer (CRC), in which the dysregulation of long non-coding RNAs (lncRNAs) is frequently observed. However, the underlying mechanisms are not clearly defined.MethodsThe TCGA database was analyzed to identify differential lncRNA expression involved in hypoxia-induced CRC progression. qRT-PCR was conducted to validate the upregulation of lncRNASTEAP3-AS1in CRC cell lines and tumor-bearing mouse and zebrafish models under hypoxia. ChIP-qRT-PCR was used to detect the transcriptional activation ofSTEAP3-AS1mediated by HIF-1α. RNA-seq, fluorescent in situ hybridization, RNA pulldown, RNA immunoprecipitation, co-immunoprecipitation, immunofluorescence and immunoblot experiments were used to ascertain the involved mechanisms. Functional assays were performed in both in vitro and in vivo models to investigate the regulatory role ofSTEAP3-AS1/STEAP3/Wnt/β-catenin axis in CRC proliferation and metastasis.ResultsHere, we identified a hypoxia-induced antisense lncRNASTEAP3-AS1that was highly expressed in clinical CRC tissues and positively correlated with poor prognosis of CRC patients. Upregulation of lncRNASTEAP3-AS1, which was induced by HIF-1α-mediated transcriptional activation, facilitated the proliferation and metastasis of CRC cells both in vitro and in vivo. Mechanistically,STEAP3-AS1interacted competitively with the YTH domain-containing family protein 2 (YTHDF2), a N6-methyladenosine (m6A) reader, leading to the disassociation of YTHDF2 withSTEAP3mRNA. This effect protectedSTEAP3mRNA from m6A-mediated degradation, enabling the high expression of STEAP3 protein and subsequent production of cellular ferrous iron (Fe2+). Increased Fe2+levels elevated Ser 9 phosphorylation of glycogen synthase kinase 3 beta (GSK3β) and inhibited its kinase activity, thus releasing β-catenin for nuclear translocation and subsequent activation of Wnt signaling to support CRC progression.ConclusionsTaken together, our study highlights the mechanisms of lncRNASTEAP3-AS1in facilitating CRC progression involving theSTEAP3-AS1/STEAP3/Wnt/β-catenin axis, which may provide novel diagnostic biomarkers or therapeutic targets to benefit CRC treatment.Graphical abstractHypoxia-induced HIF-1α transcriptionally upregulates the expression of lncRNASTEAP3-AS1, which interacts competitively with YTHDF2, thus upregulating mRNA stability ofSTEAP3and consequent STEAP3 protein expression. The enhanced STEAP3 expression results in production of cellular ferrous iron (Fe2+), which induces the Ser 9 phosphorylation and inactivation of GSK3β, releasing β-catenin for nuclear translocation and contributing to subsequent activation of Wnt signaling to promote CRC progression.
A randomized double blind comparison of atosiban in patients with recurrent implantation failure undergoing IVF treatment
Authors: Tang Chuan Ling , Li Qi Yue , Chen Feng Lian , Cai Chen Ting , Dong Yue Yan , Wu Yuan Yuan , Yang Jian Zhi , Zhao Mei , Chi Feng Li , Hong Ling , Ai Ai , Chen Miao Xin , Li Kun Ming , Teng Xiao Ming , Chen Zhi Qin 
Published: August 2022

Abstract
Background
Patients with recurrent implantation failure (RIF) may have more uterine contractions. Several observational studies suggested that atosiban administration around embryo transfer resulted in higher pregnancy rates in RIF patients. This study aimed to evaluate the effect of atosiban given before fresh embryo transfer on pregnancy outcomes of women with RIF.

Methods
A prospective, randomized, double-blind controlled clinical trial was performed in IVF center of Shanghai First Maternity and Infant Hospital. According to a computer-generated randomization list, 194 infertile women with RIF received fresh embryo transfer between July 2017 and December 2019 were randomly allocated into the atosiban (n = 97) and the placebo (n = 97) groups. Women in the treatment group received atosiban intravenously about 30 min before embryo transfer with a bolus dose of 6.75 mg over one minute. Those in the placebo group received only normal saline infusion for the same duration.

Results
There was no significant difference in the live birth rate between the atosiban and placebo groups (42.3% vs 35.1%, P = 0.302, RR = 1.206 (0.844–1.723)). No significant differences were found between the two groups in the positive pregnancy test, clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and implantation rates. Similar results were found when stratified by the number of embryos previously transferred, number of previous failed embryo transfers, frequency of endometrial peristalsis on embryo transfer day (≥ 3 waves/min) or serum estradiol (E2) on the day of hCG above the median level. And, there was no correlation between the serum E2 level on the day of hCG and the frequency of endometrial peristalsis on embryo transfer day. The frequency of endometrial peristalsis on embryo transfer day, total FSH/HMG dosage and duration were the significant factors which independently predicted the likelihood of a live birth.

Conclusions
These results suggested that atosiban treatment before fresh embryo transfer might not improve the live birth rate in RIF patients.

Trial registration
The study had been approved by the Institutional Review Board of the hospital (2017 ethics No.43) and was registered under Clinicaltrials.gov with an identifier NCT02893722.
Deconstructing design thinking as a tool for the implementation of a population health initiative
Authors: Jarrett Caitlin , Baxter Yara C. , Boch Johannes , Carrasco Conrado , Cobos Muñoz Daniel , Mauro Dib Karina , Pessoa Lara , Saric Jasmina , Silveira Mariana , Steinmann Peter 
Published: August 2022

Abstract
Background
The translation of evidence-based practices and rapid uptake of innovations into global health practice is challenging. Design thinking is a consultative process involving multiple stakeholders and has been identified as a promising solution to create and apply implementation strategies in complex environments like health systems.

Methods
We conducted a process evaluation of a real-world example, namely an initiative to innovate hypertension screening, diagnosis and care in São Paulo, Brazil. The parameters of the evaluation were informed by a specification rubric and categorization system, recommended for the investigation of implementation strategies, and the double-diamond conceptual framework to describe and examine the strategic architecture and nature of the design thinking approach, with particular emphasis on identifying potential areas of “value-add” particular to the approach. The retrospective evaluation was performed by an independent partner who had not been involved in the setting up and implementation of the design thinking process.

Results
The evaluation unveiled a dense catalogue of strategically driven, mostly theoretically based, activities involving all identified health system stakeholders including patients. Narrative reconstruction illuminated the systematic and coherent nature of this approach, with different resulting actions progressively accounting for all relevant layers of the health system to engineer a broad selection of specific implementation solutions. The relevance of the identified features and the mechanics used to promote more successful implementation practices was manifested in several distinct ways: design thinking offered a clear direction on which innovations really mattered and when, as well as several new dimensions for consideration in the development of an innovation mindset amongst stakeholders. It thereby promoted relationship quality in terms of familiarity and trust, and commitment to evidence-based enquiry and action. Design thinking was also able to navigate the territory between the need for intervention “fidelity” versus “adaptation” and provide the operational know-how to face familiar implementation hurdles. Lastly, it brought a new kind of skill set to the public health stakeholders that incorporated diplomacy, multidisciplinary approaches and management sciences—skills that are considered necessary but not yet widely taught as part of public health training.

Conclusions
Design thinking is a sound and viable tool to use as part of an implementation strategy for engaging with health system stakeholders and successfully translating evidence-based practices and new innovations into routine practice, thereby addressing an important knowledge—practice gap and, more broadly, contributing to the strategic repertoire available to implementation science.
Preoperative computed tomography-guided localization for multiple pulmonary nodules: comparison of methylene blue and coil
Authors: Zhang Sheng-Feng , Liu Hai-Ri , Ma Ai-Li , Li Er-Liang 
Published: August 2022

Abstract
Background
Preoperative computed tomography (CT)-guided localization has been used to guide the video-assisted thoracoscopic surgery (VATS) sublobar (wedge or segmental) resection for pulmonary nodules (PNs). We aimed to assess the relative efficacy and safety of CT-guided methylene blue (MB)- and coil-based approaches to the preoperative localization of multiple PNs (MPNs).

Methods
Between January 2015 and December 2020, 31 total cases suffering from MPNs at our hospital underwent CT-guided localization and subsequent VATS resection in our hospital, of whom 15 and 16 respectively underwent MB localization (MBL) and coil localization (CL). The clinical effectiveness and complication rates were compared between 2 groups.

Results
The PN- and patient-based technical success rates in the MBL group were both 100%, whereas in the CL group they were 97.2% (35/36) and 93.8% (15/16), respectively, with no substantial discrepancies between groups. Patients in the MBL group illustrated a substantially shorter CT-guided localization duration compared with the CL group (18 min vs. 29.5 min, P < 0.001). Pneumothorax rates (P = 1.000) and lung hemorrhage (P = 1.000) were comparable in both groups. In the MBL and CL groups, the median interval between localization and VATS was 1 h and 15.5 h, respectively (P < 0.001). One-stage VATS sublobar resection of the target nodules was successfully performed in all patients from both groups.

Conclusion
Both CT-guided MBL and CL can be readily and safely utilized for preoperative localization in individuals who had MPNs, with MBL being correlated with a shorter localization duration compared with CL.
Comparative transcriptome in large-scale human and cattle populations
Authors: Yao Yuelin , Liu Shuli , Xia Charley , Gao Yahui , Pan Zhangyuan , Canela-Xandri Oriol , Khamseh Ava , Rawlik Konrad , Wang Sheng , Li Bingjie , Zhang Yi , Pairo-Castineira Erola , D’Mellow Kenton , Li Xiujin , Yan Ze , Li Cong-jun , Yu Ying , Zhang Shengli , Ma Li , Cole John B. , Ross Pablo J. , Zhou Huaijun , Haley Chris , Liu George E. , Fang Lingzhao , Tenesa Albert 
Published: August 2022

Abstract
Background
Cross-species comparison of transcriptomes is important for elucidating evolutionary molecular mechanisms underpinning phenotypic variation between and within species, yet to date it has been essentially limited to model organisms with relatively small sample sizes.

Results
Here, we systematically analyze and compare 10,830 and 4866 publicly available RNA-seq samples in humans and cattle, respectively, representing 20 common tissues. Focusing on 17,315 orthologous genes, we demonstrate that mean/median gene expression, inter-individual variation of expression, expression quantitative trait loci, and gene co-expression networks are generally conserved between humans and cattle. By examining large-scale genome-wide association studies for 46 human traits (average n = 327,973) and 45 cattle traits (average n = 24,635), we reveal that the heritability of complex traits in both species is significantly more enriched in transcriptionally conserved than diverged genes across tissues.

Conclusions
In summary, our study provides a comprehensive comparison of transcriptomes between humans and cattle, which might help decipher the genetic and evolutionary basis of complex traits in both species.
Canine nematode and Giardia spp. infections in dogs in Edmonton, Alberta, the “CANIDA” study
Authors: Visscher Darcy , Porter Emilie , Sweet Sarah , Szlosek Donald , Horr Stephanie 
Published: August 2022

Abstract
Background
Canine intestinal parasite prevalence may be influenced by geographical region, age, and health status of the dog. Behaviors such as predation, scavenging, or roaming as well as routine administration of anthelmintics also play a role. The purpose of this study was to evaluate fecal test results using zinc sulfate flotation by centrifugation combined with coproantigen testing directed at protein antigens excreted or secreted by hookworms (Ancylostoma spp. Uncinaria stenocephala), ascarids (Toxocara canis, Toxascaris spp. Baylisascaris spp.), whipworms (Trichuris vulpis), and Giardia spp. during active infection in owned dogs visiting dog parks in Western Canada.

Methods
A total of 774 participants were recruited from Edmonton, Alberta, Canada. Canine fecal samples were collected from seven dedicated off-leash dog parks. Participating dog owners responded to a questionnaire regarding their dogs’ signalment, previous veterinary history, and use of parasite-preventive products. Fecal samples were tested using zinc sulfate centrifugation combined with coproantigen testing.

Results
The overall prevalence of canine intestinal parasites in client-owned dogs was similar to previous studies conducted in the US. Mean age of dogs tested was 4 years, with puppies and older dogs having higher rates of infection than the mean. Fecal flotation centrifugation found 3.2% hookworm, ascarid, whipworm, and Giardia spp.-positive infections. Coproantigen testing identified 5.8% positive infections, including all of the above that were detected using fecal flotation centrifugation.

Conclusions
Coproantigen testing detected more hookworm, ascarid, whipworm, and Giardia spp.-positive samples in addition to detecting all positive results found using fecal flotation centrifugation. Fecal flotation centrifugation combined with coproantigen testing improves sensitivity over flotation alone and may detect pre-patent or sub-clinical infections in dogs visiting public dog parks.

Graphical Abstract
Effects of different training intensities in high-intensity interval training (HIIT) on maximal aerobic velocity, hematological and muscle-damage markers in healthy young adults
Authors: Rhibi Fatma , Abderrahman Abderraouf Ben , Prioux Jacques , Clark Cain C. T. , Bideau Benoît , Besbes Sophia , Hackney Anthony C. , Granacher Urs , Zouhal Hassane 
Published: August 2022

AbstractThis study aimed to examine the effects of two high-intensity interval training programs (HIIT) on maximal aerobic velocity (MAV), hematological variations and muscle damage markers in young healthy adults. Twenty-nine male physical education students, aged 20.3 ± 3.3 years, volunteered to participate in this study, and were randomly assigned to a control group (CG, n = 9) or two intervention groups (group 1 or 2). Intervention group 1 (n = 10) exercised at 100% of their MAV (EG100) while group 2 (n = 10) exercised at 110% MAV (EG110). Before and after the eight week training program, blood samples were drawn at rest, before, and after an intermittent exercise. Aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), C reactive protein (CRP), creatine kinase (CK) concentrations and hematological parameters (white blood cells [WBC], monocytes [MO], lymphocytes [LY], neutrophil [NE]) and lactate dehydrogenase (LDH) were measured. Post-hoc tests showed that MAV was significantly higher in EG110 compared to EG100 after HIIT (p < 0.01, ηp2 = 0.05), whilst ALAT, ASAT, and CPR were significantly lower (p < 0.01; 0.02 < ηp2 < 0.11) in EG110 compared to EG100. Moreover, post-hoc tests indicated that LY decreased significantly (p < 0.001, ηp2 = 0.21) only for EG110. Furthermore, there were significant positive correlations for both EG100 and EG110 between MAV and ALAT (r = 0.66, p = 0.044 and r = 0.64, p = 0.041 respectively), CK (r = 0.67, p = 0.031 and r = 0.86, p = 0.030, respectively), LDH (r = 0.74, p = 0.014, and r = 0.071, p = 0.021, respectively). In addition, there was a significant positive correlation for both, EG100 and EG110 between MAV and LY (r = 0.79, p < 0.01; r = 0.72, p < 0.05, respectively). Concerning the relationship between MAV and NE, there was a significant positive correlation (r = 0.66; p < 0.05) only for EG110. Findings from this study revealed that HIIT at 110% MAV was more efficient to improve MAV and reduce muscle damage. In addition, we observed significant associations between performance improvements (MAV) and markers of muscle damage.