bluuebunny/crossref_metadata_2025_split huggingface dataset:
Manipulation of tissue factor-mediated basal PAR-2 signalling on macrophages determines sensitivity for IFNγ responsiveness and significantly modifies the phenotype of murine DTH
Authors: Wilkinson Hannah , Leonard Hugh , Robson Michael G. , Smith Richard , Tam ElLi , McVey John H. , Kirckhofer Daniel , Chen Daxin , Dorling Anthony 
Published: September 2022

BackgroundTissue factor (TF) generates proteases that can signal through PAR-1 and PAR-2. We have previously demonstrated PAR-1 signalling primes innate myeloid cells to be exquisitely sensitive to interferon-gamma (IFNγ). In this work we explored how TF mediated PAR-2 signalling modulated responsiveness to IFNγ and investigated the interplay between PAR-1/-2 signalling on macrophages.MethodologyWe characterised how TF through PAR-2 influenced IFNγ sensitivity in vitro using PCR and flow cytometry. and how it influenced oxazolone-induced delayed type hypersensitivity (DTH) responses in vivo. We investigated how basal signalling through PAR-2 influenced PAR-1 signalling using a combination of TF-inhibitors and PAR-1 &amp;-2 agonists and antagonists. Finally, we investigated whether this system could be targeted therapeutically using 3-mercaptopropionyl-F-Cha-Cha-RKPNDK (3-MP), which has actions on both PAR-1 and -2.ResultsTF delivered a basal signal through PAR-2 that upregulated SOCS3 expression and blunted M1 polarisation after IFNγ stimulation, opposing the priming achieved by signalling through PAR-1. PAR-1 and -2 agonists or antagonists could be used in combination to modify this basal signal in vitro and in vivo. 3-MP, by virtue of its PAR-2 agonist properties was superior to agents with only PAR-1 antagonist properties at reducing M1 polarisation induced by IFNγ and suppressing DTH. Tethering a myristoyl electrostatic switch almost completely abolished the DTH response.ConclusionsTF-mediated signalling through PARs-1 and -2 act in a homeostatic way to determine how myeloid cells respond to IFNγ. 3-MP, an agent that simultaneously inhibits PAR-1 whilst delivering a PAR-2 signal, can almost completely abolish immune responses dependent on M1 polarisation, particularly if potency is enhanced by targeting to cell membranes; this has potential therapeutic potential in multiple diseases.
Structural and functional characterization of Cas2 of CRISPR-Cas subtype I-C lacking the CRISPR component
Authors: Anand Vineet , Prabhakaran Harshini Sheeja , Gogoi Prerana , Kanaujia Shankar Prasad , Kumar Manish 
Published: September 2022

The genome of pathogenic Leptospira interrogans serovars (Copenhageni and Lai) are predicted to have CRISPR-Cas of subtypes I-B and I-C. Cas2, one of the core Cas proteins, has a crucial role in adaptive defense against foreign nucleic acids. However, subtype I-C lacks the CRISPR element at its loci essential for RNA-mediated adaptive immunity against foreign nucleic acids. The reason for sustaining the expense of cas genes are unknown in the absence of a CRISPR array. Thus, Cas2C was chosen as a representative Cas protein from two well-studied serovars of Leptospira to address whether it is functional. In this study, the recombinant Cas2C of Leptospira serovars Copenhageni (rLinCas2C, 12 kDa) and Lai (rLinCas2C_Lai, 8.6 kDa) were overexpressed and purified. Due to natural frameshift mutation in the cas2c gene of serovar Lai, rLinCas2C_Lai was overexpressed and purified as a partially translated protein. Nevertheless, the recombinant Cas2C from each serovar exhibited metal-dependent DNase and metal-independent RNase activities. The crystal structure of rLinCas2C obtained at the resolution of 2.60 Å revealed the protein is in apostate conformation and contains N- (1–71 amino acids) and C-terminal (72–90 amino acids) regions, with the former possessing a ferredoxin fold. Substitution of the conserved residues (Tyr7, Asp8, Arg33, and Phe39) with alanine and deletion of Loop L2 resulted in compromised DNase activity. On the other hand, a moderate reduction in RNase activity was evident only in selective rLinCas2C mutants. Overall, in the absence of an array, the observed catalytic activity of Cas2C may be required for biological processes distinct from the CRISPR-Cas-associated function.
The viral and inflammation hypothesis of epileptic seizures based on bioinformatic study of circulating miRNAs and peripheral whole-blood mRNAs of adult epilepsy patients
Authors: Wu Jiahuan , Meng Ying , Xu Fei , Wu Qian , Wang Cheng 
Published: September 2022

BackgroundThe study aimed to investigate the genome-wide biological significance of the circulating miRNAs markers found in peripheral whole blood of adult epileptic seizures patients by integrating analysis using bioinformatics approaches.MethodsThe Gene Expression Omnibus (GEO) dataset was accessed to retrieve epilepsy-related circulating miRNA profile data (GSE114847) including 89 subjects (n = 40 epileptic and n = 49 healthy control), peripheral whole-blood mRNA expression data (GSE143772) including 64 subjects (n = 32 epileptic and n = 32 healthy control). To eliminate age disparities in epilepsy pathophysiology only adult epileptic patients were selected. Furthermore, GEO2R was used to identify adult-related mRNAs (AD-mRNAs) against epilepsy as potential biomarkers. Moreover, to predict the potential target genes for these mRNAs, we used mirWalk. Finally, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to investigate the biological activities of AD-mRNAs. Importantly, the protein–protein network of these identified AD-mRNAs was constructed. Eventually, the overlapping AD-mRNAs and AD-miRNAs and their functions were explored to shortlist potential AD-epileptic markers.ResultThe current study resulted in the identification of 79 upregulated and 40 downregulated different expression gene (DEGs) in both applied data. These targets were cross-linked and mapped with each other to acquire common adult epilepsy-related overlapped mRNAs (Mo-mRNAs). It was found that there was a total of 36 overlapping genes. These overlapped AD-mRNAs markers were found to be functionally enriched in cell regulating pathways i.e., positive regulation of type 1 interferon signaling pathway and mitochondrial cytochrome C release pathway, respectively.ConclusionThis research gives a comprehensive depiction of the mRNAs that may be involved in adult epilepsy patients' pathophysiological progressions.
Functional network alterations in young brain tumor patients with radiotherapy-induced memory impairments and vascular injury
Authors: Morrison Melanie A. , Walter Sadie , Mueller Sabine , Felton Erin , Jakary Angela , Stoller Schuyler , Molinaro Annette M. , Braunstein Steve E. , Hess Christopher P. , Lupo Janine M. 
Published: September 2022

BackgroundCognitive impairment and cerebral microbleeds (CMBs) are long-term side-effects of cranial radiation therapy (RT). Previously we showed that memory function is disrupted in young patients and that the rate of cognitive decline correlates with CMB development. However, vascular injury alone cannot explain RT-induced cognitive decline. Here we use resting-state functional MRI (rsfMRI) to further investigate the complex mechanisms underlying memory impairment after RT.MethodsNineteen young patients previously treated with or without focal or whole-brain RT for a brain tumor underwent cognitive testing followed by 7T rsfMRI and susceptibility-weighted imaging for CMB detection. Global brain modularity and efficiency, and rsfMRI signal variability within the dorsal attention, salience, and frontoparietal networks were computed. We evaluated whether MR metrics could distinguish age- and sex-matched controls (N = 19) from patients and differentiate patients based on RT exposure and aggressiveness. We also related MR metrics with memory performance, CMB burden, and risk factors for cognitive decline after RT.ResultsCompared to controls, patients exhibited widespread hyperconnectivity, similar modularity, and significantly increased efficiency (p &lt; 0.001) and network variability (p &lt; 0.001). The most abnormal values were detected in patients treated with high dose whole-brain RT, having supratentorial tumors, and who did not undergo RT but had hydrocephalus. MR metrics and memory performance were correlated (R = 0.34–0.53), though MR metrics were more strongly related to risk factors for cognitive worsening and CMB burden with evidence of functional recovery.ConclusionsMR metrics describing brain connectivity and variability represent promising candidate imaging biomarkers for monitoring of long-term cognitive side-effects after RT.
Neuromyelitis optica spectrum disorder in Western China impacts employment and increases financial burden in women
Authors: Han Lin , Hong Peiwei , Wan Yang , Cai Linjun , Shi Ziyan , Wang Jiancheng , Lang YanLin , Zhou Hongyu 
Published: September 2022

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) often leads to disability and exerts a heavy toll on the work and life of affected female patients. This study aimed to analyze the current employment situation and economic burden as well as the risk factors for unemployment in female patients with NMSOD.MethodsWe compared the following unemployment- and employment-related aspects in with NSMOD, which were investigated using questionnaires: the specific impact of NMOSD on work, medical expenses, and factors affecting unemployment.ResultsWe enrolled 351 female patients with NMOSD. More than half (54.1%, 190/351) of participants reported that the disease led to unemployment. The unemployment group was significantly older (46.9 ± 12.1 years vs. 39.3 ± 9.4 years, P = 0.000), had a higher annual recurrence rate (ARR) (0.6 [inter quartile range [IQR]:0.4–0.9] vs. 0.5 [IQR: 0.3–0.8], P = 0.141), and a higher severe disability rate (44.2% vs. 11.2%, P = 0.000) than the employment group. Moreover, unemployed patients had lower education levels. The factors influencing unemployment included low education (junior middle-school or below), age, higher ARR, and severe disability (odds ratio [OR] = 6.943, P = 0.000; OR = 1.034, P = 0.010; OR = 1.778, P = 0.038; and OR = 4.972, P = 0.000, respectively). Medication and hospitalization costs constituted the principal economic burdens.ConclusionThe heavy financial burden, employment difficulties, and high unemployment rate are the most prominent concerns of female patients with NMOSD who require more social support and concern.
Efficacy of idebenone in the Treatment of iRBD into Synucleinopathies (EITRS): rationale, design, and methodology of a randomized, double-blind, multi-center clinical study
Authors: Li Yuanyuan , Wang Chunyi , Luo Ningdi , Chen Fangzheng , Zhou Liche , Niu Mengyue , Kang Wenyan , Liu Jun 
Published: September 2022

BackgroundAs the strongest prodromal marker of α-synuclein-specific neurodegeneration, idiopathic REM sleep behavior disorder (iRBD) is becoming a focus of interest in disease-modifying therapy. Idebenone has been widely portrayed as a potent antioxidant targeting mitochondrial dysfunction. Previous study has identified the effect of idebenone on Parkinson's disease with promising outcomes by regulating mitophagy. A novel indication of idebenone should be highlighted in iRBD population.MethodsThe EITRS study is a randomized, double-blind, multi-center clinical study assessing the efficacy and safety of idebenone in the treatment of iRBD into synucleinopathies. One hundred forty-two patients (aged 40–75 years old) with clinically diagnosed iRBD are planned to be recruited with 80% statistical power and randomly assigned to idebenone (30 mg each time, three times a day) or matching placebo orally for 5 years. The assessment of rating scales, blood testing and neuroimaging examinations will be conducted at baseline, the 1st, 3rd and 5th year of follow-up. The primary efficacy endpoint is the 5-year conversion rate in patients with iRBD. The secondary endpoint is the safety and tolerability of idebenone in the treatment of iRBD. The study has been launched in July 2020.DiscussionThis is the first prospective study designed to identify the efficacy and safety of idebenone on the treatment of iRBD into synucleinopathies. The current results are expected to promote the development of evidence-based recommendations for the management of patients with iRBD. Furthermore, we hope to provide insights on a possible disease-modifying approach with robust evidence.Trial RegistrationClinicaltrials.gov, identifier: NCT 04534023.
Baseline blood pressure does not modify the effect of intravenous thrombolysis in successfully revascularized patients
Authors: Xiaoxi Zhang , Xuan Zhu , Lei Zhang , Zifu Li , Pengfei Xing , Hongjian Shen , Yongxin Zhang , Weilong Hua , Yihan Zhou , Dongwei Dai , Qiang Li , Rui Zhao , Qinghai Huang , Yi Xu , Song Lili , Anderson Craig S. , Jianmin Liu , Yongwei Zhang , Pengfei Yang 
Published: September 2022

BackgroundStudies indicate a trajectory relationship between baseline blood pressure (BP) and outcome in patients with acute ischemic stroke (AIS) eligible for both intravenous thrombolysis (IVT) with alteplase and endovascular treatment (EVT). We determined whether baseline BP modified the effect of IVT in successfully revascularized AIS patients who participated in the Direct Intra-Arterial Thrombectomy to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals (DIECT-MT) trial.MethodsThe association of baseline systolic BP, trichotomized as high (141–185 mmHg), middle (121–140 mmHg), and low (91–120 mmHg), and the outcomes of any intracerebral hemorrhage (ICH), symptomatic ICH (sICH), and mortality and functional outcome on the modified Rankin scale at 90 days were explored. Logistic regression models determined the interaction between clinical outcomes and baseline systolic and diastolic BP, and mean arterial pressure (MAP), at 10 mmHg intervals. Data are reported as odds ratios (OR) and 95% CI.ResultsA post-hoc analysis of DIRECT-MT, in 510 of the 656 randomized participants with successful revascularization underwent MT. The overall adjusted common OR of IVT and baseline BP on any ICH, sICH, and 90-day mortality and functional outcome were 0.884 (95%CI 0.613–1.274), 0.643 (95%CI 0.283–1.458), 0.842 (95%CI 0.566–1.252), and 1.286 (95%CI 0.772–2.142), respectively. No significant interaction between baseline blood pressure and intravenous thrombolysis with clinical outcome was observed.ConclusionsIn patients with baseline SBP under 185 mmHg, baseline blood pressure does not alter the risk of hemorrhagic transformation and clinicaloutcome in successfully revascularized patients, regardless of intravenous alteplase usage. Future studies are needed to confirm our findings.RegistrationURL: http://www.clinicaltrials.gov, Identifier: NCT03469206.
Breast microbiome associations with breast tumor characteristics and neoadjuvant chemotherapy: A case-control study
Authors: Li Xuejun , Sun Xiaohu , Zhang Ai , Pang Jing , Li Yun , Yan Mengfan , Xu Zhen , Yu Yue , Yang Zhengjun , Chen Xi , Wang Xin , Cao Xu-Chen , Tang Nai-jun 
Published: September 2022

BackgroundCommensal microbiota have been proven to colonize the mammary gland, but whether their composition is altered in patients with breast cancer (BC) remains elusive. This study intends to explore the breast microbiome differences between benign and malignant diseases and to investigate the impact of neoadjuvant chemotherapy (NAC) on the breast microbiota in patients with BC.MethodsBreast normal adipose tissues (NATs) were collected from 79 patients with BC and 15 controls between July 2019 and November 2021. The BC group consisted of 29 patients who had received NAC and 50 who were non-NAC patients. Participants diagnosed with benign breast disease were recruited as controls. 16S rRNA gene sequencing was used to analyze the bacterial diversity of NATs.ResultsThe community structure of the NAT microbiome was significantly different between the BC and control groups. Proteobacteria decreased (47.40% versus 39.74%), whereas Firmicutes increased (15.71% versus 25.33%) in patients with BC when compared with that in control tissues. Nine genera were enriched in BC NATs, and four genera levels increased in the control group. The associations between differential bacterial genera and breast tumor grade were calculated by Spearman’s correlation. The results showed that tumor grade was positively associated with the relative abundance of Streptococcus and negatively related to Vibrio, Pseudoalteromonas, RB41, and Photobacterium. Moreover, menopause was associated with the microbiota composition change of non-NAC BC patients and related to the significant reduction in the abundance level of Pseudoalteromonas, Veillonella, and Alcaligenes. In addition, NAC was related to the beta diversity of patients with BC and associated with the decrease of Clostridium_sensu_stricto_7 and Clostridium_sensu_stricto_2 in postmenopausal patients. Of note, Tax4Fun functional prediction analysis revealed that the metabolic state was more exuberant in the BC group with upregulating of multiple metabolism-related pathways.ConclusionOur results offer new insight into the relationship between NAC and breast microbiota and help to better characterize the breast microbial dysbiosis that occurs in patients with BC. Further epidemiological studies with larger sample size and well-designed animal experiments are required to elucidate the role of breast microbiota in the therapeutic outcome of BC.
Comprehensive analysis of ECHDC3 as a potential biomarker and therapeutic target for acute myeloid leukemia: Bioinformatic analysis and experimental verification
Authors: Zhao Yijing , Niu Li-Ting , Hu Li-Juan , Lv Meng 
Published: September 2022

BackgroundEnoyl-CoA hydratase domain containing 3 (ECHDC3) increased in CD34+ progenitor cells of acute myeloid leukemia (AML) cells after chemotherapy. However, the prognostic significance and function of ECHDC3 in AML remain to be clarified.MethodsIn the training cohort, 24 AML (non-acute promyelocytic leukemia, APL) patients were enrolled in Peking University People’s Hospital and tested for ECHDC3 in enriched CD34+ cells at diagnosis. In the validation set, 351 bone marrow RNA-seq data of non-APL AML were obtained by two independent online datasets (TCGA-LAML and BEAT-AML). LASSO regression model was conducted to a new prediction model of ECHDC3-related genes. In addition, the ECHDC3 signature was further explored by GO, KEGG, GSEA, and immuno-infiltration analysis. By RNA interference, the function of ECHDC3 in mitochondrial DNA (mt-DNA) transcriptome and chemoresistance was further explored, and the GSE52919 database re-verified the ECHDC3 chemoresistance feature.ResultsBy Kaplan-Meier analysis, patients with ECHDC3high demonstrated inferior overall survival (OS) compared to those with ECHDC3low both in the training (2-year OS, 55.6% vs. 100%, p = 0.011) and validation cohorts (5-year OS, 9.6% vs. 24.3%, p = 0.002). In addition, ECHDC3high predicted inferior OS in the subgroup of patients with ELN 2017 intermediated (int) risk (5-year OS, 9.5% vs. 26.3%, p = 0.039) or FLT3+NPM1− adverse (adv) risk (4-year OS, 6.4% vs. 31.8%, p = 0.003). In multivariate analysis, ECHDC3 was an independent risk factor of inferior OS (HR 1.159, 95% CI 1.013–1.326, p = 0.032). In the prediction model combining ECHDC3 and nine selected genes (RPS6KL1, RELL2, FAM64A, SPATS2L, MEIS3P1, CDCP1, CD276, IL1R2, and OLFML2A) by Lasso regression, patients with high risk showed inferior 5-year OS (9.3% vs. 23.5%, p &lt; 0.001). Bioinformatic analysis suggested that ECHDC3 alters the bone marrow microenvironment by inducing NK, resting mast cell, and monocyte differentiation. Knocking down ECHDC3 in AML cells by RNAi promoted the death of leukemia cells with cytarabine and doxorubicin.ConclusionThese bioinformatic analyses and experimental verification indicated that high ECHDC3 expression might be a poor prognostic biomarker for non-APL AML, which might be a potential target for reverting chemoresistance.
Movement behaviours in paediatric cancer survivors during recovery and school weeks
Authors: Vyhlídal Tomáš , Dygrýn Jan , Pelclová Jana , Chmelík František 
Published: September 2022

PurposePaediatric cancer survivors (PCS) are a high-risk population, who can suffer from late effects of their treatment, such as metabolic syndrome, cardiovascular conditions, secondary tumours. Optimal movement behaviours (e.g., limited sedentary behaviour [SB] and sufficient physical activity [PA]) can reduce the side effects or avoid late effects of their treatment. The aims of this study were to analyse movement behaviours and meeting the recommendation of 60 minutes of moderate-to-vigorous physical activity (MVPA) a day in Czech PCS, and to compare their movement behaviours during recovery and school weeks in relation to gender, age, and cancer type.MethodsTwenty-six PCS aged 7-15 years in remission stage took part in the cross-sectional study. Movement behaviours were measured with Actigraph wGT3X+ accelerometers worn 24 hour/day for 20 consecutive days covering recovery week (13 days at recovery camp) and school week (7 days). Based on cancer types, the PCS were categorized into haematological malignancy or solid tumours group.ResultsIn the PCS, movement behaviours differed between recovery and school weeks. During recovery week, the PCS showed less SB (451.8 vs. 552.3 min/day, p &lt; 0.001) and spent more time on light PA (350.3 vs. 255.1 min/day, p &lt; 0.001), moderate PA (73.2 vs. 37.4 min/day, p &lt; 0.001), and vigorous PA (10.3 vs. 4.0 min/day p &lt; 0.001) than during school week. The PA recommendation was met by 77% (n = 20) PCS during recovery week, but only by 15% (n = 4) individuals during school week.ConclusionsThe PCS recorded higher levels of PA and lower levels of SB during recovery week than during school week. If provided with appropriate conditions, PCS in the remission stage are able to reach the PA level recommended for the healthy population. Recovery week can be a suitable platform for gaining experience that PCS are able to meet the recommended PA level and could be an integral part of reconditioning and resocialization programmes for PCS after the completion of their treatment.