bluuebunny/crossref_metadata_2025 huggingface dataset:
Fibroblasts direct differentiation of human breast epithelial progenitors
Authors: Morsing Mikkel , Kim Jiyoung , Villadsen René , Goldhammer Nadine , Jafari Abbas , Kassem Moustapha , Petersen Ole William , Ronnov-Jessen Lone
Published: September 2020

Background Breast cancer arises within specific regions in the human breast referred to as the terminal duct lobular units (TDLUs). These are relatively dynamic structures characterized by sex hormone driven cyclic epithelial turnover. TDLUs consist of unique parenchymal entities embedded within a fibroblast-rich lobular stroma. Here, we established and characterized a new human breast lobular fibroblast cell line against its interlobular counterpart with a view to assessing the role of region-specific stromal cues in the control of TDLU dynamics. Methods Primary lobular- and interlobular fibroblasts were transduced to express human telomerase reverse transcriptase (hTERT). Differentiation of the established cell lines along lobular- and interlobular pathways was determined by immunocytochemical staining and genome-wide RNA sequencing. Their functional properties were further characterized by analysis of mesenchymal stem cell (MSC) differentiation repertoire in culture and in vivo. The cells´ physiological relevance for parenchymal differentiation was examined in heterotypic co-culture with fluorescence-activated cell sorting (FACS)-purified normal breast primary luminal- or myoepithelial progenitors. The co-cultures were immunostained for quantitative assessment of epithelial branching morphogenesis, polarization, growth and luminal epithelial maturation. In extension, myoepithelial progenitors were tested for luminal differentiation capacity in culture and in mouse xenografts. To unravel the significance of transforming growth factor-beta (TGF-b)-mediated crosstalk in TDLU-like morphogenesis and differentiation, fibroblasts were incubated with the TGF-b inhibitor, SB431542, prior to heterotypic co-culture with luminal cells.Results hTERT immortalized fibroblast cell lines retained critical phenotypic traits in culture and linked to primary fibroblasts. Cell culture assays and transplantation to mice showed that the origin of fibroblasts determines TDLU-like and ductal-like differentiation of epithelial progenitors. Whereas lobular fibroblasts supported a high level of branching morphogenesis by luminal cells, interlobular fibroblasts supported ductal-like myoepithelial characteristics. TDLU-like morphogenesis, at least in part, relied on intact TGF-b signaling. Conclusions The significance of the most prominent cell type in normal breast stroma, the fibroblast, in directing epithelial differentiation is largely unknown. Through establishment of lobular and interlobular fibroblast cell lines we here demonstrate that epithelial progenitors are submitted to stromal cues for site-specific differentiation. Our findings lend credence to considering stromal subtleties of crucial importance in the development of normal breast and, in turn, breast cancer.
TLR7 promotes smoke-induced lung damage through the activity of mast cell tryptase
Authors: Haw Tatt Jhong , Starkey Malcolm , Pavlidis Stelios , Tam Sheena , Nair Prema M. , Liu Gang , Gomez Henry M. , Hanish Irwan , Hsu Alan , Kim Richard , Fukui Ryutaro , Murakami Yusuke , Horvat Jay , Foster Paul , Oliver Brian , Wark Peter , Adcock Ian , Miyake Kensuke , Sin Don , Hansbro Philip
Published: September 2020

The authors have withdrawn this preprint due to erroneous posting.
Fracture Liaison Service to Reduce Postoperative Complications and Improve the Activity of Patients With Hip Fracture: A 24-month Follow-up Survey
Authors: Imai Norio , Endo Naoto , Suda Ken , Suzuki Hayato
Published: September 2020

Background: Many models of fracture liaison services (FLS) following hip fracture have been introduced in the United Kingdom and Japan, resulting in a reduction in medical complications and secondary fractures. This study investigated improvements in time to surgery, daily activity, and the rate of medical complications and secondary hip fractures following the introduction of FLS.Methods: Patients who were over 50 years old and experienced fragility hip fractures, including femoral neck and trochanteric fractures, between January 1, 2015 and December 31, 2017, were enrolled in the study. We divided patients into a control group without FLS (94 patients; mean age: 83.8 years; 21 men and 73 women) and an FLS group (373 patients; mean age: 83.3 years; 69 men and 304 women).Results: The time from injury to surgery decreased significantly from 2.42 days to 1.83 days following the introduction of FLS (p = 0.003). The proportion of patients who were able to undergo surgery within 36 hours of injury also increased significantly in the FLS group (p = 0.014). In the FLS group, a significant decrease was observed in the total number of cases with complications, including cardiovascular disease, pulmonary disease, and cerebrovascular disease, after admission (p = 0.009, 0.010, 0.043, respectively). Significantly more patients with a Barthel index (BI) of ≥80 were observed in the FLS group at 6 months, 12 months, and 24 months following injury (p = 0.046, 0.018, and 0.048, respectively). Multiple logistic regression analysis revealed that BI at the time of injury, surgery within 36 hours of injury, and postoperative complications were associated with death within 12 or 24 months after the injury.Conclusions: Our results indicate that FLS contributed to earlier recovery and rehabilitation following surgery, and accelerated rehabilitation of medical complications following admission. Our FLS is expected to improve patient activity and decrease secondary hip fracture in patients who have undergone hip surgery. Trial registration: University Hospital Medical Information Clinical Trials Registry, UMIN000041206. Registered 24th July 2020, https://upload.umin.ac.jp/cgi-in/ctr/ctr_view_reg.cgi?recptno=R000047054
Porin protein could be a vaccine candidate against Riemerella anatipestifer for ducks
Authors: Yang Hui , Zhang Haiwen , Liao Chenghong , Zhao Jianguo , Wang Jinhua , Wu Kebang , Han Qian , guan qingfeng
Published: September 2020

such as domestic ducks and geese. Young birds have a high mortality rate after infection. The resistance caused by the abuse of antibiotics is also getting worse. Since there are 25 serotypes of RA, and the cross-immunization between serotypes is weak, it is necessary to find a vaccine that has cross-immunization against multiple serotypes of RA. In this article, the bioinformatics analysis of RA Proin protein was conducted, and it was speculated that it has the potential of a subunit vaccine. The protein was recombinantly expressed and purified, and immunized with Cherry Valley Duck. The results show that the serum antibodies of the Porin protein immunized group were positive at 1:24300 for the porin protein and RA strains CH1. The serum could improve the killing effect of complement and phagocytic cells on RA. After the challenge, the survival rate of Cherry Valley Duck can be increased by 80%.
Exploration of the Methods of Establishing the Minimum Clinical Important Difference Based on Anchor and Its Application in the Quality of Life Measurement Scale QLICP-ES (V2.0) for Esophageal Cancer
Authors: Ren Dandan , Wu Ting , Wan chonghua , Li Gaofeng , Qi Yanbo , Fang Yujing , Zhong Jiudi
Published: September 2020

Background: The development of the minimum clinical important difference (MCID) can make it easier for researchers or doctors to judge the significance of research results and the effect of intervention measures, and improve the evaluation system of efficacy. This paper is aimed to calculate the MCID based on anchor and to develop MCID for esophageal cancer scale (QLICP-ES). Methods: Q29 of EORTC QLQ-C30 was used as the subjective anchor to calculate the score difference between each domain at discharge and admission. MCID was established according to two standards, "one grade difference"(A) and "at least one grade difference"(B), and developed by three methods: anchor-based method, ROC curve method and multiple linear regression model. Results: Most of the correlation coefficients of Q29 and various domains of the QLICP-ES were higher than 0.30. The rank of MCID values determined by different methods and standards were as follows: standard B> standard A, anchor-based method >ROC curve method > multiple linear regression model. The recommended MCID values of physical domain, psychological domain, social domain, common symptom and side-effects domain, the specific domain and the overall of the QLICP-ES were 7.8, 9.7, 4.7, 3.6, 4.3, 2.3 and 2.9, respectively. Conclusion: Different methods have their own advantages and disadvantages, and also different definitions and standards can be adopted according to research purposes and methods. A lot of different MCID values were presented in this paper so that it can be easy and convenient to select by users.
Development and Evaluation of Duplex TaqMan Real-Time PCR Assay for Detection and Differentiation of Wide-Type and MGF505 Gene-Deleted African Swine Fever Viruses
Authors: Guo Zhenhua , Li Kunpeng , Qiao Songlin , Chen Xinxin , Deng Ruiguang , Zhang Gaiping
Published: September 2020

Background: African swine fever (ASF) is the most important disease to the pigs and cause serious economic losses to the countries with large-scale swine production. Vaccines are recognized as the most useful tool to prevent and control ASF virus (ASFV) infection. Currently, the MGF505 and MGF360 gene-deleted ASFVs or combined with CD2v deletion were confirmed to be the most promising vaccine candidates. Thus, it is essential to develop a diagnosis method to discriminate wide-type strain from the vaccines used. Results: In this study, we established a duplex TaqMan real-time PCR based on the B646L gene and MGF505-2R gene. The sequence alignment showed that the targeted regions of primers and probes are highly conserved in the genotype II ASFVs. The duplex real-time assay can specifically detect B646L and MGF505-2R gene single or simultaneously without cross-reaction with other porcine viruses tested. The limit of detection was 5.8 copies and 3.0 copies for the standard plasmids containing B646L and MGF505-2R genes, respectively. Clinical samples were tested in parallel by duplex real-time PCR and a commercial ASFV detection kit. The detection results of these two assays against B646L gene were well consistent. Conclusion: We successfully developed and evaluated a duplex TaqMan real-time PCR method which can effectively distinguish the wide type and MGF505 gene-deleted ASFVs. It would be a useful tool for the clinical diagnosis and control of ASF.
Naive Bayesian Machine Learning to Diagnose Breast Cancer
Authors: Hooshmand Arash
Published: September 2020

A novel MLAC (Machine Learning Against Cancer) method to distinguish between cancerous and noncancerous RNA genomic data is developed and tested with 100\% accuracy on all healthy and cancerous Breast tissue samples. A Naive Bayesian ML (Machine Learning) system is trained using WES (Whole Exome Sequencing) data in a high-level i.e. normalized quantification of RNAs obtained from 1091 breast cancer samples’ WES files from the TCGA (The Cancer Genome Atlas) and 179 healthy samples’ WES data from the GTEx (Genotype-Tissue Expression) project. We could show that both sensitivity and specificity of the method in classification of cancerous and noncancerous cells is perfectly 100%.
The Effects of Risk Factors on Recovery of Elderly Patients With Atrial Fibrillation After Non-cardiac Surgery
Authors: zhang kai , Wei Xin
Published: September 2020

Background and Objective: Atrial fibrillation (AF) is one of the most common arrhythmias in clinical practice. However, no literature has reported the correlation between the quality of recovery of AF patients after non-cardiac surgery and their preoperative basic and intraoperative conditions. The present study aimed to screen factors that affect recovery of AF patients after non-cardiac surgery.Methods: 120 patients with AF who aged ≥ 60 years old and scheduled to undergo non-cardiac surgery were included. The patients were divided into two groups according to the score of quality of recovery-15 (QoR-15) at 120 h after surgery, which were 122-150 points (satisfactory recovery, group A) and 0-121 points (poor recovery, group B). Their preoperative basic conditions (age, co-existing disease, mean ventricular rate, anticoagulant therapy, etc.), intraoperative conditions (the anesthesia satisfaction scale), and the QoR-15 scores after the surgery were recorded. Besides, the levels of plasma brain natriuretic peptide (BNP), high-sensitivity cardiac troponin (hs-cTn), and presepsin (soluble cluster-of-differentiation 14 subtype [sCD14-ST]) before and after surgery were measured. The data were analyzed to screen factors, influencing the postoperative recovery of patients with AF after non-cardiac surgery. Results: The independent risk factors for elderly patients with AF after non-cardiac surgery were mean ventricular rate (odds ratio (OR): 1.085; 95% confidence interval (CI): 1.040-1.131; P<0.001), high-risk surgery (OR: 0.185; 95% CI: 0.043-0.798; P=0.024), and anesthesia satisfaction scale score (OR: 2.392; 95% CI: 1.524-3.753; P<0.001). In the anesthesia satisfaction scale, hypotension (P=0.005), tachycardia/bradycardia (P=0.021), blood transfusion (P=0.047), and RASS score (P=0.041) were also found as risk factors for recovery. The levels of BNP and hs-cTn can be helpful to predict the prognosis in patients with AF.Conclusion: Poorly controlled ventricular rate, high-risk surgery, and high score of anesthesia satisfaction scale can affect the prognosis in elderly patients with AF undergoing non-cardiac surgery. The levels of BNP and hs-cTn may correlate with early recovery of such patients.
Serial Measurements of Paraoxonase-1 (PON-1) Activity in Horses with Experimentally Induced Endotoxemia
Authors: Scavone Donatella , Sgorbini Micaela , Borges Alexandre Secorun , de Oliveira-Filho Josè Paes , Vitale Valentina , Paltrinieri Saverio
Published: September 2020

Background: Paraoxonase-1 (PON-1) is an antioxidant enzyme, whose activity decreases during the acute phase response in many species. Little is known about PON-1 and its role as a negative acute phase protein during septic inflammation in horses, but promising findings about its utility in diagnosing SIRS and predicting the outcome in diseased horses, were recently highlighted. The objective of the study was to investigate the behaviour of PON-1 in horses after experimentally induced endotoxemia. To this aim, PON-1 activity was measured on 66 plasma samples collected from six clinically healthy mares, previously included in another study, before and at multiple time points between 12 and 240 hours after intravenous infusion of Escherichia coli O55:B5 lipopolysaccharide (LPS). Results: compared with baseline values, a progressive transient decrease of PON-1 activity was observed starting from 24 hours post-infusion, with lowest values observed between 3 to 7 days post-infusion, followed by a normalisation to pre-infusion levels the tenth day. Conclusions: the results of this study suggest that measurement and monitoring of PON-1 activity might be useful to evaluate progression and recovery from endotoxemia in horses. Further studies in horses with naturally occurring sepsis are warranted.
Development and Validation of the Peptic Ulcer Scale Under the System of Quality of Life Instruments for Chronic Diseases Based on Classical Test Theory and Generalizability Theory
Authors: wan chonghua , Chen Ying , Gao Li , Zhang Qingqing , Quan Peng , Sun Xiaoyuan
Published: September 2020

Background: Quality of life (QOL) for patients with Peptic ulcer disease (PUD) is of interest worldwide and disease-specific instruments are needed for clinical research and practice. This paper focus on the development and validation of the PUD scale under the system of Quality of Life Instruments for Chronic Diseases (QLICD-PU) by the modular approach and both classical test theory and Generalizability Theory. Methods: QLICD-PU is developed based on programmatic decision-making procedures, including multiple nominal and focus group discussions, in-depth interviews, and quantitative statistical procedures. Based on the data of 153 PUD inpatients, G and D studies using correlation analysis, factor analysis, t-test, and generalized theoretical analysis were used to assess the validity, reliability, and responsiveness of the scale.Results: When SF-36 was used as the standard, correlation and factor analysis confirmed good structural validity and standard-related validity of QLICD-PU. Except for the social domain (0.62), the internal consistency α of all domains is higher than 0.70. The overall score and the retest reliability coefficients (Pearson r and intra-class correlation ICC) in all domains are higher than 0.80 (0.77 in the social domain). After treatment, the overall scores and scores of all domains have statistically significant changes (P <0.01), except for social impact and sexual function scores. The SRM of field-level scores ranges from 0.34 to 1.03. The G coefficient and reliability index (Ф coefficient) further confirm the reliability of the scale through more accurate variance components and decision-making information about changes in the number of items.Conclusions: QLICD-PU can be used as a useful measurement to assess the quality of life of PUD patients with good psychometric characteristics and multiple advantages.
Polymorphisms of TGF-β1 and TGF-β3 in Chinese Women With Gestational Diabetes Mellitus
Authors: Xu Yinglei , Wei Chunlian , Wu Cuijiao , Han Mengmeng , Wang Jingli , Hou Huabin , Zhang Lu , Liu Shiguo , Chen Ying
Published: September 2020

Background: Gestational diabetes mellitus (GDM) is a pregnancy-specific carbohydrate intolerance Which can cause a large number of perinatal and postpartum complications. The members of Transforming growth factor-β (TGF-β) superfamily play key roles in the homeostasis of pancreatic β-cell and may involve in the development of GDM. This study aimed to explore the association between the polymorphisms of TGF-β1 , TGF-β3 and the risk to GDM in Chinese women.Methods: This study included 919 GDM patients(464 with preeclampsia and 455 without preeclampsia) and 1177 healthy pregnant women. TaqMan allelic discrimination real-Time PCR was used to genotyped the TGF-β1 (rs4803455) and TGF-β3 (rs2284792 and rs3917201) were by, The Hardy-Weinberg equilibrium (HWE) was evaluated by chi-square test.Results: An increased frequency of TGF-β3 rs2284792 AA and AG genotype carriers was founded in GDM patients (AA vs. AG+GG: χ²=6.314, P=0.012, OR=1.270, 95%CI 1.054-1.530; AG vs. GG+AA: χ²=8.545, P=0.003, OR=0.773, 95%CI 0.650-0.919). But there were no significant differences in the distribution of TGF-β1 rs4803455 and TGF-β3 rs3917201 between GDM and healthy women. And no significant differences were found in allele and genotype frequencies among GDM patients with preeclampsia (PE). Conclusions: The AA and AG genotype of TGF-β3 rs2284792 polymorphism may be significantly associated with increased risk of GDM in Chinese population.
Significance of KDM6A Mutation in Bladder Cancer Immune Escape
Authors: Chen Xingxing , Lin Xuehua , Pang Guofu , Deng Jian , Xie Qun , Zhang Zhengrong
Published: September 2020

Background: Bladder cancer (BC) is the fourth most prevalent neoplasm in men and is associated with high tumour recurrence rates, leading to major treatment challenges. Lysine-specific demethylase 6A (KDM6A) is frequently mutated in several cancer types; however, its effects on tumour progression and clinical outcome in BC remain unclear. Here, we explored the potential role of KDM6A in regulating the antitumor immune response. Methods: We mined The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases for somatic mutation and clinical data in patients with BC. Results: We found frequent mutations in 12 genes in both cohorts, including TP53, KDM6A, CSMD3, MUC16, STAG2, PIK3CA, ARID1A, RB1, EP300, ERBB2, ERBB3, and FGFR3. The frequency of KDM6A mutations in the TCGA and ICGC datasets was 25.97% and 24.27%, respectively. In addition, KDM6A mutation was associated with a lower number of tumour-infiltrating lymphocytes and indicated a state of immune tolerance. KDM6A mutation was associated with lower KDM6A expression level compared with that in samples carrying the wild-type gene. Further, survival analysis showed that the prognosis of patients with low KDM6A expression was worse than that with high KDM6A expression. Using the CIBERSORT algorithm, Tumor Immune Estimation Resource site, and Gene Set Enrichment Analysis, we found that KDM6A mutation downregulated nine signalling pathways that participate in the immune system and attenuated the tumour immune response. Conclusion: Overall, we conclude that KDM6A mutation is frequent in BC and promotes tumour immune escape, which may serve as a novel biomarker to predict the immune response. Key Words: KDM6A, bladder cancer, mutation, immune
Tailoring of a Visible-Light-Absorbing Biaxial Ferroelectric towards Broadband Self-Driven Photodetection
Authors: Han Shiguo , Li Maofan , Liu Yi , Guo Wuqian , Hong Mao-Chun , Sun Zhihua , Luo Junhua
Published: September 2020

In term of strong light-polarization coupling, ferroelectric materials with bulk photovoltaic effects (BPVEs) afford a promising avenue for newly-conceptual optoelectronic devices. However, due to severe polarization deterioration caused by leakage current of photoexcited carriers, most of ferroelectrics are merely capable of absorbing 8 ~ 20% of visible-light spectra. BPVE-active ferroelectrics with the narrow bandgap (Eg < 2.0 eV) are still scarce, hindering their practical applications. Here, we present a new 2D lead-iodide hybrid biaxial ferroelectric, [(CH3)2CH(CH2)2NH3]2(CH3CH2NH3)2Pb3I10 (1), which shows large spontaneous polarization (Ps = 5.2 µC/cm2) and the narrow direct bandgap (Eg = 1.80 eV). To the best of our knowledge, this Eg value of 1 is the smallest figure ever observed for the existing molecular ferroelectrics. Particularly, the symmetry breaking of 4/mmmFmm2 species results in its biaxial attributes, that is, four equivalent Ps directions for 1. Accordingly, exceptional in-plane BPVEs are exploited along the crystallographic [001] and [010] axes directions inside the crystallographic bc-plane, of which the directions can be facilely switched through external electric poling. At zero bias, the intriguing self-driven photoactivities were created in a wide range of 365–670 nm, including large switching ratio (> 105), high-density photocurrent (~ 1.5 µA/cm2) and ultrafast transient responding time (~ 2.7 ns). It is the coupling between ferroelectricity and in-plane BPVEs that endows great potentials of 1 toward broadband self-driven photodetection. This innovative study on in-plane ferroelectric BPVEs is unprecedent, which sheds light on new properties for their future optoelectronic device applications.
Future flood risk exacerbated by the dynamic impacts of sea level rise
Authors: Bilskie Matthew , Angel Diana Del , Yoskowitz David , Hagen Scott
Published: September 2020

A growing concern of coastal communities is an increase in flood risk and non-monetary consequences as a result of climate-induced impacts such as sea level rise (SLR). While previous studies have outlined the importance of quantifying future flood risk, most have focused on broad aggregations of monetary loss using bathtub SLR-type models. Here we quantify, for the first time at the multi-state scale, actual impacts to coastal communities at the census block level using a dynamic, high-resolution, biogeophysical modeling framework that accounts for future sea-levels and coastal landscapes. We demonstrate that future SLR can increase the number of damaged residential buildings by 600%, the population of displaced people by 500% and the need for shelter assistance of up to 460% from present-day conditions. An exponential increase in flood damage associated with increasing sea level deems it essential for stakeholders to plan for plausible future conditions rather than the current reality.
Diagnostic value of plasma neurofilament light: A multicentre validation study
Authors: Ashton Nicholas , Janelidze Shorena , Khleifat Ahmad Al , Leuzy Antoine , Ende Emma van der , Karikari Thomas , Benedet Andrea , Pascoal Tharick , Lleó Alberto , Parnetti Lucilla , Galimberti Daniela , Bonanni Laura , Pilotto Andrea , Padovani Alessandro , Lycke Jan , Novakova Lenka , Axelsson Markus , Velayudhan Latha , Rabinovici Gil , Miller Bruce , Pariante Carmine , Nikkheslat Naghmeh , Resnick Susan , Thambisetty Madhav , Schöll Michael , Fernandez-Eulate Gorka , Gil-Bea Francisco , de Munain Adolfo López , Al-Chalabi Ammar , Rosa-Neto Pedro , Strydom Andre , Svenningsson Per , Stomrud Erik , Santillo Alexander , Aarsland Dag , Swieten John van , Palmqvist Sebastian , Zetterberg Henrik , Blennow Kaj , Hye Abdul , Hansson Oskar
Published: September 2020

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in fifteen neurodegenerative diseases from two multicenter cohorts: King’s College London (n = 847) and the Swedish BioFINDER study (n = 1464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We further demonstrate that plasma NfL is clinically useful in identifying, i) atypical parkinsonian disorders in patients with parkinsonism, ii) dementia in individuals with Down Syndrome, iii) detect cases of frontotemporal dementia among psychiatric disorders such as moderate and severe depression, iv) identify frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related plasma NfL cut-offs for disorders with a younger age of onset. Finally, our findings suggest that plasma NfL performs best when a concentration cut-off is applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
99mTc-HMPAO SPECT imaging reveals brain hypoperfusion during status epilepticus
Authors: Bascuñana Pablo , Wolf Bettina J. , Jahreis Ina , Brackhan Mirjam , García-García Luis , Ross Tobias L. , Bengel Frank M. , Bankstahl Marion , Bankstahl Jens P.
Published: September 2020

Status epilepticus (SE) is a clinical emergency with high mortality. SE can trigger neuronal death or injury and alteration of neuronal networks resulting in long-term cognitive decline or epilepsy. Among the multiple factors contributing to this damage, imbalance between oxygen and glucose requirements and brain perfusion during SE has been proposed. Herein, we aimed to quantify by neuroimaging the spatiotemporal course of brain perfusion during and after lithium-pilocarpine-induced SE in rats. To this purpose, animals underwent 99mTc-HMPAO SPECT imaging at different time points during and after SE using a small animal SPECT/CT system. 99mTc-HMPAO regional uptake was normalized to the injected dose. In addition, voxel-based statistical parametric mapping was performed. SPECT imaging showed an increase of cortical perfusion before clinical seizure activity onset followed by regional hypo-perfusion starting with the first convulsive seizure and during SE. Twenty-four hours after SE, brain 99mTc-HMPAO uptake was widely decreased. Finally, chronic epileptic animals showed regionally decreased perfusion affecting hippocampus and cortical sub-regions. Despite elevated energy and oxygen requirements, brain hypo-perfusion is present during SE. Our results suggest that insufficient compensation of required blood flow might contribute to the neuronal damage and neuroinflammation, and ultimately to chronic epilepsy generated by SE.
A case report of Salmonella meningitis in three Chinese children and a literature review
Authors: Zhao Jingli , Hua Chunzhen , Zhou Mingming , Wang Hongjiao , Xie Yongping , Wang Gaoliang
Published: September 2020

Background: Salmonella is a common pathogen for gastroenteritis, but it rarely causes intracranial infection in China. To improve the understanding of pediatric Salmonella meningitis, we report three cases of Salmonella meningitis in Chinese children.Case presentation: The patients were aged from 1 day to 14 months. Fever was the first symptom in two patients, while loose stool with a little mucus occurred in one patient during the course of disease. Peripheral white blood cell count, neutrophils count, and C-reactive protein were 20.08 - 25.2 *109/L, 15.4 - 19.7 *109/L, and 1.6 - >160 mg/L, respectively. CSF analysis showed that white blood cell count, glucose, and protein were 70 - 1473 *106/L, 0.18 - 3.19 mmol/L, and 598.1 - 6639.0 mg/L, respectively. Three isolates of Salmonella were detected in cerebrospinal fluid cultures, including Salmonella newport, Salmonella paratyphi, and Salmonella typhimurium (one case per each). All strains were sensitive to ceftriaxone, ceftazidime, cefoperazone / sulbactam, meropenem, and imipenem, while one strain was resistant to ampicillin. The blood cultures were all negative. All patients were treated with carbapenems after failed therapies of cefotaxime or ceftriaxone, for a total duration of 3 - 5 weeks. One patient died, and subdural effusion occurred in one of the two survivors. Conclusions: Salmonella meningitis was rare, but the clinical conditions were serious. Carbapenems might be the first choice for treating Salmonella meningitis.
Food Environmental Interventions Protocol Using Social Marketing or Incentive-Based Strategies for Improving Dietary Behaviours and Health Outcomes - Systematic Review and Meta-Analysis
Authors: Sawada Kimi , Yamamoto Yoshiko , Lopes Katharina da Silva , Watanabe Norio
Published: September 2020

Background: In recent years, behavioural science theories such as social marketing or incentive-based food price strategies have been proposed to promote healthy and desirable eating habits potentially staving off a global increase in certain non-communicable disease (NCDs) such as obesity.This paper describes a systematic review protocol that validates the effectiveness of social marketing including financial incentive interventions in preventing unhealthy eating behaviour and diet-related NCDs.Methods: We will search online databases for interventions using randomized controlled trials (RCTs) and cluster RCTs. We will assess social marketing included financial incentive interventions in setting such as supermarkets, places of work, or school cafeterias and vending machines for all people. Two authors will read the papers independently, discuss the content, and come to a consensus on the judgment. If two authors cannot reach an agreement, they will consult with the other authors to reach a resolution. For the qualitative assessment, methodology relying on the Cochrane Collaboration Risk of Bias Tool 2 will be used to confirm the risk of bias for the included trials. Discussion: This is a protocol for a systematic review, and the main purpose of the review is to identify the effectiveness of social marketing and incentive-based approaches to increase desirable eating and consumption behaviours to prevent NCDs in communities, workplaces, and schools. Trial registration: This review protocol is registered with PROSPERO(CRD××) on〇, 〇, 2020.
Analysis of the Gap in PCR Monitoring Availability for Patients with Chronic Myeloid Leukemia in 60 Low- and Middle-Income Countries
Authors: Rowley Seth , Garcia-Gonzalez Patricia , Radich Jerald P , Usherenko Irina , Babigumira Joseph B
Published: September 2020

Purpose: To estimate the resource gap in the polymerase chain reaction (PCR) monitoring for patients with chronic myeloid leukemia (CML) in low- and middle-income countries (LMICs). Methods: We developed a model of demand and supply of PCR monitoring of CML patients in 60 LMICs. PCR testing was assumed to use Cepheid’s GeneXpert® IV system. We included costs of GeneXpert® instruments, uninterrupted power supplies, warranties, calibration kits, test cartridges, and shipping. We calculated the country-specific monetary gap in PCR monitoring, stratified by country priority defined as the availability of tyrosine kinase inhibitors (TKIs) through The Max Foundation initiatives. Results: The five-year gap in PCR monitoring was $29.1 million across all countries, 22% ($6.4 million) in countries with all five TKIs available, 20% ($5.7 million) in countries with four TKIs available, 50% ($14.5 million) in countries with three TKIs available, 8% ($2.2 million) in countries with two TKIs available, and 1% ($0.3 million) in countries with one TKI available. The gap was highest in South Asia (52%; $15.1 million) and lowest in Latin America (6%; $1.9 million). Excluding labor costs, the bulk of the resource needs (86%; $25.2 million) were for procurement of BCR-ABL cartridges. Conclusion: Removing the five-year gap in PCR monitoring capacity for CML in LMICs will require the mobilization of significant resources and will likely lead to better treatment outcomes and reduced treatment costs through optimization of treatment, discontinuation of therapy in appropriate patients, and facilitation of clinical research. Development of streamlined monitoring guidelines for resource-limited countries should be considered.
miR-17-5p Promotes the Invasion and Migration of Colorectal Cancer by Regulating HSPB2
Authors: Yu Wei fang , Wang Jia , Li Chao , Xuan Mingda , Han Shuangshuang , Zhang Yingfu , Liu Pengfei , Zhao Zengren
Published: September 2020

Background: MicroRNA (miRNA) can affect tumor progression by regulating cell proliferation, apoptosis and metastasis. After miRNA microarray chip analysis of colorectal cancer (CRC) tissues and adjacent normal tissues, a significant upregulation of miR-17-5p expression was found in CRC tissues. However, the underlying mechanism of miR-17-5p in CRC is still unclear.Methods: The levels of miR-17-5p in 47 paired CRC and adjacent normal tissue samples were determined by quantitative real-time PCR (qRT-PCR). CCK-8, colony formation, flow cytometry and transwell assays were used to explore the biological effects of miR-17-5p on CRC cells. In addition, the transcriptome sequencing and miRNA target prediction software were employed to identify targets of miR-17-5p. Luciferase reporter detection was used to demonstrate the direct binding of target genes by miR-17-5p. The rescue experiment was conducted to investigate the biological function of target genes and regulatory mechanism of miR-17-5p on target genes.Results: The expression of miR-17-5p was significantly higher in CRC tissues than in adjacent normal tissues. In CRC group, the expression of miR-17-5p in cancer tissues with lymph node metastasis was higher compared with those without lymph node metastasis. Overexpression of miR-17-5p inhibited CRC cell apoptosis, as well as promoting proliferation, migration and invasion. We hypothesized that HSPB2 might be a target gene of miR-17-5p and validated for the first time that miR-17-5p binds directly to the 3’-UTR of HSPB2. In the rescue experiment, the tumor suppressive effect of HSPB2 was detected and miR-17-5p could promote cell proliferation, migration and invasion by targeting HSPB2.Conclusion: MiR-17-5p promotes invasion and migration by inhibiting HSPB2 in CRC, thereby implicating its potential as a novel diagnostic biomarker and therapeutic target for CRC.
UXT, a novel DNMT3b-binding protein, promotes breast cancer progression via negatively modulating lncRNA MEG3/p53 axis
Authors: Huang Zhong-Feng , Tang Yu-Ling , Shen Zhao-Long , Yang Kai-Yan , Gao Kai
Published: September 2020

Background
UXT is highly expressed in tumor tissues, which function as a vital role in tumor progression. However, the exact role and potential mechanism of UXT in the tumorigenesis of breast cancer remains largely unknown.
Methods
Expression patterns of UXT and MEG3 were examined using qRT-PCR and western blot, respectively. The capacity of cell proliferation, apoptosis, migration and invasion was assessed using CCK-8, flow cytometry and transwell assays. The methylation of MEG3 promoter was determined using methylation specific PCR. Co-immunoprecipitation was performed to measure the UXT/DNMT3b interaction. RNA-immunoprecipitation was subjected to evaluate the regulation of MEG3 on p53 activity. The xenograft tumor experiment was further conducted to certify the molecular mechanism.
Results
UXT was up-regulated while MEG3 was down-regulated in breast cancer tissues and cell lines. UXT knockdown or MEG3 overexpression significantly inhibited the proliferation, promoted the apoptosis, and weakened the migration and invasion of MCF7 and ZR75 cells. The hypermethylation of MEG3 promoter was found in breast cancer cells, which was modulated by highly expressed DNMT3b. UXT inhibited the level of MEG3 via recruiting DNMT3b to its promoter. Mechanistically, MEG3 positively regulated the transcriptional activity of p53 via binding with it, thus regulating cell apoptosis, migration and invasion. The xenograft tumor experiment indicated that UXT negatively regulated the MEG3/p53 axis in a DNMT3b-dependent manner to promote the tumor growth.
Conclusions
UXT, a novel DNMT3b-binding protein, aggravates the progression of breast cancer through MEG3/p53 axis, which may provide a new insight involving in the treatment of breast cancer.
CAZyome and Sugar Transportome Unveil Singular Aspects of the Lignocellulolytic Enzyme System of Penicillium echinulatum 2HH
Authors: Lenz Alexandre Rafael , Balbinot Eduardo , Oliveira Nikael Souza de , Abreu Fernanda Pessi de , Silva Scheila de Avila e , Camassola Marli , Dillon Aldo José Pinheiro , Perez-Rueda Ernesto
Published: September 2020

Background: The production of bioethanol using lignocellulosic feedstocks has proved to be a cutting-edge technology. However, this technology faces limitations such as cost and yield of enzymatic systems, required to degrade efficiently the polysaccharides of plant cell walls. Penicillium echinulatum 2HH is a widely studied ascomycete, known by its efficient cellulolytic cocktails. One strategy to improve the saccharification yields for commercial exploitation is the design of hypersecreting strains. However, molecular knowledge about the lignocellulolytic system of this specific fungus is scarce. Understanding both lignocellulolytic and sugar uptake systems is essential to obtain industrial strains with adequate efficiency for bioethanol production. Results: We report a comprehensive in silico characterization of CAZymes and sugar transporters of P. echinulatum 2HH. The CAZyome reveals an outstanding repertoire of enzymes involved in plant biomass degradation. Among them, we highlight the cellulolytic enzyme system whose genes are predominantly orthologous to P. oxalicum 114-2, demonstrating the high similarity of these phylogenetically related enzyme producers. We also report a LPMO-type enzyme of the AA16 family described for the first time in these fungi. In addition to the well-known high activity of ß-glucosidases, we found that coding genes for the AA16, GH5-4 and GH45 families comprehend the main differences in the cellulolytic complexes of P. echinulatum 2HH and P. oxalicum 114-2, when both are compared to commercial producers. Our phylogenetic analysis of the sugar transportome suggests that P. echinulatum 2HH diversity and specificity of STs include eight major families with specificity to different groups of sugars. Finally, our phylogenetic analyses enabled the identification of several iBGLs and STs potentially involved in the accumulation of intracellular cellodextrins.Conclusions: Overall, both CAZyome and sugar transportome of P. echinulatum revealed new insights into the mechanisms underlying a flexible and highly functional metabolism to degrade plant biomass. Peculiarities found in our study help to highlight the cellulolytic complex of P. echinulatum 2HH, contributing to the commercial ascendance of Penicillium spp. as cellulolytic enzyme producers. Furthermore, the first phylogenetic classification of STs and iBGLs shed new light into the role of these genes regarding the preferred carbon source during fungal growth. Along these lines, these iBGLs and STs comprise valuable gene targets to understand the regulatory mechanisms underlying cellulolytic enzymes and to design hypersecreting strains with adequate efficiency for bioethanol production in large-scale.
Systematic Analysis of Direct Antiglobulin Test Results in Post-artesunate Delayed Hemolysis
Authors: Bartoli Tommaso Ascoli , Lepore Luciana , D'Abramo Alessandra , Adamo Giovanna , Corpolongo Angela , Scorzolini Laura , Giancola Maria Letizia , Bevilacqua Nazario , Palazzolo Claudia , Mariano Andrea , Ippolito Giuseppe , Buffet Pierre , Nicastri Emanuele
Published: September 2020

Background: “Post-Artesunate Delayed Hemolysis” (PADH) is common after severe malaria episodes. PADH is related to the “pitting” phenomenon and the synchronous delayed clearance of once-infected erythrocytes, initially spared during treatment. However, direct antiglobulin test (DAT) positivity has been reported in several PADH cases, suggesting a contribution of immune-mediated erythrocyte clearance. The aim of the present study was to compare clinical features of cases presenting a positive or negative DAT.Method: Articles reporting clinical data of patients diagnosed with PADH, for whom DAT had been performed, were collected from PubMed database. Data retrieved from single patients were extracted and univariate analysis was performed in order to identify features potentially related to DAT results and steroids use.Results: Twenty-two studies reporting 39 PADH cases were included: median baseline parasitemia was 20.8% (IQR: 11.2-30) and DAT was positive in 17 cases (45.5%). Compared to DAT-negative individuals, DAT-positive patients were older (49.5 vs 31; p=0.01), had a higher baseline parasitemia (27% vs 17%; p=0.03) and were more commonly treated with systemic steroids (11 vs 3 patients, p=0.002). Depth and kinetics of delayed anemia were not associated with DAT positivity.Conclusions: In this case series, almost half of the patients affected by PADH had a positive DAT. An obvious difference between the clinical courses of patients presenting with a positive or negative DAT was lacking. This observation strongly suggests that DAT result is not indicative of a pathogenic role of anti-erythrocytes antibodies in patients affected by PADH, but is rather a marker of immune activation.
HRD1 Elicitation of an Anti-Warburg Effect by Targeting PFKP to Inhibit Breast Cancer Growth and Progression
Authors: Fan Ya , Wang Jia , Xu Yuemei , Wang Yipin , Song Tao , Liang Xiubin , Jin Feng , Su Dongming
Published: September 2020

Background: Our previous studies have shown that the E3 ubiquitin ligase of HMG-CoA reductase degradation 1 (HRD1) functions as a tumor suppressor, as overexpression of HRD1 suppressed breast cancer proliferation and invasion. However, its role in breast cancer cell glucose metabolism was unclear. Here, our aim was to uncover the role and molecular mechanisms of HRD1 in regulating aerobic glycolysis in breast cancer. Methods: The effect of HRD1 on robic glycolysis in breast cancer cells were assessed. Then the proliferation, colony formation ability, invasion and migration of breast cancer cells were evaluated. The relationship between HRD1 and PFKP was validated by Mass spectrometry analysis, immunofluorescence and co-immunoprecipitation. The level of PFKP ubiquitination was measured using ubiquitylation assay. Furthermore, the tumor growth and metastasis in mice xenografts were observed. Results: We found that upregulation of HRD1 clearly decreased aerobic glycolysis, and subsequently inhibited breast cancer proliferation and invasion. Mass spectrometry analysis results revealed a large HRD1 interactome, which included PFKP (platelet isoform of phosphofructokinase), a critical enzyme involved in the Warburg Effect in breast cancer. Mechanistically, HRD1 interacted and colocalized with PFKP in the cytoplasm, targeted PFKP for ubiquitination and degradation, and ultimately reduced PFKP expression and activity in breast cancer cells. HRD1 inhibited breast cancer growth and metastasis in vivo through a PFKP-dependent way.Conclusions: Our findings reveal a new regulatory role of HRD1 in Warburg effect and provide a key contributor in breast cancer metabolism.
CXCR7: A β-arrestin-biased receptor that potentiates cell migration and recruits β-arrestin2 exclusively through Gβγ subunits and GRK2
Authors: Nguyen Huong Thi , Alcaraz Arfaxad Reyes , Yong Hyo Jeong , Nguyen Lan Phuong , Park Hee kyung , Inoue Asuka , Lee Cheol Soon , Seong Jae Young , Hwang Jong-Ik
Published: September 2020

Background
Some chemokine receptors referred to as atypical chemokine receptors (ACKRs) are thought to non-signaling decoys because of their inability to activate typical G-protein signaling pathways. It is generally accepted that their main role focuses on scavenging several chemokines to limit their spatial availability in biological processes. CXCR7, also known as ACKR3, unlike other ACKRs, binds to only two chemokines, SDF-1α and I-TAC, and recruits β-arrestins to plasma membrane. Other than CXCR7, SDF-1α binds to its own conventional receptor, CXCR4, involving in homeostatic modulation such as development and immune surveillance as well as pathological condition such as inflammation, ischemia, and cancers. Recently, CXCR7 is suggested as a key therapeutic target together with CXCR4 in such conditions. However, the molecular mechanisms underlying cellular responses and functional relation with CXCR7 and CXCR4 have not been elucidated, despite massive studies. Therefore, we aimed to reveal the molecular networks of CXCR7 and CXCR4 and compare their effects on cell migration.
Methods
Base on structural complementation assay using NanoBiT technology, we characterized the distinct mechanisms underlying β-arrestin2 recruitment by both CXCR4 and CXCR7 through molecular-interaction of the signaling molecules. Crosslinking and immunoprecipitation were conducted to analyze complex formation of the receptors. Gene deletion using CRISPR and reconstitution of the receptors in cells were applied to analysis of ligand dependent ERK phosphorylation and cell migration. All experiments were performed in triplicate and repeated more than three times. Unpaired Student’s t-tests or ANOVA using PRISM5 software were employed for statistical analyses.
Results
We found that ligand binding to CXCR7 does not result in activation of typical signaling pathways via Gα subunits but activation of GRK2 via βγ subunits and receptor phosphorylation with subsequent β-arrestin2 recruitment. In contrast, CXCR4 induced Gαi activation and recruited β-arrestin2 through C-terminal phosphorylation by both GRK2 and GRK5. SDF-1α-stimulated ERK phosphorylation was facilitated by CXCR4, but not CXCR7. Heterodimerization of CXCR4 and CXCR7 was not confirmed in this study, while homodimerization of them was verified by crosslinking experiment and NanoBiT assay. Regarding to chemotaxis, a deletion and reconstitution of the receptors revealed that SDF-1α-stimulated cell migration was mediated by both CXCR4 and CXCR7.
Conclusion
This study demonstrates that SDF-1α-stimulated CXCR7 mediates β-arrestin2 recruitment via different molecular networking from that of CXCR4. CXCR7 may be neither a simple scavenger nor auxiliary receptor but plays an essential role in cell migration through cooperation with CXCR4.