bluuebunny/crossref_metadata_2025_split huggingface dataset:
Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy
Authors: Khan Anzer , Paro Simona , McGurk Leeanne , Sambrani Nagraj , Hogg Marion C. , Brindle James , Pennetta Giuseppa , Keegan Liam P. , O’Connell Mary A. 
Published: February 2020

AbstractBackgroundIn fly brains, theDrosophilaAdar (adenosine deaminase acting on RNA) enzyme edits hundreds of transcripts to generate edited isoforms of encoded proteins. Nearly all editing events are absent or less efficient in larvae but increase at metamorphosis; the larger number and higher levels of editing suggest editing is most required when the brain is most complex. This idea is consistent with the fact thatAdarmutations affect the adult brain most dramatically. However, it is unknown whetherDrosophilaAdar RNA editing events mediate some coherent physiological effect. To address this question, we performed a genetic screen for suppressors ofAdarmutant defects.Adar5G1null mutant flies are partially viable, severely locomotion defective, aberrantly accumulate axonal neurotransmitter pre-synaptic vesicles and associated proteins, and develop an age-dependent vacuolar brain neurodegeneration.ResultsA genetic screen revealed suppression of allAdar5G1mutant phenotypes tested by reduced dosage of theTorgene, which encodes a pro-growth kinase that increases translation and reduces autophagy in well-fed conditions. Suppression ofAdar5G1phenotypes by reduced Tor is due to increased autophagy; overexpression ofAtg5, which increases canonical autophagy initiation, reduces aberrant accumulation of synaptic vesicle proteins and suppresses allAdarmutant phenotypes tested. Endosomal microautophagy (eMI) is another Tor-inhibited autophagy pathway involved in synaptic homeostasis inDrosophila. Increased expression of the key eMI protein Hsc70-4 also reduces aberrant accumulation of synaptic vesicle proteins and suppresses allAdar5G1mutant phenotypes tested.ConclusionsThese findings linkDrosophila Adarmutant synaptic and neurotransmission defects to more general cellular defects in autophagy; presumably, edited isoforms of CNS proteins are required for optimum synaptic response capabilities in the brain during the behaviorally complex adult life stage.
Two novel protein chips for the detection of antibodies against porcine parvovirus
Authors: Wu Yue , Wu Xudan , Hou Jinxiu , Chen Xiongnan , Huang Xiaobo , Zhou Bin 
Published: February 2020

Abstract
Background
PPV is one of the most important pathogens causing porcine reproductive disorder. It has been shown in clinical cases to be a commonly mixed infection with other important swine diseases which can aggravate the severity of the disease and bring serious economic losses to the pig industry. Serological methods, such as hemagglutination inhibition assays (HAI), serum neutralization (SN), and the modified direct complement-fixation (MDCF) test were utilized earlier, whereas the enzyme-linked immunosorbent assay (ELISA) is the most frequently applied assay to detect PPV-specific antibodies.

Results
We establish the visible protein chip and the cyanine dye 3 (Cy3)-labeled protein chip to detect the clinical serum from pigs. In this study, the recombinant protein VP2 of PPV was expressed in E.coli, purified with nickel magnetic beads, and then printed onto epoxy-coated glass slides for preparation of the protein chip. After a series of experiments, the conditions of antigen protein concentration, incubation time of primary antibody or secondary antibody, and optimal serum dilution fold were optimized, resulting in a successful visible protein chip and Cy3-labeled protein chip. The results showed that the positive serum, diluted up to 6000-fold, can be detected by the visible protein chip, and the positive serum, diluted up to 12,800-fold, can be detected by the Cy3-labeled protein chip, suggesting the high sensitivity of these protein chips. Moreover, the positive detection ratio, sensitivity, and specificity of these two kinds of protein chips were higher than those of commercial ELISA antibody detection kits.

Conclusion
Overall, these two protein chips can be used to rapidly diagnose clinical samples with high throughput.
Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice
Authors: Lax Neta , Fainstein Nina , Nishri Yossi , Ben-Zvi Ayal , Ben-Hur Tamir 
Published: February 2020

Abstract
Background
Accumulating data suggest a central role for brain microglia in mediating cortical neuronal death in Alzheimer’s disease (AD), and for Toll-like receptor 2 (TLR2) in their toxic activation. Amyloid deposition in preclinical AD is associated with microglial activation but not directly with neurodegeneration. We examined in transgenic 5xFAD mice the hypothesis that systemic TLR2 agonists, derived from common infectious agents, may accelerate neurodegeneration in AD.

Methods
Microbial wall-derived TLR2 agonists zymosan and lipoteichoic acid were administered intraperitoneally or intracerebroventricularly to 7-month-old wild-type or 5xFAD mice. Immunofluorescent stainings were used to quantify cortical neurons and evaluate tissue reaction. Microglial activation was assessed using functional assays, RNA expression, and FACS analysis.

Results
Repeated low-dose systemic administration of zymosan or lipoteichoic acid killed cortical neurons in 5xFAD mice but not in wild-type mice. Direct CNS delivery of a selective TLR2 antagonist blocked the neurotoxicity of systemically administered zymosan, indicating that CNS TLR2 mediates this effect. Systemically administered zymosan crossed the disrupted blood-brain barrier in 5xFAD mice and entered brain parenchyma. By intracerebroventricular delivery, we found a dose- and exposure time-dependent acute neurotoxic effect of the microbial TLR2 agonist, killing cortical neurons. 5xFAD mice exhibited significantly increased vulnerability to TLR2 agonist-induced neuronal loss as compared to wild-type mice. Microbial TLR2-induced neurodegeneration was abolished by inhibiting microglia. The vulnerability of 5xFAD mice brains was mediated by an increase in number and neurotoxic phenotype of TLR2-expressing microglia.

Conclusions
We suggest that repeated exposure to microbial TLR2 agonists may facilitate neurodegeneration in AD by their microglial-mediated toxicity to the hyper-vulnerable environment of the AD brain.
Stereotactic radiosurgery combined with targeted/ immunotherapy in patients with melanoma brain metastasis
Authors: Hadi Indrawati , Roengvoraphoj Olarn , Bodensohn Raphael , Hofmaier Jan , Niyazi Maximilian , Belka Claus , Nachbichler Silke Birgit 
Published: February 2020

Abstract
Background
There is limited data on the use of targeted or immunotherapy (TT/IT) in combination with single fraction stereotactic radiosurgery (SRS) in patients with melanoma brain metastasis (MBM). Therefore, we analyzed the outcome and toxicity of SRS alone compared to SRS in combination with TT/IT.

Methods
Patients with MBM treated with single session SRS at our department between 2014 and 2017 with a minimum follow-up of 3 months after first SRS were included. The primary endpoint of this study was local control (LC). Secondary endpoints were distant intracranial control, radiation necrosis-free survival (RNFS), and overall survival (OS). The local/ distant intracranial control rates, RNFS and OS were analyzed using the Kaplan-Meier method. The log-rank test was used to test differences between groups. Cox proportional hazard model was performed for univariate continuous variables and multivariate analyses.

Results
Twenty-eight patients (17 male and 11 female) with 52 SRS-lesions were included. The median follow-up was 19 months (range 14–24 months) after first SRS. Thirty-six lesions (69.2%) were treated with TT/IT simultaneously (4 weeks before and 4 weeks after SRS), while 16 lesions (30.8%) were treated with SRS alone or with sequential TT/IT. The 1-year local control rate was 100 and 83.3% for SRS with TT/IT and SRS alone (p = 0.023), respectively. The estimated 1-year RNFS was 90.0 and 82.1% for SRS in combination with TT/IT and SRS alone (p = 0.935). The distant intracranial control rate after 1 year was 47.7 and 50% for SRS in combination with TT/IT and SRS alone (p = 0.933). On univariate analysis, the diagnosis-specific Graded Prognostic Assessment including the BRAF status (Melanoma-molGPA) was associated with a significantly improved LC. Neither gender nor SRS-PTV margin had a prognostic impact on LC. V10 and V12 were significantly associated with RNFS (p < 0.001 and p = 0.004).

Conclusion
SRS with simultaneous TT/IT significantly improved LC with no significant difference in radiation necrosis rate. The therapy combination appears to be effective and safe. However, prospective studies on SRS with simultaneous TT/IT are necessary and ongoing.

Trial registration
The institutional review board approved this analysis on 10th of February 2015 and all patients signed informed consent (UE nr. 128–14).
The effect of human gene therapy for RPE65-associated Leber’s congenital amaurosis on visual function: a systematic review and meta-analysis
Authors: Wang Xue , Yu Chaofeng , Tzekov Radouil T. , Zhu Yihua , Li Wensheng 
Published: February 2020

Abstract
Background
RPE65-associated LCA (RPE65-LCA) is an inherited retinal degeneration caused by the mutations of RPE65 gene and gene therapy has been developed to be a promising treatment. This study aims to evaluate the association between changes in visual function and application of gene therapy in patients with RPE65-LCA.

Methods
Several databases (PubMed, Cochrane Library, and Web of Science) were searched for results of studies describing efficacy of gene therapy in patients with RPE65-LCA. Six studies, which included one randomized and five prospective non-randomized clinical trials, 164 eyes met our search criteria and were assessed.

Results
The BCVA significantly improved in treated eyes at 1 yr post treatment by − 0.10 logMAR (95% CI, − 0.17 - -0.04; p = 0·002), while there was no significant difference at 2–3 years post treatment (WMD: 0.01; 95% CI, − 0.00 - 0.02; p = 0·15). FST sensitivity to blue flashes also improved by 1.60 log (95% CI, 0.66–2.55; p = 0.0009), but no significant difference to red flashes (WMD: 0.86; 95% CI, − 0·29–2.01; p = 0.14) at 1 yr. There was no significant difference in central retinal thickness at 1 yr, but central retina in treated eyes appeared thinner at 2–3 years post treatment by 19.21 μm (95% CI, − 34.22 - -4.20; p = 0.01).

Conclusions
Human gene therapy is a pioneering treatment option for RPE65-LCA. Although its efficacy appears to be limited to less than 2 yrs after treatment, it carries the potential for further improvement and prolongation of efficacy.
Short and long term effect of treatment non-pharmacological and lifestyle in patients with metabolic syndrome
Authors: Brandão Ana Denise , da Silva Jeferson Hernandes , Mariane Oliveira Lima Sarah , Lima Leiciane , Loize Bhianca , de Castro Antônio Adolfo Mattos , Kümpel Claudia , Porto Elias Ferreira 
Published: February 2020

Abstract
Background
Metabolic syndrome (MS) is a complex disorder represented by a set of cardiovascular risk factors usually related to central fat deposition, insulin resistance, hypertension and dyslipidemia. It is associated with accelerated atherosclerosis in response to chronic inflammation and vascular endothelial dysfunction, increasing overall mortality. The objective to evaluate the short and long term effect of the comprehensive cardiac rehabilitation program and intensive lifestyle intervention in metabolic syndrome patients.

Methods
This is longitudinal interventional study. All patients underwent a 20-session cardiac rehabilitation program with aerobic and resisted exercises as well as an educational program for lifestyle changes and follow up 1 year.

Results
Forty seven patients participated in the present study, but only 28 concluded the follow up. 77.7% were females and the majority was older than 60 years (63.1%). After cardiac rehabilitation, the percentage of overweight (0.04) patients who controlled the SBP (0.04) increased, and obesity levels I and II were reduced, as well as a significant reduction in total cholesterol and triglycerides (0.01 and 0.05), all of these variables remained similar after 1 year of follow-up. After cardiac rehabilitation all participants were practicing the five factors of healthy lifestyle, and reduced to 73% after follow up.

Conclusion
A comprehensive cardiac rehabilitation program and lifestyle change is an effective approach in the treatment of patients with MS mainly, it has positive short and long term effects on weight control, reducing total cholesterol and triglycerides.
miR-765 inhibits the osteogenic differentiation of human bone marrow mesenchymal stem cells by targeting BMP6 via regulating the BMP6/Smad1/5/9 signaling pathway
Authors: Wang Tao , Zhang Chao , Wu Cihu , Liu Jianyun , Yu Hui , Zhou Xiaoou , Zhang Jie , Wang Xinping , He Shan , Xu Xiaoyuan , Ma Baicheng , Che Xiangxin , Li Weidong 
Published: February 2020

AbstractBackgroundThe process of bone repair is heavily dependent on the ability of human bone marrow mesenchymal stem cells (hMSCs) to undergo osteogenic differentiation. MicroRNAs have been shown to regulate this osteogenic process. This study aimed to investigate the role of miR-765 in the osteogenic differentiation of hMSCs.MethodsWe transfected hMSCs with lentiviral constructs to knock down or overexpress this miRNA, allowing us to assess its role in osteogenesis via assessing the expression of the relevant markers alkaline phosphatase (ALP), runt-related gene-2 (RUNX-2), and osteocalcin (OCN), with further functional measurements made via quantifying ALP activity and conducting Alizarin Red S staining. The targeting of the 3′-untranslated region (UTR) of BMP6 by miR-765 was examined via luciferase assay. We used hMSCs with altered miR-765 expression to assess p-Smad1/5/9 levels via Western blotting over the course of osteogenic differentiation. We also assessed the osteogenic differentiation of hMSCs in which miR-765 was knocked down and at the same time as a BMP/Smad signaling inhibitor was added to disrupt Smad1/5/9 phosphorylation.ResultsWe found miR-765 overexpression to inhibit osteogenesis-associated gene upregulation during osteogenic differentiation of hMSCs, whereas knockdown of this miRNA was associated with increased expression of these genes. Using luciferase reporter assays, we confirmed direct miR-765 binding to the 3′-untranslated region (UTR) of BMP6. We also found that miR-765 overexpression reduced Smad1/5/9 phosphorylation, and knockdown of this miRNA enhanced this phosphorylation on BMP6/Smad1/5/9 signaling. The osteogenic differentiation of hMSCs in which miR-765 had been knocked down was further weakened upon the addition of a BMP/Smad signaling inhibitor relative to miR-765 knockdown alone.ConclusionsTogether, these results thus suggest that miR-765 is able to inhibit hMSC osteogenic differentiation by targeting BMP6 via regulation of the BMP6/Smad1/5/9 signaling pathway. Our findings may offer molecular insights of value for the development of novel therapeutic treatments for bone diseases including osteoporosis.
Subdural haematomas drain into the extracranial lymphatic system through the meningeal lymphatic vessels
Authors: Liu Xuanhui , Gao Chuang , Yuan Jiangyuan , Xiang Tangtang , Gong Zhitao , Luo Hongliang , Jiang Weiwei , Song Yiming , Huang Jinhao , Quan Wei , Wang Dong , Tian Ye , Ge Xintong , Lei Ping , Zhang Jianning , Jiang Rongcai 
Published: February 2020

AbstractSubdural haematomas (SDHs) are characterized by rapidly or gradually accumulated haematomas between the arachnoid and dura mater. The mechanism of haematoma clearance has not been clearly elucidated until now. The meningeal lymphatic vessel (mLV) drainage pathway is a novel system that takes part in the clearance of waste products in the central nervous system (CNS). This study aimed to explore the roles of the mLV drainage pathway in SDH clearance and its impacting factors. We injected FITC-500D, A488-fibrinogen and autologous blood into the subdural space of mice/rats and found that these substances drained into deep cervical lymph nodes (dCLNs). FITC-500D was also observed in the lymphatic vessels (LYVE+) of the meninges and the dCLNs in mice. The SDH clearance rate in SDH rats that received deep cervical lymph vessel (dCLV) ligation surgery was significantly lower than that in the control group, as evaluated by haemoglobin quantification and MRI scanning. The drainage rate of mLVs was significantly slower after the SDH model was established, and the expression of lymphangiogenesis-related proteins, including LYVE1, FOXC2 and VEGF-C, in meninges was downregulated. In summary, our findings proved that SDH was absorbed through the mLV drainage pathway and that haematomas could inhibit the function of mLVs.
Should we treat sepsis-induced DIC with anticoagulants?
Authors: Inata Yu 
Published: February 2020

Abstract
Background
Disseminated intravascular coagulation (DIC) is a common complication in sepsis because of crosstalk between the immune system and the coagulation system. Several anticoagulant agents have been tested in an attempt to improve the survival of patients with sepsis and sepsis-induced DIC. Here, we discuss the rationale against using anticoagulation therapy in septic DIC.

Main body of the abstract
Coagulopathy and DIC are associated with increased mortality in sepsis. Several anticoagulant agents have been tested in an attempt to improve the survival of patients with sepsis and sepsis-induced DIC, but have proven largely ineffective. This is because of two major factors. First, the coagulation system is complex and closely related to the immune system. When we manipulate one of the factors involved in these systems, we may disturb the delicate homeostasis between them. A second factor may be failure to identify patients who will benefit from anticoagulation therapy. This may be attributed partly to the fact that there is no gold standard for the diagnosis of DIC, and there are consequently several diagnostic criteria, none of which are specifically designed for sepsis-induced DIC. Application of precision medicine, of the kind currently being applied in other intensive care fields, may be the key to overcoming these challenges. Until we know the precise target population, we should not use anticoagulation therapy in sepsis-induced DIC outside a research setting.

Short conclusion
There is no strong evidence to support the effectiveness of routine anticoagulation therapy in sepsis-induced DIC, and it should not be used clinically until more is known regarding the population of patients who may benefit from it.
Development of a diabetes self-management + mHealth program: tailoring the intervention for a pilot study in a low-income setting in Mexico
Authors: Whittemore Robin , Vilar-Compte Mireya , Burrola-Méndez Soraya , Lozano-Marrufo Annel , Delvy Roberta , Pardo-Carrillo Mariana , De La Cerda Selene , Pena-Purcell Ninfa , Pérez-Escamilla Rafael 
Published: February 2020

Abstract
Background
Type 2 diabetes (T2D) is a public health pandemic disproportionately affecting low- and middle-income countries. The purpose of this formative research was to adapt evidence-based diabetes self-management education programs to the context of Seguro Popular clinics in Mexico. A theory-based mHealth (pictorial text messaging) component was developed.

Method
Our formative research and development of the program protocol consisted of six phases: (1) interviews and focus groups with stakeholders on the challenges to T2D management, curriculum content needs, and the use of mHealth as a supplement to a DSME program; (2) review of the theoretical underpinning, curriculum, and interactive strategies of four evidence-based DSME programs and modification to meet the needs of adults with T2D and systems of care in Mexico City; (3) development of theory-based illustrated text messages; (4) evaluation of text messaging acceptability and access in adults with T2D via focus groups; (5) development of program manual; and (6) development of a training program for health care providers.

Results
The ¡Sí, Yo Puedo Vivir Sano Con Diabetes! included 7 group-based weekly lessons; simple, interactive content; weekly empowerment messages; video novellas; group activities; and goal setting. Adaptations to the cultural context of Mexico included content/activities on diabetes etiology (addressing cultural misconceptions), nutrition (indigenous foods and plate method), self-blood glucose monitoring, and diabetes-related stress/coping. We used the Health Action Process Approach to guide the text message development, which posits that adoption, initiation, and maintenance of health behaviors require the development of intentions, plans, coping, and self-efficacy. Our final text message bank consisted of 181 messages. There were approximately 20–30 messages for each process of behavior change (e.g., action planning, maintenance self-efficacy) and 30 messages for each content topic (e.g., eating healthy, physical activity). There were 96 messages that were illustrated. Training materials were also developed.

Discussion
We used a systematic approach, collaboration with stakeholders, and a well-established behavior change theory to develop an evidence-based intervention to an international context and system of care. Collectively, this process has the potential to enhance the feasibility, acceptability, and efficacy of the program.
Hospitalized cancer patients with acquired long QT syndrome-a matched case-control study
Authors: Lin Yajuan , Yu Haixu , Liu Fei , Chen Cheng , Zhang Yanli , Wang Binhao , Yang Yiheng , Liu Ying , Zhang Li , Xia Yunlong 
Published: February 2020

Abstract
Background
Our recent study has revealed that many hospitalized patients with acquired long QT syndrome (ALQTS) are cancer patients. This study aims to determine the risk factors and outcomes of hospitalized cancer patients with ALQTS.

Methods
We performed a matched case-control study within a cohort of 10,180 cancer patients hospitalized between September 2013 and April 2016. Among them, 150 patients defined as having severe ALQTS with a markedly prolonged QT interval (QTc ≥ 500 ms) were compared with 293 age-, sex- and cancer-type-matched controls (non-ALQTS). Death as the endpoint was followed for up to 2 years. Cox regression and Kaplan-Meier survival analyses were performed to assess the effects of particular clinical variables on all-cause mortality. Multivariate logistic regression was performed to calculate odds ratios (OR) for various predictors of QT prolongation.

Results
The mortality was significantly higher in ALQTS group (63.3% vs. 33.4%). Hypertension, hypokalemia, hypocalcemia, QT-prolonging drugs, infection, anemia, anti-microtubule agents were contributing factors to ALQTS. Renal insufficiency, male gender and hypokalemia were found to be independent risk factors for all-cause mortality in ALQTS group.

Conclusion
Markedly prolonged QT interval was seen in 1.5% of hospitalized cancer patients. The all-cause mortality was high in cancer patients with severe ALQTS.