bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of alcohol intake on the development of mild cognitive impairment into dementia
Authors: Yao Lihe , Hou Lijuan , Lao Yongfeng , Luo Wei , Lu Zhenxing , Chen Jun , Liu Yongming
Published: July 2020

Objective:

To assess the dose–response relationship between alcohol consumption and the progression of MCI to dementia.

Method:

This study adheres to the Preferred Reporting Items for Systematic Reviews and Meta analysis for Protocols. Chinese Biomedical Literature Database (CBM), PubMed, Cochrane Library, EMBASE will be searched for all relevant published articles, with no restrictions on the year of publication or language. Case–control and cohort studies explored the relationship between alcohol exposure and the incidence of dementia in patients with MCI will be included. Study selection, data collection and assessment of study bias will be conducted independently at each level by a pair of independent reviewers. The Newcastle-Ottawa Scale (NOS) tool will be used for the risk of bias assessment. The methodological quality of systematic review will be based on A measurement Tool to Assess Systematic Review (AMSTAR 2). The Grading of Recommendations Assessment Development and Evaluation (GRADE) system will be used to assess the quality of evidence. Stata 15.0 will be used for general meta-analysis and exploring the dose–response relationship. Piecewise linear regression model and the restricted cubic spline model will be used for nonlinear trend estimation, and the generalized least-square method will be used to estimate the parameters.

Discussion:

This dose–response meta-analysis is the first to investigate the dose–effect relationship between alcohol exposure and the incidence of dementia in patients with MCI, providing a comprehensive understanding of the prevention of alcohol-related cognitive impairment.

Registration:

The dose–response meta-analysis is registered in the PROSPERO (CRD42019127226) international prospective register of systematic review.
Brain natriuretic peptide levels predict 6-month mortality in patients with cardiogenic shock who were weaned off extracorporeal membrane oxygenation
Authors: Kim Hyoung Soo , Lee Kyu Jin , Ha Sang Ook , Han Sang Jin , Park Kyoung-Ha , Lee Sun Hee , Hwang Yong Il , Jang Seung Hun , Park Sunghoon
Published: July 2020

There are limited data regarding the association between brain natriuretic peptide (BNP) levels obtained after weaning from extracorporeal membrane oxygenation (ECMO) and the outcomes of patients with acute coronary syndrome (ACS)-associated cardiogenic shock.

We prospectively obtained data regarding patients (aged ≥ 19 years) with ACS-associated cardiogenic shock who received ECMO and were subsequently weaned off the treatment. BNP levels were collected at 5 time points: pre-ECMO implantation, post-ECMO implantation, pre-ECMO weaning, day 1 after ECMO weaning, and day 5 after ECMO weaning.

Of 48 patients with ACS-related cardiogenic shock, 33 were included in this analysis. Mean patient age was 59.0 (50.0–66.5) years, and 5 patients (15.2%) were women. Eight patients had asystole/pulseless electrical activity before ECMO and 14 (42.4%) had 3-vessel disease on coronary angiography. During the 6-month follow up, 12 (36.4%) patients died. BNP levels after ECMO weaning were significantly different between 6-month survivors and non-survivors. Cox proportional hazards model revealed that BNP levels (tertiles) on days 1 and 5 after ECMO weaning were significantly associated with 6-month mortality (hazard ratio, 7.872; 95% confidence interval, 1.870–32.756; 8.658 and 1.904–39.365, respectively). According to the Kaplan–Meier curves, the first tertile had significantly longer survival compared to the third tertile for both days 1 and 5 after ECMO weaning.

Post-ECMO weaning BNP levels (days 1 and 5) were significantly associated with increased 6-month mortality in patients with ACS complicated by refractory cardiogenic shock who were weaned off ECMO.
Identification of key genes in calcific aortic valve disease by integrated bioinformatics analysis
Authors: Teng Peng , Xu Xingjie , Ni Chengyao , Yan Haimeng , Sun Qianhui , Zhang Enfan , Ni Yiming
Published: July 2020

Calcific aortic valve disease (CAVD) is highly prevalent in our aging world and has no effective pharmaceutical treatment. Intense efforts have been made but the underlying molecular mechanisms of CAVD are still unclear.

This study was designed to identify the critical genes and pathways in CAVD by bioinformatics analysis. Microarray datasets of GSE12644, GSE51472, and GSE83453 were obtained from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified and functional and pathway enrichment analysis was performed. Subsequently, the protein–protein interaction network (PPI) was constructed with Search Tool for the Retrieval of Interacting Genes and was visualized with Cytoscape to identify the most significant module. Hub genes were identified by Cytoscape plugin cytoHubba.

A total of 179 DEGs, including 101 upregulated genes and 78 downregulated genes, were identified. The enriched functions and pathways of the DEGs include inflammatory and immune response, chemotaxis, extracellular matrix (ECM) organization, complement and coagulation cascades, ECM receptor interaction, and focal adhesion. The most significant module in the PPI network was analyzed and genes among it were mainly enriched in chemotaxis, locomotory behavior, immune response, chemokine signaling pathway, and extracellular space. In addition, DEGs, with degrees ≥ 10 and the top 10 highest Maximal Chique Centrality (MCC) score, were identified as hub genes. CCR1, MMP9, VCAM1, and ITGAX, which were of the highest degree or MCC score, were manually reviewed.

The DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the pathogenesis of CAVD and might serve as candidate therapeutic targets for CAVD.
Relationship between a 7-mRNA signature of the pancreatic adenocarcinoma microenvironment and patient prognosis (a STROBE-compliant article)
Authors: He Qing-lin , Jiang Hai-xing , Zhang Xiang-lian , Qin Shan-yu
Published: July 2020

The potential association between the prognosis of the pancreatic adenocarcinoma (PAAD) and its microenvironment is unclear. This study aims to construct a prognostic index (PI) model of the PAAD microenvironment to predict PAAD patient survival outcomes.

The mRNA sequencing and the clinical parameters data were obtained from The Cancer Genome Atlas. Immune and stromal scores were computed using the expression data algorithm to capture infiltration of immune and stromal cells in the PAAD tissue, where patients were categorized as high and low score groups according to these scores. Differentially expressed genes were identified using the R package LIMMA. Univariate and multivariate Cox regression analysis were conducted to select candidate survival-correlated gene signatures from the tumor microenvironment for constructing a model. The Kaplan-Meier method was used to access overall survival of the primary and validation cohorts. The immunological features of the PI model was explored using the Tumor Immune Estimation Resource (TIMER) database. Bioinformatic analyses were conducted based on the DAVID database.

A total of 1266 overlapping differentially expressed genes and 49 prognosis-associated genes were identified. A 7-mRNA signature (GBP5, BICC1, SLC7A14, CYSLTR1, P2RY6, VENTX, and RAB39B) was screened for the construction of a PI model (area under the curve = 0.791). In both the primary and validation cohorts, Kaplan Meier analysis revealed that the overall survival of the high-risk group was significantly worse compared to the low-risk group (P < .0001, P = .0028 respectively). The TIMER database described that the 7 signature genes were correlated with immune infiltrating cells and tumor purity. Bioinformatic analyses revealed that these prognosis-associated genes were significantly enriched during inflammation, the defense response, would response, calcium ion transport, and plasma membrane part.

A list of the prognosis-correlated genes was generated based on the PAAD microenvironment. A 7-mRNA PI model may be used for predicting the prognosis of PAAD patients.
To use indwelling drainage or not in dual-plane breast augmentation mammoplasty patients
Authors: Xiao Yiding , Hu Jianqiang , Zhang Mingzi , Zhang Wenchao , Qin Feng , Zeng Ang , Wang Xiaojun , Liu Zhifei , Zhu Lin , Yu Nanze , Si Loubin , Long Fei , Ding Yu
Published: July 2020

To explore the necessity of indwelling drainage in dual-plane breast augmentation mammoplasty patients.

Female patients (123 in total) were selected from June 2015 to June 2018 in the Department of Plastic Surgery at Peking Union Medical College Hospital and were randomly divided into 2 different groups: the with drainage group (WD group, 57 patients) and the without drainage group (WOD group, 66 patients). In the 2 groups, the operation time, postoperative stay, and hospitalization expenses were recorded. The BREAST-Q Version 2.0 Augmentation Module Pre- and Postoperative Scales (Chinese Version) were used to evaluate psychosocial well-being, sexual well-being, physical well-being, and satisfaction with breasts preoperatively and postoperatively (1 year after operation).

Before the operation, no significant differences were found in psychosocial well-being, sexual well-being, physical well-being, or satisfaction with breasts between these 2 groups. In the WOD group, postoperative stay and hospitalization expenses were remarkably decreased, but the operation time was similar, compared with the WD group. Compared with before the operation, both groups had significantly increased scores in psychosocial well-being, sexual well-being, and satisfaction with breasts after the operation. However, no significant differences were found between the 2 groups. No complications were found in any of the patients.

Although the operation time was not significantly decreased, patients without drainage could save much more time and money and simultaneously reach similar postoperative effects in psychosocial well-being, sexual well-being, physical well-being, and satisfaction with breasts. Therefore, drainage may not be necessary in patients who undergo dual-plane breast augmentation mammoplasty.
Prognostic value of neutrophil-to-lymphocyte ratio in peripheral blood and pathological tissue in patients with esophageal squamous cell carcinoma
Authors: Guo Quanquan , Shao Zhiying , Xu Dan , Fan Lili , Xiong Huiru , Ding Xin , You Chuanwen , Zhang Longzhen
Published: July 2020

The aim of this study was to investigate the prognostic value of neutrophils-to-lymphocyte ratio in peripheral blood (NLR) and in cancer nest (iNLR) in patients with esophageal squamous cell carcinoma (ESCC).

Totally 103 patients with ESCC treated with surgical radical surgery in the Shuyang People's Hospital from February 2010 to November 2014 were collected retrospectively. Peripheral blood routine test and immunohistochemistry examination of carcinoma nest were mainly performed. Survival rates were analyzed with Kaplan–Meier curves. Univariate analysis and multivariate analysis were also performed to explore potential prognostic factors of ESCC.

The median survival time after surgery of low NLR group and high NLR group were 48 months and 30 months, respectively. The difference of overall survival between the 2 groups was statistically significant (χ

2
 = 7.435, P 
= .006). The median survival time after surgery of low iNLR group and high iNLR group were 37 months and 24.5 months, respectively. The difference between the 2 groups was also statistically significant (χ
2 = 33.640, P 
= .000). Univariate analysis showed influence factors of postoperative survival in patients with ESCC included tumor-node-metastasis staging, NLR, iNLR, and grade of NLR score + iNLR score (P ≤ .05). Multivariate analysis confirmed NLR, iNLR, and tumor-node-metastasis staging were independent influence factors of postoperative survival in patients with ESCC (P ≤ .05).

High level of NLR and iNLR implies a poor prognosis of ESCC. The application of both NLR and iNLR could guide clinicians to take aggressive treatments for high risk population.
A systematic review and meta-analysis of acupuncture treatment for oral ulcer
Authors: Yan Hang , Jin Zhao , Jin Wenqin , Zhong Yanmei , Ai Huangping , Wu Yeke , Xu Qianrong , Bai Xiaoyan , Liu Donghao , Nie Wenhan , Zuo Yuling
Published: July 2020

Background:

Oral ulcers (OU) is a common oral mucosal disease manifested with obvious pain; in some studies, the efficacy of acupuncture in OU has been confirmed, but the systematic reviews and meta-analyses for them are lacking. Our aim is to evaluate the efficacy and safety of acupuncture in the treatment of OU.

Methods:

Relevant randomized controlled trials (RCTs), quasi RCTs and non-RCTs will be identified by systematic searching from the following electronic databases: PubMed, Embase, the Cochrane Library, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal database, and Wanfang Data (since inception of the databases to present). In addition, ongoing trials will be retrieved from the Chinese Clinical Trial Register, World Health Organization International Clinical Trials Registry Platform, Clinical Trials, and The Clinical Trials Register. Grey literature will be also taken into consideration, including academic dissertation, minutes of the meeting from Chinese Biomedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal database, and Wanfang Data. There are no language restrictions.

Results:

Ethical approval is not required because this study is based on published papers. After peer-review, the study will be disseminated in scientific journals and conferences.

Conclusion:

This systematic review will provide evidence for the efficacy and safety of acupuncture for Oral ulcers.

Trial registration number:

CRD42020144911.
Chemotherapy efficacy after first-line immunotherapy in 18 advanced melanoma patients
Authors: Saint-Jean Mélanie , Fronteau Clémentine , Peuvrel Lucie , Khammari Amir , Varey Emilie , Quéreux Gaëlle , Dréno Brigitte
Published: July 2020

In BRAF wild type advanced melanoma, immune checkpoint blockers such as anti-PD1 (anti-programmed cell death 1) are usually continued beyond progression for a hypothetical rare further response. Chemotherapy as a second-line option is considered ineffective by many practitioners based on historical data. Continuing anti-PD1 beyond progression has a high health-economic impact and is not recommended by the FDA. This study aimed to describe the efficacy and survival of advanced melanoma patients who received second-line (or more) chemotherapy after immunotherapy failure.

This was a retrospective single center study conducted in a French University Hospital during an 11-month period. All advanced melanoma patients treated with chemotherapy after immunotherapy failure were included.

Eighteen patients were analyzed. Therapeutic response to chemotherapy was evaluable in 16 patients: partial response was achieved in 3/16 (19%), stable disease in 1/16 (6%) and progressive disease in 12/16 (75%). Median overall survival from chemotherapy start was 12 months. Median progression-free survival was 5.4 months. The 6-month overall survival rate was 81% and the 6-month progression-free survival rate was 40%.

Although the disease control rate with chemotherapy was low (25%), survival data in our study are far superior to those previously published. This could be linked to a high proportion of patients treated with anti-PD1 just prior to chemotherapy, which may suggest a potential synergy between immunotherapy and chemotherapy.
Risk factors for suicidal ideation among the older people living alone in rural region of China
Authors: Hu Caiyun , Zhao Dongdong , Gong Fengfeng , Zhao Yuanyuan , Li Jie , Sun Yehuan
Published: July 2020

In China, suicide accounts for twenty-six percent of all suicides worldwide; however, researches on the suicidal ideation among older people living alone in the rural region are few. We performed a cross-sectional study to explore the prevalence and influence factors of suicidal ideation, and provide a theoretical basis for suicide prevention among older people living alone in rural region.

695 older people living alone in rural region were selected by using stratified cluster sampling. Chi-square for categorical variables,T-test for continuous variables, and path analysis were conducted to statistical analysis.

The prevalence of suicidal ideation among the elderly living alone in rural China was 23.6%. Path analyses showed that depression had the most substantial influence on suicidal ideation among the elderly living alone, it was also as a mediator between physical, economic status, social support, anxiety, and suicidal ideation; anxiety and social support had both direct and indirect influence on suicidal ideation; physical status and economic status had indirection impact.

The incidence of suicidal ideation among the elderly living alone was high in Dangtu county. Psychological disorders (anxiety and depression) had the strongest impact on suicidal ideation. Strategies and measures targeting these relevant factors (economic status, physical status, and social support) should be taken to reduce the burdens of suicidal ideation among the elderly living alone in China.
Dynamics and future of SARS-CoV-2 in the human host
Authors: Gillman Michael , Crokidakis Nuno
Published: July 2020

Forecasting trends in COVID-19 infections is vital for the global economy, national governments and physical and mental well-being. Using the per capita number of new cases as a proxy for the abundance of the SARS-CoV-2 virus, and the number of deaths as a measure of virulence, the dynamics of the pandemic and the outcomes emerging from it are examined for three locations (England, Italy and New York State). The data are analysed with a new version of a population dynamics model that combines exponential/logistic growth with time-varying carrying capacity, allowing predictions of persistence or extinction of the virus. In agreement with coevolutionary theory, the model suggests a transition from exponential virus growth to low abundance, coupled with reduced virulence, during colonisation of the alternate human host. The structure of the model allows a straightforward assessment of key parameters, which can be contrasted with standard epidemiological models and interpreted with respect to ecological and evolutionary processes and isolation policies.
The utility of Resting Pulse Rate in Defining High Blood Pressure among Adolescents in Mbarara Municipality, Uganda
Authors: Katamba Godfrey , Agaba David Collins , Namayanja Rosemary , Namaganda Agnes , Musasizi Abdul , Kinene Mivule Abdul , Migisha Richard
Published: July 2020

High resting pulse rate (RPR) is associated with adverse cardiovascular events, and could be used as a marker of cardiovascular health. We determined the correlation between RPR and blood pressure (BP); and its accuracy in defining high blood pressure among adolescents attending secondary schools in Mbarara municipality, south-western Uganda. We conducted a cross-sectional study among secondary school adolescents aged 12-19 years in Mbarara municipality, Uganda. We captured demographic characteristics using a structured questionnaire; and measured anthropometric indices and BP. We performed a linear regression analysis to determine the relationship between RPR and blood pressure and plotted receiver operating characteristics curves (ROC) to assess the accuracy of RPR in defining high BP. We enrolled 616 adolescents with a mean age of 15.6±2.0 years and 65.6% (404/616) were female. The RPR was significantly correlated with diastolic blood pressure (DBP) in both boys (Beta = 0.22 [95%CI: 0.10; 0.36]), p<0.001 and girls (Beta = 0.51 [95%CI: 0.43; 0.60]), p<0.001. RPR was significantly correlated with systolic blood pressure (SBP) only in the girls (Beta = 0.23 [95%CI: 0.15; 0.30]), p<0.001. The optimal threshold for RPR in defining prehypertension was RPR≥76bpm with an area under the curve (AUC) of 0.653[95%CI: 0.583-0.722], the sensitivity of 0.737 and specificity of 0.577. In defining hypertension, the optimal threshold was RPR ≥ 79bpm at a sensitivity of 0.737 and specificity of 0.719, with an AUC of 0.728[95%CI: 0.624-0.831]. Resting pulse rate was positively correlated with BP and was more accurate in defining hypertension compared to prehypertension in the study.
Methylome-wide analysis reveals epigenetic marks associated with resistance to tuberculosis in HIV-infected individuals from East Africa
Authors: Stein Catherine M. , Benchek Penelope , Bartlett Jacquelaine , Igo Robert P. , Sobota Rafal S. , Chervenak Keith , Mayanja-Kizza Harriet , von Reyn C. Fordham , Lahey Timothy , Bush William S. , Boom W. Henry , Scott William K. , Marsit Carmen , Sirugo Giorgio , Williams Scott M.
Published: July 2020

Background

Tuberculosis (TB) is the most deadly infectious disease globally and highly prevalent in the developing world, especially sub-Saharan Africa. Even though a third of humans are exposed to Myocbacterium tuberculosis (Mtb), most infected immunocompetent individuals do not develop active TB. In contrast, for individuals infected with both TB and the human immunodeficiency virus (HIV), the risk of active disease is 10% or more per year. Previously, we identified in a genome-wide association study a region on chromosome 5 that was associated with resistance to TB. This region included epigenetic marks that could influence gene regulation so we hypothesized that HIV-infected individuals exposed to Mtb, who remain disease free, carry epigenetic changes that strongly protect them from active TB. To test this hypothesis, we conducted a methylome-wide study in HIV-infected, TB-exposed cohorts from Uganda and Tanzania.

Results

In 221 HIV-infected adults from Uganda and Tanzania, we identified 3 regions of interest that included markers that were differentially methylated between TB cases and LTBI controls, that also included methylation QTLs and associated SNPs: chromosome 1 (RNF220, p=4×10−5), chromosome 2 (between COPS8 and COL6A3 genes, p=2.7×10−5), and chromosome 5 (CEP72, p=1.3×10−5). These methylation results colocalized with associated SNPs, methylation QTLs, and methylation × SNP interaction effects. These markers were in regions with regulatory markers for cells involved in TB immunity and/or lung.

Conclusion

Epigenetic regulation is a potential biologic factor underlying resistance to TB in immunocompromised individuals that can act in conjunction with genetic variants.
Estimating the size of undetected cases of the SARS-CoV-2 outbreak in Europe: An upper bound estimator
Authors: Rocchetti Irene , Böhning Dankmar , Holling Heinz , Maruotti Antonello
Published: July 2020

Background

While the number of detected SARS-CoV-2 infections are widely available, an understanding of the extent of undetected cases is urgently needed for an effective tackling of the pandemic. The aim of this work is to estimate the true number of SARS-CoV-2 (detected and undetected) infections in several European Countries. The question being asked is: How many cases have actually occurred?

Methods

We propose an upper bound estimator under cumulative data distributions, in an open population, based on a day-wise estimator that allows for heterogeneity. The estimator is data-driven and can be easily computed from the distributions of daily cases and deaths. Uncertainty surrounding the estimates is obtained using bootstrap methods.

Results

We focus on the ratio of the total estimated cases to the observed cases at April 17th. Differences arise at the Country level, and we get estimates ranging from the 3.93 times of Norway to the 7.94 times of France. Accurate estimates are obtained, as bootstrap-based intervals are rather narrow.

Conclusions

Many parametric or semi-parametric models have been developed to estimate the population size from aggregated counts leading to an approximation of the missed population and/or to the estimate of the threshold under which the number of missed people cannot fall (i.e. a lower bound). Here, we provide a methodological contribution introducing an upper bound estimator and provide reliable estimates on the dark number, i.e. how many undetected cases are going around for several European Countries, where the epidemic spreads differently.
NetCoMi: Network Construction and Comparison for Microbiome Data in R
Authors: Peschel Stefanie , Müller Christian L. , von Mutius Erika , Boulesteix Anne-Laure , Depner Martin
Published: July 2020

Estimating microbial association networks from high-throughput sequencing data is a common exploratory data analysis approach aiming at understanding the complex interplay of microbial communities in their natural habitat. Statistical network estimation workflows comprise several analysis steps, including methods for zero handling, data normalization, and computing microbial associations. Since microbial interactions are likely to change between conditions, e.g. between healthy individuals and patients, identifying network differences between groups is often an integral secondary analysis step. Thus far, however, no unifying computational tool is available that facilitates the whole analysis workflow of constructing, analyzing, and comparing microbial association networks from high-throughput sequencing data.

Here, we introduceNetCoMi(NetworkConstruction and comparison forMicrobiome data), anRpackage that integrates existing methods for each analysis step in a single reproducible computational workflow. The package offers functionality for constructing and analyzing single microbial association networks as well as quantifying network differences. This enables insights into whether single taxa, groups of taxa, or the overall network structure change between groups. NetCoMi also contains functionality for constructingdifferential networks, thus allowing to assess whether single pairs of taxa are differentially associated between two groups. Furthermore, NetCoMi facilitates the construction and analysis of dissimilarity networks of microbiome samples, enabling a high-level graphical summary of the heterogeneity of an entire microbiome sample collection. We illustrate NetCoMi’s wide applicability using data sets from the GABRIELA study to compare microbial associations in settled dust from children’s rooms between samples from two study centers (Ulm and Munich).

Availability

A script withRcode used for producing the examples shown in this manuscript are provided as Supplementary data. The NetCoMi package, together with a tutorial, is available athttps://github.com/stefpeschel/NetCoMi.
When does geography matter most? Age-specific geographical effects in the patterning of, and relationship between, mental wellbeing and mental illness
Authors: Griffith Gareth J , Jones Kelvyn
Published: July 2020

Mental illness and mental wellbeing are related but distinct constructs. Despite this, geographical enquiry often references the two as interchangeable indicators of mental health and assumes the relationship between the two is consistent across different geographical scales. Furthermore, the importance of geography in such research is commonly assumed to be static for all age groups, despite the large body of evidence demonstrating contextual effects in age-specific populations. We leverage simultaneous measurement of a mental illness and mental wellbeing metric from Understanding Society, a UK population-based survey, and employ bivariate, cross-classified multilevel modelling to characterise the relationship between geographical context and mental health. Results provide strong evidence for contextual effects for both responses before and after covariate adjustment, with weaker evidence for area-classification and PSU-level contextual effects for the GHQ-12 after covariate adjustment. Results support a two-continua model of mental health at the individual level, but indicates that consensual benefit may be achieved across both dimensions by intervening at household and regional levels. There is also some evidence of a greater contextual effects for mental wellbeing than for mental illness. Results highlight the potential of the household as a target for intervention design for consensual benefit across both constructs. Results highlight the increased importance of geographical context for older respondents across both responses. This research supports an area-based approach to improving both mental illness and mental wellbeing in older populations.
Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration
Authors: Cunza Nilsa La , Tan Li Xuan , Thamban Thushara , Germer Colin J. , Rathnasamy Gurugirijha , Toops Kimberly A. , Lakkaraju Aparna
Published: July 2020

Age-related macular degeneration (AMD) damages the retinal pigment epithelium (RPE), the tissue that safeguards photoreceptor health, leading to irreversible vision loss. Polymorphisms in cholesterol and complement genes are implicated in AMD, yet mechanisms linking risk variants to RPE injury remain unclear. We sought to determine how allelic variants in the apolipoprotein E cholesterol transporter modulate RPE homeostasis and function. Using live-cell imaging, we show that inefficient cholesterol transport by the AMD risk-associated ApoE2 increases RPE ceramide, leading to autophagic defects and complement-mediated mitochondrial damage. Mitochondrial injury drives redox state-sensitive cysteine-mediated phase separation of ApoE2, forming biomolecular condensates that could nucleate drusen. The protective ApoE4 isoform lacks these cysteines and is resistant to phase separation and condensate formation. InAbca4-/-Stargardt macular degeneration mice, mitochondrial dysfunction induces liquid-liquid phase separation of p62/SQSTM1, a multifunctional protein that regulates autophagy. Drugs that decrease RPE cholesterol or ceramide prevent mitochondrial injury and phase separation in vitro and in vivo. In AMD donor RPE, mitochondrial fragmentation correlates with ApoE and p62 condensates. Our studies demonstrate that major AMD genetic and biological risk pathways converge upon RPE mitochondria, and identify mitochondrial stress-mediated protein phase separation as an important pathogenic mechanism and promising therapeutic target in AMD.
Coincidence detection of mitogenic signals via cytosolic pH regulates Cyclin D1 expression
Authors: Koch Lisa Maria , Birkeland Eivind , Battaglioni Stefania , Helle Xiao , Meerang Mayura , Hiltbrunner Stefanie , Ibáñez Alfredo J. , Peter Matthias , Curioni Alessandra , Opitz Isabelle , Dechant Reinhard
Published: July 2020

Enhanced cell growth and proliferation are accompanied by profound changes in cellular metabolism. Originally identified as the Warburg effect in cancer, such metabolic changes are also common under physiological conditions and include increased fermentation and elevated cytosolic pH (pHc)1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we demonstrate that elevated pHc specifically orchestrates an E2F-dependent transcriptional program to drive cell proliferation by promoting Cyclin D1 expression. pHc-dependent transcription of Cyclin D1 requires the transcription factors CREB1/ATF1 and ETS1 and the Histone Acetyltransferases p300/CBP. Interestingly, biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH-sensor and coincidence detector linking different mitotic signals to Cyclin D1 transcription. We also show that elevated pHc contributes to increased Cyclin D1 expression in Malignant Pleural Mesotheliomas (MPMs) and renders them hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression and provide a mechanism linking elevated pHc to oncogenic activation of Cyclin D1 in MPMs and possibly other Cyclin D1-dependent tumors. Thus, an increase of pHc may represent a functionally important, early event in the etiology of cancer amenable to therapeutic intervention.
BiPOLES: a tool for bidirectional dual-color optogenetic control of neurons
Authors: Vierock Johannes , Rodriguez-Rozada Silvia , Pieper Florian , Dieter Alexander , Bergs Amelie , Zeitzschel Nadja , Ahlbeck Joachim , Sauter Kathrin , Gottschalk Alexander , Engel Andreas K. , Hegemann Peter , Wiegert J. Simon
Published: July 2020

Optogenetic manipulation of neuronal activity has become an indispensable experimental strategy in neuroscience research. A large repertoire of excitatory and inhibitory tools allows precise activation or inhibition of genetically targetable neuronal populations. However, an optogenetic tool for reliable bidirectional control of neuronal activity allowing both up- and downregulation of the same neurons in a single experiment is still missing. Here we report BiPOLES, an optogenetic tool for potent excitation and inhibition of the same population of neurons with light of two different colors. BiPOLES consists of an inhibitory, blue-light-sensitive anion-conducting channelrhodopsin fused to an excitatory, red-light-sensitive cation-conducting channelrhodopsin in a single, trafficking-optimized tandem protein. BiPOLES enables multiple new applications including potent dual-color spiking and silencing of the same neuronsin vivoand dual-color optogenetic control of two independent neuronal populations.
Liver inflammation before spinal cord injury worsens neuropathology, hepatic injury, metabolic syndrome and locomotor deficits
Authors: Goodus Matthew T. , Carson Kaitlin E. , Sauerbeck Andrew D. , Dey Priyankar , Alfredo Anthony N. , Popovich Phillip G. , Bruno Richard S. , McTigue Dana M.
Published: July 2020

Liver inflammation can enhance acute leukocyte recruitment to sites of central nervous system (CNS) injury. The consequences of hepatic inflammation on recovery after injury, however, are unknown. Here, we hypothesize that liver inflammation at the time of spinal cord injury (SCI) will exacerbate spinal cord pathology and impair recovery. Rats receiving SCI with concomitant liver inflammation had worse intraspinal pathology and greater locomotor deficits than rats with baseline liver inflammation. Hepatic inflammation also potentiated SCI-induced non-alcoholic steatohepatitis (NASH), endotoxemia, insulin resistance and adiposity. Circulating and cerebrospinal levels of Fetuin-A were higher in SCI rats with liver inflammation. When microinjected into intact spinal cords, Fetuin-A caused robust macrophage activation, iron accumulation and neuron loss. These studies verify that outcomes from CNS injury are worse if the liver is concomitantly inflamed and implicate Fetuin-A as a potential neuropathological mediator. These novel data suggest hepatic inflammation is a potential clinical target for improving recovery from SCI.
Interleukin-19 alleviates experimental autoimmune encephalomyelitis by attenuating antigen-presenting cell activation
Authors: Horiuchi Hiroshi , Parajuli Bijay , Komiya Hiroyasu , Ogawa Yuki , Jin Shijie , Takahashi Keita , Azuma Yasu-Taka , Tanaka Fumiaki , Suzumura Akio , Takeuchi Hideyuki
Published: July 2020

Interleukin-19 (IL-19) acts as an anti-inflammatory cytokine in various inflammatory diseases. Multiple sclerosis (MS) is a major neuroinflammatory disease in the central nervous system, but it remains uncertain how IL-19 contributes to MS pathogenesis. Here, we demonstrate that IL-19 deficiency aggravates experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by promoting IL-17–producing helper T cell (Th17 cell) infiltration into the central nervous system. In addition, IL-19–deficient splenic macrophages expressed elevated levels of major histocompatibility complex class II, co-stimulatory molecules, and Th17 cell differentiation–associated cytokines such as IL-1β, IL-6, IL-23, TGF-β1, and TNF-α. These observations indicated that IL-19 plays a critical role in suppression of MS pathogenesis by inhibiting macrophage antigen presentation, Th17 cell expansion, and subsequent inflammatory responses. Furthermore, treatment with IL-19 significantly abrogated EAE. Our data suggest that IL-19 could provide significant therapeutic benefits in patients with MS.
Genomic prediction in the wild: A case study in Soay sheep
Authors: Ashraf B , Hunter DC , Bérénos C , Ellis PA , Johnston SE , Pilkington JG , Pemberton JM , Slate J
Published: July 2020

Genomic prediction, the technique whereby an individual’s genetic component of their phenotype is estimated from its genome, has revolutionised animal and plant breeding and medical genetics. However, despite being first introduced nearly two decades ago, it has hardly been adopted by the evolutionary genetics community studying wild organisms. Here, genomic prediction is performed on eight traits in a wild population of Soay sheep. The population has been the focus of a >30 year evolutionary ecology study and there is already considerable understanding of the genetic architecture of the focal Mendelian and quantitative traits. We show that the accuracy of genomic prediction is high for all traits, but especially those with loci of large effect segregating. Five different methods are compared, and the two methods that can accommodate zero-effect and large-effect loci in the same model tend to perform best. If the accuracy of genomic prediction is similar in other wild populations, then there is a real opportunity for pedigree-free molecular quantitative genetics research to be enabled in many more wild populations; currently the literature is dominated by studies that have required decades of field data collection to generate sufficiently deep pedigrees. Finally, some of the potential applications of genomic prediction in wild populations are discussed.
Sense the Moment: a highly sensitive antimicrobial activity predictor based on hydrophobic moment
Authors: Porto William F. , Ferreira Karla C. V. , Ribeiro Suzana M. , Franco Octavio L.
Published: July 2020

Background

Computer-aided identification and design tools are indispensable for developing antimicrobial agents for controlling antibiotic-resistant bacteria. Antimicrobial peptides (AMPs) have aroused intense interest, since they have a broad spectrum of activity, and therefore, several systems for predicting antimicrobial peptides have been developed, using scalar physicochemical properties; however, regardless of the machine learning algorithm, these systems often fail in discriminating AMPs from their shuffled versions, leading to the need for new training methods to overcome this bias. Aiming to solve this bias, here we present “Sense the Moment”, a prediction system capable of discriminating AMPs and shuffled versions.

Methods

The system was trained using 776 entries: 388 from known AMPs and another 388 based on shuffled versions of known AMPs. Each entry contained the geometric average of three hydrophobic moments measured with different scales.

Results

The model showed good accuracy (>80 %) and excellent sensitivity (>90 %) for AMP prediction, exceeding deep-learning-based methods.

Conclusion

Our results demonstrate the system’s applicability, aiding in identifying and discarding non-AMPs, since the number of false negatives is lower than false positives. General Significance: The application of this model in virtual screening protocols for identifying and/or creating antimicrobial agents could aid in the identification of potential drugs to control pathogenic microorganisms and in solving the antibiotic resistance crisis.

Availability

The system was implemented as a web application, available at .
Multiscale label-free volumetric holographic histopathology of thick-tissue slides with subcellular resolution
Authors: Hugonnet Herve , Kim Yeon Wook , Lee Moosung , Shin Seungwoo , Hruban Ralph H. , Hong Seung-Mo , Park YongKeun
Published: July 2020

Histopathology relies upon the staining and sectioning of biological tissues, which can be laborious and may cause artefacts and distort tissues. Here, we demonstrate label-free volumetric imaging of thick-tissue slides, exploiting refractive index distributions as intrinsic imaging contrast. The present method systematically exploits label-free quantitative phase imaging techniques, volumetric reconstruction of intrinsic refractive index distributions in tissues, and numerical algorithms for the seamless stitching of multiple 3D tomograms and for reducing scattering-induced image distortion. We demonstrate demonstrated label-free volumetric imaging of thick tissues with the field of view of 2 mm × 1.75 mm × 0.2 mm with a spatial resolution of 170 nm × 170 nm × 1200 nm. The number of optical modes, calculated as the reconstructed volume divided by the size of the point spread function, was approximately 20 Giga voxels. We have also demonstrated that different tumour types, and a variety of precursor lesions and pathologies can be visualized with the present method.

Abstract Figure
Development ofArabidopsis thalianatransformants showing the self-recognition activity ofBrassica rapa
Authors: Yamamoto Masaya , Kitashiba Hiroyasu , Nishio Takeshi
Published: July 2020

Self-incompatibility in the Brassicaceae family is governed by two-linked highly polymorphic genes located at theSlocus,SRKandSCR. Previously, theSRKandSCRgenes ofArabidopsis lyratawere introduced intoArabidopsis thalianatransformants to generate self-incompatible lines. However, it has not been reported that theSRKandSCRgenes ofBrassicaspecies confer self-incompatibility inA. thaliana. In this study, we attempted to construct self-incompatibleA. thalianatransformants expressing the self-recognition activity ofBrassica rapaby introducing theBrSCRgene along with a chimericBrSRKgene (BrSRK chimera, in which the kinase domain ofBrSRKwas replaced with that ofAlSKRb). We found thatBrSRK chimeraandBrSCRofB. rapa S-9andS-46haplotypes, but not those ofS-29,S-44, andS-60haplotypes, conferred self-recognition activity inA. thaliana. We also investigated the importance of amino acid residues involved in the BrSRK9–BrSCR9 interaction usingA. thalianatransformants expressing mutant variants ofBrSRK-9 chimeraandBrSCR-9. The results showed that some of the amino acid residues are essential for self-recognition. The method developed in this study for the construction of self-incompatibleA. thalianatransformants showingB. rapaself-recognition activity will be useful for analysis of self-recognition mechanisms in Brassicaceae.
Tau in the brain interstitial fluid is fragmented and seeding-competent
Authors: Barini Erica , Plotzky Gudrun , Mordashova Yulia , Hoppe Jonas , Rodriguez-Correa Esther , Julier Sonja , LePrieult Florie , Mairhofer Ina , Mezler Mario , Biesinger Sandra , Cik Miroslav , Meinhardt Marcus W , Ercan-Herbst Ebru , Ehrnhoefer Dagmar E. , Striebinger Andreas , Bodie Karen , Klein Corinna , Gasparini Laura , Schlegel Kerstin
Published: July 2020

In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology.

Highlights

In interstitial fluid (ISF) of transgenic mice, Tau comprises >10 distinct fragments

ISF Tau decreases with Tauopathy progression, while its phosphorylation increases

Only ISF from mice with established Tauopathy is seeding competent in vitro

Removal of phospho-Tau reduces ISF seeding competence

ISF seeding competence is driven by less soluble, aggregated and phosphorylated Tau

Graphical abstract
Rapid Establishment of Tracheal Stenosis in Pigs Using Endotracheal Tube Cuff Overpressure and Electrocautery
Authors: Kim Jin Hyoung , Ahn Jong Joon , Jegal Yangjin , Seo Kwang Won , Ra Seung Won , Kang Byung Ju , Bae Soohyun , Park Soon Eun , Jung Moon Sik , Park Ju Ik , Cha Hee Jeong , Lee Yongjik , Lee Taehoon
Published: July 2020

Background

Central airway obstruction can be caused by cancer, tracheal intubation, or tuberculosis, among others. If surgery is contraindicated, bronchoscopic therapy may be performed. Bronchoscopic treatment for airway obstruction is continuously evolving. In particular, attempts to overcome the current shortcomings of airway stents (stent migration, mucostasis, and granulation tissue formation) are currently ongoing. To apply a new airway stent to humans, preclinical studies in an appropriate animal model is needed. Canine and porcine tracheas have been used as animal airway stenosis models. However, existing models take a long time to develop (3–8 weeks) and have a disadvantage that the mechanism of stenosis is different from that in humans.

Purpose

To establish a new and fast tracheal stenosis model in pigs using a combination of cuff overpressure intubation and electrocautery.

Methods

Fourteen pigs were divided into three groups: tracheal cautery (TC) group (n = 3), cuff overpressure intubation (COI) group (n = 3), and COI-TC combination group (n = 8). Cuff overpressure (200/400/500 mmHg) was applied using a 9-mm internal diameter endotracheal tube. Tracheal cautery (40/60 watts) was performed using a rigid bronchoscopic electrocoagulator. After intervention, the pigs were observed for 3 weeks and bronchoscopy was performed every 7 days. When the cross-sectional area decreased by > 50%, it was judged that tracheal stenosis was established.

Results

The time for tracheal stenosis was 14 days in the TC group and 7 days in the COI-TC combination group. In the COI group, no stenosis occurred. In the COI-TC group, electrocautery (40 watts) immediately after intubation for > 1 hour with a cuff pressure of 200 mmHg or more resulted in sufficient tracheal stenosis within 7 days. Moreover, the degree of tracheal stenosis increased in proportion to the cuff pressure and tracheal intubation time.

Conclusions

The combined use of cuff overpressure and electrocautery helped to establish tracheal stenosis in pigs rapidly. This animal model was technically simple and reproducible, and used a mechanism similar to that in human tracheal stenosis. It is expected to help develop new treatments for airway stenosis