bluuebunny/crossref_metadata_2025 huggingface dataset:
Delivering the diluted contrast agent with saline via a spiral flow tube improves arterial enhancement for contrast enhancement of magnetic resonance angiography of the neck
Authors: Hamaguchi Akiyoshi , Fujima Noriyuki , Hamaguchi Naoko , Hayashi Tetsuji , Kodera Shuichi
Published: December 2019

A contrast agent can be pushed by a saline solution more effectively through a spiral flow tube than through a conventional T-shaped tube in contrast-enhanced magnetic resonance angiography (CEMRA). To compare the degree of contrast enhancement and signal stability in the carotid artery by using CEMRA between a spiral flow tube and a T-shaped tube.

A total of 100 patients were analyzed in this retrospective study. The first 50 patients underwent CEMRA of the carotid artery with the T-shaped tube, while the last 50 patients used the spiral flow tube. Gadoterate meglumine was diluted with saline to make a total volume of 20 mL. Injection was performed with a bolus rate of 2.5 mL/s for 8 seconds. Five regions of interest (ROIs) were placed on the contrast-enhanced area in each carotid artery and the signal intensity (SI) in the ROI was used for the analysis. The ROIs on the brain stem were also placed and the average SI in this ROI was used as a reference signal. The enhancement of the artery (E
artery) was calculated as a normalized signal using the following equation: E
artery = SI in the ROI of the carotid bifurcation/SI in the ROI of the brain stem. Signal homogeneity in the contrast-enhanced area (SHenhance) was assessed by calculating the coefficient of variation from the SI in the 5 ROIs. The value of SHenhance and E
artery between the data obtained from the spiral flow tube and the T-shaped tube were compared. P-values <.05 were considered significant.

We found a significant difference in SHenhance between the data obtained from the spiral flow tube (0.20 ± 0.060) and the T-shaped tube (0.24 ± 0.056) (P = .001). The E
artery values significantly increased by 15% (spiral flow tube, median 14.1 with interquartile range [IQR] 11.8–15.4 vs T-shaped tube, median 12.3 IQR 11.3–14.0, P = .02) using the spiral flow tube.

These findings suggest that, by using the Spiral flow tube, the homogeneity of the contrast-enhanced signal intensity in the carotid artery was significantly improved without decreasing the signal intensity in CEMRA.
Acupuncture for patients with atopic dermatitis
Authors: Liu Yijiang , Cui Hai , Du Ruosang , Zhang Lu , Yuan Hongwen , Zhang Xiaohui , Zheng Shumei
Published: December 2019

Background:

The systematic review protocol is aim to evaluate the efficacy and safety of acupuncture in the treatment of atopic dermatitis (AD).

Methods:

We will search the database on the Cochrane Library, PubMed, Medline, Excerpta Medica Database, Chinese Biomedical Literature Database, PsychINFO, China National Knowledge Infrastructure, Wanfang data, Chinese Scientific Journal Database, including studies and published systematic review in the reference list and grey. And will use Cochrane Collaboration's tools to evaluate the risk of bias of the included randomized controlled trials. The Review Manager 5.3 will be used to synthesize collected data.

Results:

This study will assess the safety and effectiveness based on current evidence of acupuncture for AD, especially scoring atopic dermatitis, eczema area, and severity index, patient-oriented eczema measure, and quality of life.

Conclusion:

This study will provide high-quality recently evidence for evaluating the efficacy of acupuncture for patients with AD.

PROSPERO registration number: CRD42019135919.
Effectiveness and safety of repetitive transcranial magnetic stimulation (rTMS) on aphasia in cerebrovascular accident patients
Authors: Zheng Yaling , Zhong Dongling , Huang Yijie , He Mingxing , Xiao Qiwei , Jin Rongjiang , Li Juan
Published: December 2019

Background:

Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation approach, might be a promising technique in the management of aphasia after cerebrovascular accidents (CVA). This protocol of systematic review (SR) aims to investigate the effectiveness and safety of rTMS in patients with aphasia after CVA.

Methods:

The following databases will be searched: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), China National Knowledge infrastructure (CNKI), Technology Periodical Database (VIP), WanFang Data, and China Biology Medicine (CBM) from inception to August 2019. Randomized controlled trials (RCTs) investigating the effectiveness and safety of rTMS for aphasia patients after CVA will be included. Primary outcome will include Boston Diagnostic Aphasia Examination (BDAE). Secondary outcomes will include Aphasia Battery of Chinese (ABC), Aachen Aphasia Test (AAT), Aphasia Quotient (AQ), the Western Aphasia Battery (WAB), Standard Language Test of Aphasia (SLTA), Aphasia Severity Rating Scale (ASRS), Concise China Aphasia Test Scale (CCAT), Amsterdam-Nijmegen Everyday Language Test (ANELT), or other related outcomes. Adverse events such as headache, tinnitus, anxiety, fatigue, or epileptic seizure will be considered as safety measurement. Studies screening, data extraction, and methodological quality assessment will be performed independently by two reviewers. Meta-analysis will be conducted with Review Manager 5.3 software and R software 3.6.1.

Results:

This study will provide a high-quality synthesis of RCTs on the effectiveness and safety of rTMS as an adjuvant therapy in the treatment of aphasia.

Conclusion:

The conclusion of this study will help clinicians and patients with aphasia after CVA to make decision.

Ethics and dissemination:

No privacy health information will be collected, thus formal ethics approval is not required. The findings of this SR will be submitted to a peer-reviewed journal.

PROSPERO registration number:

CRD42019144587.
Subdural empyema complicated after trepanation and drainage of chronic subdural hematoma
Authors: Xue Hang , Zhang Weitao , Shi Lin , Zhang Yiming , Yu Bing , Yang Hongfa
Published: December 2019

Rationale:

Chronic subdural hematoma (CSDH) is one of the most common neurosurgical diseases. However, complicated subdural empyema rarely occurs after trepanation and drainage of chronic subdural hematoma.

Patient concerns:

A male patient (77 years old) was admitted to the hospital on the 2nd day of fever after an undergoing a “trepanation and drainage of chronic subdural hematoma” operation at a local hospital. After admission, the patient was treated with an emergency operation in which a subdural abscess was diagnosed and then administered antibiotics after the operation.

Diagnosis:

According to the clinical manifestations, intraoperative findings of imaging examination and the results of pus culture, the diagnosis was subdural empyema.

Intervention:

We surgically removed the subdural empyema. Postoperative antibiotics were administered according to the results of bacterial culture.

Outcomes:

At 3 months after the operation, the patient returned to the hospital for reexamination and was found to have achieved a good recovery and good self-care.

Lessons:

Subdural empyema after trepanation and drainage of chronic subdural hematoma is a very rare and severe disease. Early diagnosis and operative intervention as well as the intravenous administration of antibiotics can improve the prognosis of patients and enhance their quality of life.
Association between vascular endothelial growth factor receptor 2 rs11941492 C/T polymorphism and Chinese Han patients in rheumatoid arthritis
Authors: Yang Zhicheng , Wang Mingjie , Yan Ting , Hu Zhiyong , Zhang Hui , Liu Ruiping
Published: December 2019

The aim of the present study was to examine the association between vascular endothelial growth factor receptor 2 (VEGFR2) rs11941492 C/T polymorphism and rheumatoid arthritis (RA) risk in an eastern Chinese Han population. We examined VEGFR2 rs11941492 C/T polymorphism in 615 RA patients and 839 controls in an East Chinese Han population. The power analysis was used for evaluating the reliability of the results. Genotyping was performed using a custom-by-design 48-Plex single nucleotide polymorphism scan Kit. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression.

Our results indicated that VEGFR2 rs11941492 C/T polymorphism (TT vs CC, P = .012, OR = 0.61, 95% CI = 0.41–0.89; TT vs CT + CC, P = .017, OR = 0.63, 95% CI = 0.43–0.92) was associated with a significantly decreased risk of RA. The power analysis showed that this study had a power of 98.5% to detect the effect of rs11941492 C/T polymorphism on RA susceptibility, assuming an OR of 0.61. After stratification analysis, a decreased risk of RA was associated with VEGFR2 rs11941492 TT genotype (TT vs CC) among female patients (TT vs CC, P = .007, OR = 0.53, 95% CI = 0.33–0.84), older patients (Yr ≥55) (TT vs CC, P = .039, OR = 0.58, 95% CI = 0.35–0.97), C-reactive protein-positive patients, anti-cyclic citrullinated peptide antibody-negative patients, rheumatoid factor-positive patients (TT vs CT + CC, P = .015, OR = 0.60, 95% CI = 0.39–0.90), functional class III + IV patients, patients with a DAS28 of ≥3.20, and those with an erythrocyte sedimentation rate of <25. However, our results were obtained from only a moderate-sized sample. Studies with larger sample sizes in other ethnic populations are needed to confirm these results. The VEGFR2 rs11941492 genotype is associated with decreased susceptibility to RA.
Weight Loss for Patients With Obesity
Authors: Liu Natalie , Birstler Jen , Venkatesh Manasa , Hanrahan Lawrence P. , Chen Guanhua , Funk Luke M.
Published: December 2019

Background:

Numerous studies have reported that losing as little as 5% of one’s total body weight (TBW) can improve health, but no studies have used electronic health record data to examine long-term changes in weight, particularly for adults with severe obesity [body mass index (BMI) ≥35 kg/m2].

Objective:

To measure long-term weight changes and examine their predictors for adults in a large academic health care system.

Research Design:

Observational study.

Subjects:

We included 59,816 patients aged 18–70 years who had at least 2 BMI measurements 5 years apart. Patients who were underweight, pregnant, diagnosed with cancer, or had undergone bariatric surgery were excluded.

Measures:

Over a 5-year period: (1) ≥5% TBW loss; (2) weight loss into a nonobese BMI category (BMI <30 kg/m2); and (3) predictors of %TBW change via quantile regression.

Results:

Of those with class 2 or 3 obesity, 24.2% and 27.8%, respectively, lost at least 5% TBW. Only 3.2% and 0.2% of patients with class 2 and 3 obesity, respectively, lost enough weight to attain a BMI <30 kg/m2. In quantile regression, the median weight change for the population was a net gain of 2.5% TBW.

Conclusions:

Although adults with severe obesity were more likely to lose at least 5% TBW compared with overweight patients and patients with class 1 obesity, sufficient weight loss to attain a nonobese weight class was very uncommon. The pattern of ongoing weight gain found in our study population requires solutions at societal and health systems levels.
Racial/Ethnic Disparities in Longitudinal Trajectories of Community Integration After Burn Injury
Authors: Pierce Bradford S. , Perrin Paul B. , Pugh Mickeal , Cariello Annahir N. , Henry Richard S. , Sutter Megan E. , Wiechman Shelley A. , Schneider Jeffrey C.
Published: December 2019

Objectives

The aim of this study was to examine potential racial/ethnic disparities in community integration for the 2 yrs after burn injury.

Design

A sample of 1773 adults with burn injury from the Burn Model Systems database was used with data on community integration collected at discharge (preinjury recall), 6, 12, and 24 mos after discharge.

Methods

Four sets of hierarchal linear models determined the most appropriate model for understanding racial/ethnic differences in Community Integration Questionnaire trajectories over time.

Results

Data indicated a decrease in community integration between discharge and 6 mos, a slight increase between 6 mos and 1 yr, and then a plateau between 1 and 2 yrs. White individuals had higher community integration score trajectories over time than black (b = 0.53, P < 0.001) and Hispanic (b = 0.58, P < 0.001) individuals, and community integration scores were similar between black and Hispanic individuals (b = −0.05, P = 0.788). These racial/ethnic disparities remained after accounting for age, sex, total burned surface area, number of days in rehabilitation, and active range of motion deficits.

Conclusions

Additional rehabilitation resources should be targeted to helping black and Hispanic individuals integrate back into their communities after burn injury.
Feasibility and Acceptability of a Lifestyle Intervention For Individuals With Bipolar Disorder
Authors: SYLVIA LOUISA G. , JANOS JESSICA A. , PEGG SAMANTHA L. , DUFOUR STEVEN C. , CHANG WEILYNN C. , BERNSTEIN EMILY E. , DAVIS BRETT , ELLARD KRISTEN K. , DECKERSBACH THILO , NIERENBERG ANDREW A.
Published: December 2019

Individuals with bipolar disorder are at greater risk for cardiovascular disease and are less likely to adhere to lifestyle interventions than the general population. To decrease cardiovascular risk and improve adherence to lifestyle interventions, we developed the Nutrition Exercise and Wellness Treatment (NEW Tx). NEW Tx is an 18-session, 20-week cognitive behavioral therapy–based treatment comprising 3 modules: Nutrition, Exercise, and Wellness. To evaluate the feasibility and acceptability of this intervention as well as predictors of treatment satisfaction and expectations, 38 adult outpatients with bipolar disorder were randomized to either NEW Tx or a waitlist control condition. There was no statistically significant difference in dropout rates between the groups (26.3% in NEW Tx, 31.6% in the control condition). In the NEW Tx condition, participants attended a mean of 66.7% of sessions and reported moderate to high satisfaction. There were no study-related adverse events. We also found that expectations, but not perceived credibility (or believability), of NEW Tx (as measured by the Credibility/Expectancy Questionnaire) at baseline predicted treatment satisfaction (as measured by the Care Satisfaction Questionnaire) posttreatment. Manic symptoms at baseline predicted treatment satisfaction, and marital status predicted one’s expectations of lifestyle interventions. Data suggest that NEW Tx is a feasible and acceptable intervention for individuals with bipolar disorder and that further research is warranted to explore potential moderators of treatment expectations and credibility in this clinical population.
Surface Texturization of Breast Implants Impacts Extracellular Matrix and Inflammatory Gene Expression in Asymptomatic Capsules
Authors: Brigaud Isabelle , Garabédian Charles , Bricout Nathalie , Pieuchot Laurent , Ponche Arnaud , Deltombe Raphaël , Delille Rémi , Atlan Michael , Bigerelle Maxence , Anselme Karine
Published: December 2019

Background:

Texturing processes have been designed to improve biocompatibility and mechanical anchoring of breast implants. However, a high degree of texturing has been associated with severe abnormalities. In this study, the authors aimed to determine whether implant surface topography could also affect physiology of asymptomatic capsules.

Methods:

The authors collected topographic measurements from 17 different breast implant devices by interferometry and radiographic microtomography. Morphologic structures were analyzed statistically to obtain a robust breast implant surface classification. The authors obtained three topographic categories of textured implants (i.e., “peak and valleys,” “open cavities,” and “semiopened cavities”) based on the cross-sectional aspects. The authors simultaneously collected 31 Baker grade I capsules, sorted them according to the new classification, established their molecular profile, and examined the tissue organization.

Results:

Each of the categories showed distinct expression patterns of genes associated with the extracellular matrix (Timp and Mmp members) and inflammatory response (Saa1, Tnsf11, and Il8), despite originating from healthy capsules. In addition, slight variations were observed in the organization of capsular tissues at the histologic level.

Conclusions:

The authors combined a novel surface implant classification system and gene profiling analysis to show that implant surface topography is a bioactive cue that can trigger gene expression changes in surrounding tissue, even in Baker grade I capsules. The authors’ new classification system avoids confusion regarding the word “texture,” and could be transposed to implant ranges of every manufacturer. This new classification could prove useful in studies on potential links between specific texturizations and the incidence of certain breast-implant associated complications.
Assessment of Oral Propranolol Administration for Infantile Hemangioma in Oral and Maxillofacial Region Aided by Ultrasonography
Authors: Al-Mahdi Akmam H. , Al-Sada Milad A.
Published: December 2019

Background:

Propranolol has become the first-line therapy for the treatment of complicated infantile hemangioma. However, there are still many queries regarding the hemangioma volume in relation to drug's dose and duration.

Objective:

The aim of this study was to evaluate the therapeutic effect of oral propranolol for treating infantile hemangiomas in the oral and maxillofacial region aided by gray scale ultrasonography (GSU).

Materials and Methods:

Twelve patients with infantile hemangioma, age ranged between 2 and 11 months, have been treated with oral propranolol for 6 months’ period. They received a dose of 1 mg/kg per body weight per day, increased after 1 week to 2 mg/ kg per body weight per day maintenance for 24 weeks. The changes in tumor sizes were evaluated by ultrasonography (GSU) using 4-points scale system: excellent, good, fair, poor)

Results:

All infants less than 6 months of age showed more hemangiomas regression in size in comparison with of those aged >6 months (P value 0.042) as a rapid response. After the 24th week; 5 patients had excellent results, 4 patients had good results, 2 patients had fair results, and only 1 patient had poor results. None of the treated infants showed rebound phenomena after cessation of treatment.

Conclusion:

Oral propranolol at dose of 2 mg/kg/day in 2 divided doses for 24 weeks aided by GSU is shown to be a safe and effective treatment of infantile hemangioma during the proliferative phase.
Neuroprotection of dihydrotestosterone via suppression of the toll-like receptor 4/nuclear factor-kappa B signaling pathway in high glucose-induced BV-2 microglia inflammatory responses
Authors: Yang Lei , Tong Yu , Chen Peng-Fei , Miao Shuai , Zhou Ren-yuan
Published: December 2019

Hyperglycemia is considered to induce neuronal apoptosis via activating microglia inflammatory responses, thus involving in the development and progression of diabetic encephalopathy and neurodegenerative disorders. Increasing evidences suggest that androgen exerts neuroprotective functions including antiapoptosis, anti-inflammation and antioxidative stress. In this study, we investigate the anti-inflammatory role of dihydrotestosterone (DHT) in high glucose (HG)-induced neuroinflammatory response in BV-2 microglia. Our results revealed that DHT significantly inhibited HG-induced production of nitric oxide and prostaglandin E2 through suppressing the expression of corresponding regulatory enzymes – inducible NO synthase and cyclooxygenase-2. Also, DHT inhibited HG-induced expression of TNF-α and IL-1β. Moreover, DHT suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway. Furthermore, when SH-SY5Y neurons were cultured in HG-treated BV-2 microglial supernatant, DHT pretreatment significantly increased neuronal survival, indicating the neuroprotective role of DHT. Collectively, these results suggest that DHT could protect SH-SY5Y neurons from HG-mediated BV-2 microglia inflammatory damage through inhibiting TLR4/NF-κB signaling, suggesting that maintenance of androgen level in brain might have potential benefit in neurodegenerative diseases, especially in diabetes patients combined with cognitive disorders.
Explaining the genetic causality for complex diseasesviadeep association kernel learning
Authors: Bao Feng , Deng Yue , Du Mulong , Ren Zhiquan , Wan Sen , Xin Junyi , Chen Feng , Christiani David C. , Wang Meilin , Dai Qionghai
Published: December 2019

The genetic effect explains the causality from genetic mutation to the development of complex diseases. Existing genome-wide association study (GWAS) approaches are always built under a linear assumption, restricting their generalization in dissecting complicated causality such as the recessive genetic effect. Therefore, a sophisticated and general GWAS model that can work with different types of genetic effects is highly desired. Here, we introduce a Deep Association Kernel learning (DAK) model to enable automatic causal genotype encoding for GWAS at pathway level. DAK can detect both common and rare variants with complicated genetic effects that existing approaches fail. When applied to real-world GWAS data, our approach discovered potential casual pathways that could be explained by alternative biological studies.
No strong evidence that social network index is associated with gray matter volume from a data-driven investigation
Authors: Lin Chujun , Keles Umit , Tyszka J. Michael , Gallo Marcos , Paul Lynn , Adolphs Ralph
Published: December 2019

Recent studies in adult humans have reported correlations between individual differences in people’s Social Network Index (SNI) and gray matter volume (GMV) across multiple regions of the brain. However, the cortical and subcortical loci identified are inconsistent across studies. These discrepancies might arise because different regions of interest were hypothesized and tested in different studies without controlling for multiple comparisons, and/or from insufficiently large sample sizes to fully protect against statistically unreliable findings. Here we took a data-driven approach in a pre-registered study to comprehensively investigate the relationship between SNI and GMV in every cortical and subcortical region, using three predictive modeling frameworks. We also included psychological predictors such as cognitive and emotional intelligence, personality, and mood. In a sample of healthy adults (n = 92), neither multivariate frameworks (e.g., ridge regression with cross-validation) nor univariate frameworks (e.g., univariate linear regression with cross-validation) showed a significant association between SNI and any GMV or psychological feature after multiple comparison corrections (all R-squared values ≤ 0.1). These results emphasize the importance of large sample sizes and hypothesis-driven studies to derive statistically reliable conclusions, and suggest that future meta-analyses will be needed to more accurately estimate the true effect sizes in this field.
Multinational qEEG developmental surfaces
Authors: Hu Shiang , Ngulugulu Ally , Bosch-Bayard Jorge , Bringas-Vega Maria L. , Valdes-Sosa Pedro A.
Published: December 2019

The quantitative electroencephalogram (qEEG) is a diagnostic method based on the spectral features of the resting state EEG. The departure of spectral features from normality is gauged by theztransform with respect to the age-adjusted mean and deviation of normative databases – known as the developmental equations/surfaces. However, the extent to which the data collected from different countries with various equipment require separate developmental equations remains unanswered. Here, we analyzed the EEG of 535 subjects from 3 countries, Switzerland, the USA and Cuba. The EEG power spectra of all samples were log transformed and their relations to the covariables (‘age’, ‘frequency’, ‘country’ and ‘individual’) were analyzed using the linear mixed effects model. We found that the origin ‘country’ of the subjects did not play a significant effect on the log spectra, even without interactions with other independent variables, whereas, ‘age’ and ‘frequency’ were highly significant. To estimate the developmental surfaces in greater detail, we carried out kernel regression (lowess) in two dimensions of log-age and frequency. We found two main phenomena: 1) slow rhythms (δ, θ) predominated in the lower ages and then decreased with a tendency to disappear at higher ages; 2)αrhythm was absent at lower ages, but gradually appeared more relevant in occipital and parietal regions, and increased with aging with an increasing centering frequency ofαrhythm. We consider both phenomena as an expression of healthy neurodevelopmental and maturation related to age. It is the first study of multinational qEEG developmental surfaces accounting for ‘country’. The results demonstrate the possibility of creating international qEEG norms since the ‘individual’ and ‘age’ variability are much larger than the specific factors like ‘country’, or the technology employed ‘device’.
Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity
Authors: Farris Joseph , Calhoun Barbara , Alam Md Suhail , Lee Shaun , Haldar Kasturi
Published: December 2019

Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states. It is characterized by elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated disease. A major challenge has been that there are 255 unique disease-causing missense mutations inGLDC, of which 206 remain entirely uncharacterized. Here we report a Multiparametric Mutation Score (MMS) developed by combiningin silicopredictions of stability, evolutionary conservation and protein interaction models and suitable to assess 251 of 255 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of four major disease domains (seizure, cognitive failure, muscular and motor control and brain-malformation) to comprehensively score patient symptoms identified in 131 clinical reports published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were used to optimize the MMS for biological and clinical relevance and yield a patient Weighted Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological disease (p < 3.5e-5). Our study provides understanding for developing quantitative tools to predict clinical severity of neurological disease and a clinical scale that advances monitoring disease progression needed to evaluate new treatments for NKH.
Metagenomic Study Revealed the Potential Role of the Gut Microbiome in Gout
Authors: Chu Yongliang , Huang Yufen , Huang Qingchun , Xie Xuefeng , Wang Peng , Li Junxia , Liang Lifeng , He Xiaohong , Jiang Yiqi , Wang Maojie , Yang Jianhua , Chen Xiumin , Zhou Chu , Zhao Yue , Ding Fen , Zhang Yi , Wu Xiaodong , Bai Xueyuan , Wu JiaQi , Wei Xia , Chen XiangHong , Fang Xiaodong , Wang Zhang , Gao Qiang , Sun Silong , Huang Runyue
Published: December 2019

Emerging evidence has indicated an association between the gut microbiome and arthritis diseases including gout. This metagenomic study aims to investigate the possible role of gut microbiota in the development of gout. The results exhibit gout patients have higher abundance of Prevotella, Fusobacterium spp. and Bacteroides spp., whereas healthy controls have higher abundance of Enterobacteriaceae spp., butyrate-producing species, including Roseburia spp., Butyrivibrio spp. and Coprococcus spp. and anti-inflammatory Faecalibacterium prausnitzii. Functional analysis shows gut microbiome of gout patients have higher potential for fructose, mannose metabolism and lipid A biosynthesis, but lower potential for urate degradation and SCFAs production. Enterobacteriaceae spp. may contribute to urate degradation and provide immunostimulatory effect in healthy controls. A disease classifier based on gut microbiota shows positive performance in the discovery and validation cohorts (93.03% and 89.13% accuracy, respectively). The effect of uric-acid-lowering and anti-inflammatory drugs on the gut microbiome is mild. Integrative analyses of four additional diseases (obesity, type 2 diabetes, ankylosing spondylitis and rheumatoid arthritis) indicates gout seems to be more similar to autoimmune diseases than metabolic diseases. This work demonstrates an altered gut microbiota might influence the development of gout and provides new insights into the diagnosis and treatment of the disease.
Reclassification of SLC22 Transporters: Analysis of OAT, OCT, OCTN, and other Family Members Reveals 8 Functional Subgroups
Authors: Engelhart Darcy , Granados Jeffry C. , Shi Da , Saier Milton , Baker Michael , Abagyan Ruben , Nigam Sanjay K.
Published: December 2019

Among transporters, the SLC22 family is emerging as a central hub of endogenous physiology. The family consists of organic anion transporters (OATs), organic cation transporters (OCTs) and zwitterion transporters (OCTNs). Despite being known as “drug” transporters, these multi-specific, oligo-specific, and relatively mono-specific transporters facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups with four new subgroups arising from the previously defined OAT subclade. These OAT subgroups are: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Functional support for the eight subgroups comes from network analysis of data from GWAS, in vivo models, and in vitro assays. These data emphasize shared substrate specificity of SLC22 transporters for characteristic metabolites such as prostaglandins, uric acid, carnitine, creatinine, and estrone sulfate. Some important subgroup associations include: OATS1 with metabolites, signaling molecules, uremic toxins and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with monoamine neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. The OAT-like and OAT-related subgroups remain understudied and therefore do not have assigned functionality. Relatedness within subgroups is supported by multiple sequence alignments, evolutionarily conserved protein motifs, genomic localization, and tissue expression. We also highlight low level sequence similarity of SLC22 members with other non-transport proteins. Our data suggest that the SLC22 family can work among itself, as well as with other transporters and enzymes, to optimize levels of numerous metabolites and signaling molecules, as proposed by the Remote Sensing and Signaling Theory.
Donor specific transcriptomic analysis of Alzheimer’s disease associated hypometabolism highlights a unique donor, microglia, and ribosomal proteins
Authors: Patel Sejal , Howard Derek , Man Alana , Schwartz Deborah , Jee Joelle , Felsky Daniel , Pausova Zdenka , Paus Tomas , French Leon
Published: December 2019

Alzheimer’s disease (AD) starts decades before clinical symptoms appear. Low glucose utilization in regions of the cerebral cortex marks early AD and is clinically useful. To identify these regions, we conducted a voxel-wise meta-analysis of positron emission tomography studies that compared AD patients with healthy controls. This meta-analysis included 27 studies that assayed glucose utilization in 915 AD patients and 715 healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes with expression patterns associated with this hypometabolism pattern in the cerebral cortex. Of the six brains in the Atlas, one demonstrated a strong spatial association with the hypometabolism pattern. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when compared with the other five brains. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which primarily encode cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes progressively increases across AD-associated states of microglial activation. In addition, genes involved in cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, and vacuole sorting are associated with the hypometabolism map. These genes suggest disruption of the protein life cycle and neuroimmune activation. Taken together, our molecular characterization of cortical hypometabolism reveals a molecular link to AD associated hypometabolism that may be relevant to preclinical stages.
Epigenetics of skeletal muscle-associated genes in theASB, LRRC, TMEM, andOSBPLgene families
Authors: Ehrlich Kenneth C. , Lacey Michelle , Ehrlich Melanie
Published: December 2019

Much remains to be discovered about the intersection of tissue-specific transcription control and the epigenetics of skeletal muscle (SkM), a very complex and dynamic organ. From four gene families,ASB, LRRC, TMEM, andOSBPL, we chose 21 genes that are preferentially expressed in human SkM relative to 52 other tissue types and analyzed relationships between their tissue-specific epigenetics and expression. We also compared their genetics, proteomics, and descriptions in the literature. For this study, we identified genes with little or no previous descriptions of SkM functionality (ASB4, ASB8, ASB10, ASB12, ASB16, LRRC14B, LRRC20, LRRC30, TMEM52, TMEM233, OSBPL6/ORP6, andOSBPL11/ORP11) and included genes whose SkM functions had been previously addressed (ASB2, ASB5, ASB11, ASB15, LRRC2, LRRC38, LRRC39, TMEM38A/TRIC-A, andTMEM38B/TRIC-B). Among the transcription-related SkM epigenetic features that we identified were super-enhancers, promoter DNA hypomethylation, lengthening of constitutive low-methylated promoter regions, and SkM-related enhancers for one gene embedded in a neighboring gene (e.g.,ASB8-PFKM, LRRC39-DBT, andLRRC14B-PLEKHG4Bgene-pairs). In addition, highly or lowly co-expressed long non-coding RNA (lncRNA) genes probably regulate several of these genes. Our findings give insights into tissue-specific epigenetic patterns and functionality of related genes in a gene family and can elucidate normal and disease-related regulation of gene expression in SkM.
Excess extracellular K+causes inner hair cell ribbon synapse degeneration
Authors: Zhao Hong-Bo , Zhu Yan , Liu Li-Man
Published: December 2019

Inner hair cell (IHC) ribbon synapses are the first synapse in the auditory system and can be degenerated by noise and aging, thereby leading to hidden hearing loss (HHL) and other hearing disorders. However, the mechanism underlying this cochlear synaptopathy remains unclear. Here, we report that elevation of extracellular K+, which is a consequence of noise exposure, could cause IHC ribbon synapse degeneration and swelling. Like intensity dependence in noise-induced cochlear synaptopathy, the K+-induced degeneration was dose-dependent, and could be attenuated by BK channel blockers. However, application of glutamate receptor (GluR) agonists caused ribbon swelling but not degeneration. In addition, consistent with synaptopathy in HHL, both K+and noise exposure only caused IHC but not outer hair cell ribbon synapse degeneration. These data reveal that K+excitotoxicity can degenerate IHC ribbon synapses in HHL, and suggest that BK channel may be a potential target for prevention and treatment of HHL.
The Innate Immune Toll-Like Receptor-2 modulates the Depressogenic and Anorexiolytic Neuroinflammatory Response in Obstructive Sleep Apnoea
Authors: Polsek Dora , Cash Diana , Veronese Mattia , Ilic Katarina , Wood Tobias C. , Milosevic Milan , Kalanj-Bognar Svjetlana , Morrell Mary J. , Williams Steve C.R. , Gajovic Srecko , Leschziner Guy D. , Mitrecic Dinko , Rosenzweig Ivana
Published: December 2019

Background

The neurological mechanisms of the disease process of obstructive sleep apnea, the second most frequent sleep disorder, remain unclear whilst its links with several major neuropsychiatric disorders, such as depression, anxiety and even Alzheimer’s disorder, are increasingly recognised. A radical theory, that inflammation in the brain may underlie certain phenotypes of many of these disorders, has been proposed, and the microglial TLR2 system may serve as an important crossroad at the borderlands of several pathogenesis. This study undertook to investigate whether a neuroinflammatory response occurs under conditions of OSA, and whether it might be related to a modulated response due to TLR2 functionality in an established rodent model of OSA.

Methods

The effects of three weeks’ exposure to chronic intermittent hypoxia were monitored in mice with or without functional TLR2 (C57BL/6-Tyrc-Brd-Tg(Tlr2-luc/gfp)Kri/Gaj; TLR2−/−, C57BL/6-Tlr2tm1Kir), that were investigated by multimodalin vivoandex vivoimaging, combining magnetic resonance and bioluminescence imaging and a variety of functional tests.

Results

An acute neuroinflammatory response was demonstrated following the three days in the basal forebrain of mice, and more chronically in other parts of the frontal cortex. Adaptive changes in specific neurocircuitry were demonstrated, with significant links to agitated (mal)adaptive behaviour under episodes of stress, and an increased ability to gain weight.

Conclusions

Our results suggest that microglial activation and an innate immune response might be the missing link underlying the pathogenesis of well known structural, psychologic and metabolic changes experienced by some patients with OSA.
Different salicylic and jasmonic acids imbalances are involved in the oxidative stress-mediated cell death, induced by fumonisin B1 in maize seedlings with contrasting resistance toFusarium verticillioidesear rot in the field
Authors: Otaiza-González Santiago N. , Mary Verónica S. , Arias Silvina L. , Bertrand Lidwina , Velez Pilar A. , Rodriguez María G. , Rubinstein Héctor R. , Theumer Martín G.
Published: December 2019

Background and aim

Fungal and plant secondary metabolites modulate the plant-pathogen interactions. However, the participation of fumonisins in theFusarium verticillioides-maize pathosystem is unclear. In this work was studied the cell death, and the reactive oxygen species (ROS) - phytohormone imbalance interplay underlying the phytotoxicity of fumonisin B1 (FB1) in maize germplasms with contrasting resistance toFusariumear rot in the field.

Methods

Resistant (RH) and susceptible hybrid (SH) maize seedlings, grown from uninoculated seeds irrigated with FB1 (1 and 20 ppm), were harvested at 7, 14 and 21 days after planting, and were examined for electrolyte leakage (aerial parts); and for oxidative stress biomarkers (aerial parts and roots). The phytohormone (salicylic and jasmonic acids) imbalance interplay underlying the FB1-induced cell death were further explored in seedlings exposed 24 h to the mycotoxin (1 ppm) in hydroponics.

Results

Cell death increased in RH and SH watered with 1 and 20 ppm of mycotoxin, respectively. Both toxin concentrations were pro-oxidant, and the major perturbations were found in roots. An Integrated Biomarker Response index was calculated suggesting that phytotoxicity occurs in a redox context more efficiently controlled by RH.

Conclusion

The pre-treatment with the antioxidant ascorbic acid led to the conclusion that cell death in RH was related to a salicylic acid increase mediated by ROS. Nevertheless, FB1 induced two different phytohormonal regulatory mechanisms mediated by oxidative stress in both maize hybrids.
Molecular dynamics simulation of local structural models of PrPScreveals how codon 129 polymorphism affects propagation of PrPSc
Authors: Otaki Hiroki , Taguchi Yuzuru , Nishida Noriyuki
Published: December 2019

Prions are unconventional pathogen without nucleotide genome and their pathogenic properties are defined by the primary structure and the conformation of the constituent abnormal isoform (PrPSc) of prion protein (PrP). A polymorphic codon 129 of human PrP that is valine (V129) or methionine (M129) is particularly influential on properties of PrPSc, affecting transmission efficiencies and clinicopathological features. However, how the single residue is so influential has not been elucidated because the detailed structures of PrPSchave not been determined yet due to its incompatibility with high-resolution structural analysis. Previously we created an in-register parallel β-sheet local structural model of human PrPScencompassing residues 107 to 143 that seemed more compatible with V129 than M129, based on knowledge from α-synuclein amyloids and an NMR-based model of the amyloid of Y145Stop mutant of PrP in the literature. Here, we created an M129-compatible local structural model of PrPSc. Severe destabilization of the model by G127V mutation was consistent with the protective effects of V127 polymorphism of human PrP against prions. It was highly sensitive to the length of the hydrophobic side chain of codon 129 and replacement of M129 with leucine or valine destabilized the structures. Interestingly, the U-shaped β-arch which comprises M129 flexibly changed hydrophobic interaction networks inside the β-arch depending on the interactions with the surrounding structures, whereas the previous model with V129 maintained the similar network patterns irrespective of the surroundings. The differences between the two models may explain influences of the codon 129 polymorphism on transmissions and properties of human prions.
Clamping, bending, and twisting inter-domain motions in the misfold-recognising portion of UDP-glucose:glycoprotein glucosyl-transferase
Authors: Modenutti Carlos P. , Blanco Capurro Juan I. , Ibba Roberta , Vasiljević Snežana , Hensen Mario , Alonzi Dominic S. , Chandran Anu V. , Hill Johan C. , Rushton Jonathan , Kumar Abhinav , Rubichi Simone , Lia Andrea , Tax Gábor , Marti Lucia , Santino Angelo , Martí Marcelo A. , Zitzmann Nicole , Roversi Pietro
Published: December 2019

UDP-glucose:glycoprotein glucosyltransferase (UGGT) is the only known glycoprotein folding quality control checkpoint in the eukaryotic glycoprotein secretory pathway. When the enzyme detects a misfolded glycoprotein in the Endoplasmic Reticulum (ER), it dispatches it for ER retention by re-glucosylating it on one of its N-linked glycans. Recent crystal structures of a fungal UGGT have suggested the enzyme is conformationally mobile. Here, a negative stain electron microscopy reconstruction of UGGT in complex with a monoclonal antibody confirms that the misfold-sensing N-terminal portion of UGGT and its C-terminal catalytic domain are tightly associated. Molecular Dynamics (MD) simulations capture UGGT in so far unobserved conformational states, giving new insights into the molecule’s flexibility. Principal component analysis of the MD trajectories affords a description of UGGT’s overall inter-domain motions, highlighting three types of inter-domain movements: bending, twisting and clamping. These inter-domain motions modify the accessible surface area of the enzyme’s central saddle, likely enabling the protein to recognize and re-glucosylate substrates of different sizes and shapes, and/or re-glucosylate N-linked glycans situated at variable distances from the site of misfold. We propose to name “Parodi limit” the maximum distance between a site of misfolding on a UGGT glycoprotein substrate and an N-linked glycan that monomeric UGGT can re-glucosylate on the same glycoprotein. MD simulations estimate the Parodi limit to be around 60-70 Å. Re-glucosylation assays using UGGT deletion mutants suggest that the TRXL2 domain is necessary for activity against urea-misfolded bovine thyroglobulin. Taken together, our findings support a “one-size-fits-all adjustable spanner” substrate recognition model, with a crucial role for the TRXL2 domain in the recruitment of misfolded substrates to the enzyme’s active site.
Identifying groups of people with similar sociobehavioural characteristics in Malawi to inform HIV interventions: a Latent Class Analysis
Authors: Merzouki Aziza , Styles Amanda , Estill Janne , Baranczuk Zofia , Petrie Karen , Keiser Olivia
Published: December 2019

Background

Within many sub-Saharan African countries including Malawi, HIV prevalence varies widely between regions. This variability may be related to the distribution of population groups with specific sociobehavioural characteristics that influence the transmission of HIV and the uptake of prevention. In this study, we intended to identify groups of people in Malawi with similar risk profiles.

Methods

We used data from the Demographic and Health Survey in Malawi from 2016, and stratified the analysis by sex. We considered demographic, socio-behavioural and HIV-related variables. Using Latent Class Analysis (LCA), we identified clusters of people sharing common sociobehavioural characteristics. The optimal number of clusters was selected based on the Bayesian information criterion. We compared the proportions of individuals belonging to the different clusters across the three regions and 28 districts of Malawi.

Results

We found nine clusters of women and six clusters of men. Most women in the clusters with highest risk of being HIV infected were living in female-headed households and were formerly married or in a union. Among men, older men had the highest risk of being HIV infected, followed by young (20-25) single men. Generally, low HIV testing uptake correlated with lower risk of having HIV. However, rural adolescent girls had a low probability of being tested (48.7%) despite a relatively high HIV prevalence. Urban districts and Southern region had a higher percentage of high-prevalence and less tested clusters of individuals than other areas.

Conclusions

LCA is an efficient method to find clusters of people sharing common HIV risk profiles, identify particularly vulnerable population groups, and plan targeted interventions focusing on these groups. Tailored support, prevention and HIV testing programmes should focus particularly on female household heads, adolescent girls living in rural areas, older married men, and young men who have never been married.

Funding

The project was funded by the Swiss National Science Foundation (grant no 163878).