bluuebunny/crossref_metadata_2025 huggingface dataset:
Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14
Authors: Liu Bin , Zhang Zhijian , Hu Yanyun , Lu Yan , Li Duanzhuo , Liu Jie , Liao Shengjie , Hu Min , Wang Yuxing , Zhang Die , Chen Yulu , Qian Qilan , Lv Xianfeng , Wu Duojiao , Tan Minjia , Hu Cheng , Xiong Xuelian , Li Xiaoying
Published: October 2019

Endoplasmic reticulum (ER) stress plays an important role in metabolic diseases like obesity and type 2 diabetes mellitus (T2DM), although the underlying mechanisms and regulatory pathways remain to be elucidated. Here, we induced chronic low-grade ER stress in lean mice to levels similar to those in high-fat diet (HFD)–fed obese mice and found that it promoted hyperglycemia due to enhanced hepatic gluconeogenesis. Mechanistically, sustained ER stress up-regulated the deubiquitinating enzyme ubiquitin-specific peptidase 14 (USP14), which increased the stability and levels of 3′,5′-cyclic monophosphate–responsive element binding (CREB) protein (CBP) to enhance glucagon action and hepatic gluconeogenesis. Exogenous overexpression of USP14 in the liver significantly increased hepatic glucose output. Consistent with this, liver-specific knockdown of USP14 abrogated the effects of ER stress on glucose metabolism, and also improved hyperglycemia and glucose intolerance in obese mice. In conclusion, our findings show a mechanism underlying ER stress-induced disruption of glucose homeostasis, and present USP14 as a potential therapeutic target against T2DM.
Controlling silk fibroin conformation for dynamic, responsive, multifunctional, micropatterned surfaces
Authors: Wang Yu , Kim Beom Joon , Peng Berney , Li Wenyi , Wang Yuqi , Li Meng , Omenetto Fiorenzo G.
Published: October 2019

Significance

Silk polymorphism is used to generate composite materials that can wrinkle reversibly and in complex patterns. This is achieved by leveraging and controlling the ability of structural proteins to change their conformation and their stimulus-responsive behavior to offer a different approach to micro/nanopatterning of dynamic, multifunctional biocompatible interfaces. The results show the ability to reshape protein films on the nano- and microscale on demand and generate functional protein surfaces with tunable topography opening possibilities in programmable biomaterial-based interfaces.
A small-molecule inhibitor of BamA impervious to efflux and the outer membrane permeability barrier
Authors: Hart Elizabeth M. , Mitchell Angela M. , Konovalova Anna , Grabowicz Marcin , Sheng Jessica , Han Xiaoqing , Rodriguez-Rivera Frances P. , Schwaid Adam G. , Malinverni Juliana C. , Balibar Carl J. , Bodea Smaranda , Si Qian , Wang Hao , Homsher Michelle F. , Painter Ronald E. , Ogawa Anthony K. , Sutterlin Holly , Roemer Terry , Black Todd A. , Rothman Deborah M. , Walker Scott S. , Silhavy Thomas J.
Published: October 2019

Significance

The spread of multidrug-resistant infections demands antibiotic development. Although new antibiotics targeting gram-positive bacteria have been developed, it has been more than 50 y since a new class of antibiotics targeting gram-negative bacteria has been approved for clinical use. The strong outer membrane permeability barrier makes it difficult for compounds to reach intracellular targets, contributing greatly to the lack of new antibiotics targeting this class of microbes. Here, we describe a compound, MRL-494, that inhibits the assembly of proteins into the outer membrane by targeting an essential member of β-barrel assembly machine. This compound appears to act at the cell surface, avoiding both the outer membrane permeability barrier and the action of multidrug-resistance efflux pumps.
Distinct Laminar Requirements for NMDA Receptors in Experience-Dependent Visual Cortical Plasticity
Authors: Fong Ming-fai , Finnie Peter Sb , Kim Taekeun , Thomazeau Aurore , Kaplan Eitan S , Cooke Samuel F , Bear Mark F
Published: October 2019

Primary visual cortex (V1) is the locus of numerous forms of experience-dependent plasticity. Restricting visual stimulation to one eye at a time has revealed that many such forms of plasticity are eye-specific, indicating that synaptic modification occurs prior to binocular integration of thalamocortical inputs. A common feature of these forms of plasticity is the requirement for NMDA receptor (NMDAR) activation in V1. We therefore hypothesized that NMDARs in cortical layer 4 (L4), which receives the densest thalamocortical input, would be necessary for all forms of NMDAR-dependent and input-specific V1 plasticity. We tested this hypothesis in awake mice using a genetic approach to selectively delete NMDARs from L4 principal cells. We found, unexpectedly, that both stimulus-selective response potentiation and potentiation of open-eye responses following monocular deprivation (MD) persist in the absence of L4 NMDARs. In contrast, MD-driven depression of deprived-eye responses was impaired in mice lacking L4 NMDARs, as was L4 long-term depression in V1 slices. Our findings reveal a crucial requirement for L4 NMDARs in visual cortical synaptic depression, and a surprisingly negligible role for them in cortical response potentiation. These results demonstrate that NMDARs within distinct cellular subpopulations support different forms of experience-dependent plasticity.
Magnetic-Dispersive Solid Phase Extraction Based on Graphene Oxide–Fe3O4 Nanocomposites Followed by High Performance Liquid Chromatography-Fluorescence for the Preconcentration and Determination of Terazosin Hydrochloride in Human Plasma
Authors: Pashaei Yaser , Daraei Bahram , Shekarchi Maryam
Published: October 2019

In the present study, a facile modified impregnation method was employed to synthesize superparamagnetic graphene oxide–Fe3O4 (GO–Fe3O4) nanocomposites. Based on the GO–Fe3O4 as adsorbent, a simple and fast magnetic-dispersive solid phase extraction followed by high performance liquid chromatography with fluorescence detection (M-dSPE–HPLC–FL) method was established and validated for the preconcentration and determination of terazosin hydrochloride (TRZ) in human plasma samples. The obtained nanomaterials were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy and vibrating sample magnetometry. Different parameters affecting the extraction efficiency, such as sample pH, amount of sorbent, extraction time, elution solvent and its volume and desorption time, were evaluated and optimized. The linearity of the proposed method was excellent over the range 0.3–50.0 ng mL−1 with an acceptable coefficient of determination (R2 = 0.9989). The limit of quantification and limit of detection were found to be 0.3 and 0.09 ng mL−1, respectively, and the preconcentration factor of 10 was achieved. Intra- and inter-day precision expressed as relative standard deviation (RSD %, n = 6) were between 2.2–3.8% and 4.7–6.4%, respectively. Accuracy, estimated by recovery assays, was 97.7–106.6% with RSD ≤ 5.2%. Ultimately, the applicability of the method was successfully confirmed by the extraction and determination of TRZ in human plasma samples.
A High-Performance Liquid Chromatographic Method for the Determination of Meropenem in Serum
Authors: Dincel Demet , Sagirli Olcay , Topcu Gulacti
Published: October 2019

In this study, a new, sensitive and selective high-performance liquid chromatographic method was developed for the determination of meropenem (MEM) in human serum. In the developed method, C18 column (3.9 × 150 mm, 5 μm) was selected as stationary phase at 30°C, and methanol: acetic acid solution mixture was used as mobile phase with gradient program. Chromatographic separation was carried out at a flow rate of 1 mL/min, and detection was performed at 300 nm with diode array detector. Doripenem was selected as an internal standard, and the analytes were extracted from serum using protein precipitation method with ortho-phosphoric acid: methanol. Detection wavelength was selected as 300 nm. The developed method was validated according to International Council for Harmonisation (ICH) guidelines. The calibration curve was linear over a concentration range of 4–240 μg/mL with correlation coefficient of 0.9985. The limit of detection and limit of quantification values were found as 0.057 and 0.192 μg/mL, respectively. The validated method was successfully applied for the determination of MEM in human serum samples collected from patient volunteers at different time intervals, and therapeutic drug monitoring of MEM has been investigated.
Detection of Anti-CagA Antibodies in Sera of Helicobacter pylori-Infected Patients Using an Immunochromatographic Test Strip
Authors: Karakus Cebrail , Ulupinar Zeynep , Akbas Fahri , Yazici Duygu
Published: October 2019

The cagA gene of Helicobacter pylori that encodes an immunodominant CagA protein provokes severe mucosal damage and acts as a risk factor for the development of peptic ulcer disease and gastric cancer. Our aim is to develop an immunochromatographic test strip (ICTS) using our previously developed recombinant CagA (rCagA) protein and anti-rCagA monoclonal antibody (Mab) for the detection of anti-CagA antibodies in sera of infected patients. The rCagA was firstly conjugated to gold nanoparticle and placed into the conjugate pad. A nonconjugated rCagA and anti-rCagA Mab (CK-02) were immobilized on the test line and control line, respectively. Biopsy and serum samples from 30 H. pylori-infected patients were used. The presence of cagA gene in biopsy samples was first detected by PCR (Polymerase Chain Reaction), and 22 patients were found positive while 8 were negative. When serum samples were tested by our developed ICTS, 21 were positive for anti-CagA antibodies while 9 were negative. The serum samples were also tested by a commercial ELISA (Enzyme Linked Immunosorbent Assay), and when compared to the ICTS a sensitivity of 95% and a specificity of 100% were obtained. The ICTS can be used for rapid detection of CagA-positive H. pylori infection instead of expensive, time consuming and laborious invasive approaches.
Network depth: identifying median and contours in complex networks
Authors: Bertagnolli Giulia , Agostinelli Claudio , De Domenico Manlio
Published: October 2019

Centrality descriptors are widely used to rank nodes according to specific concept(s) of importance. Despite the large number of centrality measures available nowadays, it is still poorly understood how to identify the node which can be considered as the ‘centre’ of a complex network. In fact, this problem corresponds to finding the median of a complex network. The median is a non-parametric—or better, distribution-free—and robust estimator of the location parameter of a probability distribution. In this work, we present the statistical and most natural generalization of the concept of median to the realm of complex networks, discussing its advantages for defining the centre of the system and percentiles around that centre. To this aim, we introduce a new statistical data depth and we apply it to networks embedded in a geometric space induced by different metrics. The application of our framework to empirical networks allows us to identify central nodes which are socially or biologically relevant.
Benefits and challenges of Big Data in healthcare: an overview of the European initiatives
Authors: Pastorino Roberta , De Vito Corrado , Migliara Giuseppe , Glocker Katrin , Binenbaum Ilona , Ricciardi Walter , Boccia Stefania
Published: October 2019

Healthcare systems around the world are facing incredible challenges due to the ageing population and the related disability, and the increasing use of technologies and citizen’s expectations. Improving health outcomes while containing costs acts as a stumbling block. In this context, Big Data can help healthcare providers meet these goals in unprecedented ways. The potential of Big Data in healthcare relies on the ability to detect patterns and to turn high volumes of data into actionable knowledge for precision medicine and decision makers. In several contexts, the use of Big Data in healthcare is already offering solutions for the improvement of patient care and the generation of value in healthcare organizations. This approach requires, however, that all the relevant stakeholders collaborate and adapt the design and performance of their systems. They must build the technological infrastructure to house and converge the massive volume of healthcare data, and to invest in the human capital to guide citizens into this new frontier of human health and well-being. The present work reports an overview of best practice initiatives in Europe related to Big Data analytics in public health and oncology sectors, aimed to generate new knowledge, improve clinical care and streamline public health surveillance.
Implementation of the adverse childhood experiences conversation in primary care
Authors: Bodendorfer Victoria , Koball Afton M , Rasmussen Cary , Klevan Judy , Ramirez Luis , Olson-Dorff Denyse
Published: October 2019

Background

Research has focused on screening for adverse childhood experiences, rather than provision of education as a part of routine anticipatory guidance. An adverse childhood experiences ‘conversation’ is one method that has not been studied empirically but represents a complimentary or alternative approach to screening which could overcome many existing barriers.

Objectives

This study aims to examine parent/guardian and provider acceptability/feasibility of the adverse childhood experiences conversation during well-child visits in primary care.

Methods

Providers engaged in a conversation with parents/guardians of patients during well-child visits in a family medicine residency clinic. Parents/guardians and providers were surveyed following the visit to examine acceptability and feasibility. Quarterly assessments to further examine provider perspectives were completed. Data were collected for 1 year.

Results

In total, 238 parent/guardian and 231 provider surveys were completed. Most parents/guardians felt positively (76%) about and comfortable (81%) with the information discussed and 97% felt that the conversation should be had with their primary care provider specifically. Most providers (71%) indicated that parents/guardians were receptive to the conversation, that the conversations took 1–2 minutes (60%) and that there were few disclosures of adversity (9%), none of which required mandatory reporting.

Conclusions

Results suggest that the adverse childhood experiences conversation is well received by parents/guardians and providers and is feasible to implement into primary care. The conversation could be used as a complimentary or alternative method to screening to further spread knowledge of toxic stress and health, provide resources for families and promote resilience.
Total Variation Distance Estimates via L2-Norm for Polynomials in Log-concave Random Vectors
Authors: Kosov Egor D
Published: October 2019

This paper provides an estimate of the total variation distance between distributions of polynomials defined on a space equipped with a logarithmically concave measure in terms of the $L^2$-distance between these polynomials.
Discordance in the Epithelial Cell-Dendritic Cell Major Histocompatibility Complex Class II Immunoproteome: Implications for Chlamydia Vaccine Development
Authors: Karunakaran Karuna P , Yu Hong , Jiang Xiaozhou , Chan Queenie W T , Foster Leonard J , Johnson Raymond M , Brunham Robert C
Published: October 2019

Background

Chlamydia trachomatis and Chlamydia muridarum are intracellular bacterial pathogens of mucosal epithelial cells. CD4 T cells and major histocompatibility complex (MHC) class II molecules are essential for protective immunity against them. Antigens presented by dendritic cells (DCs) expand naive pathogen-specific T cells (inductive phase), whereas antigens presented by epithelial cells identify infected epithelial cells as targets during the effector phase. We previously showed that DCs infected by C trachomatis or C muridarum present epitopes from a limited spectrum of chlamydial proteins recognized by Chlamydia-specific CD4 T cells from immune mice.

Methods

We hypothesized that Chlamydia-infected DCs and epithelial cells present overlapping sets of Chlamydia-MHC class II epitopes to link inductive and effector phases to generate protective immunity. We tested that hypothesis by infecting an oviductal epithelial cell line with C muridarum, followed by immunoaffinity isolation and sequencing of MHC class I- and II-bound peptides.

Results

We identified 26 class I-bound and 4 class II-bound Chlamydia-derived peptides from infected epithelial cells. We were surprised to find that none of the epithelial cell class I- and class II-bound chlamydial peptides overlapped with peptides presented by DCs.

Conclusions

We suggest the discordance between the DC and epithelial cell immunoproteomes has implications for delayed clearance of Chlamydia and design of a Chlamydia vaccine.
A novel mechanism-based pharmacokinetic–pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against β-lactamase-producing Gram-negative bacteria
Authors: Kristoffersson Anders N , Bissantz Caterina , Okujava Rusudan , Haldimann Andreas , Walter Isabelle , Shi Tianlai , Zampaloni Claudia , Nielsen Elisabet I
Published: October 2019

Background

Diazabicyclooctanes (DBOs) are an increasingly important group of non β-lactam β-lactamase inhibitors, employed clinically in combinations such as ceftazidime/avibactam. The dose finding of such combinations is complicated using the traditional pharmacokinetic/pharmacodynamic (PK/PD) index approach, especially if the β-lactamase inhibitor has an antibiotic effect of its own.

Objectives

To develop a novel mechanism-based pharmacokinetic–pharmacodynamic (PKPD) model for ceftazidime/avibactam against Gram-negative pathogens, with the potential for combination dosage simulation.

Methods

Four β-lactamase-producing Enterobacteriaceae, covering Ambler classes A, B and D, were exposed to ceftazidime and avibactam, alone and in combination, in static time–kill experiments. A PKPD model was developed and evaluated using internal and external evaluation, and combined with a population PK model and applied in dosage simulations.

Results

The developed PKPD model included the effects of ceftazidime alone, avibactam alone and an ‘enhancer’ effect of avibactam on ceftazidime in addition to the β-lactamase inhibitory effect of avibactam. The model could describe an extensive external Pseudomonas aeruginosa data set with minor modifications to the enhancer effect, and the utility of the model for clinical dosage simulation was demonstrated by investigating the influence of the addition of avibactam.

Conclusions

A novel mechanism-based PKPD model for the DBO/β-lactam combination ceftazidime/avibactam was developed that enables future comparison of the effect of avibactam with other DBO/β-lactam inhibitors in simulations, and may be an aid in translating PKPD results from in vitro to animals and humans.
Bayesian clinical decision support-guided versus clinician-guided vancomycin dosing in attainment of targeted pharmacokinetic parameters in a paediatric population
Authors: Hughes David M , Goswami Srijib , Keizer Ron J , Hughes Maria-Stephanie A , Faldasz Jonathan D
Published: October 2019

Objectives

To compare a Bayesian clinical decision support (CDS) dose-optimizing software program with clinician judgement in individualizing vancomycin dosing regimens to achieve vancomycin pharmacokinetic (PK)/pharmacodynamic (PD) targets in a paediatric population.

Methods

A retrospective review combined with a model-based simulation of vancomycin dosing was performed on children aged 1 year to 18 years at the University of California, San Francisco Benioff Children’s Hospital Mission Bay. Dosing regimens recommended by the clinical pharmacists, ‘clinician-guided’, were compared with alternative ‘CDS-guided’ dosing regimens. The primary outcome was the percentage of occasions predicted to achieve steady-state trough levels within the target range of 10–15 mg/L, with a secondary outcome of predicted attainment of AUC24 ≥400 mg·h/L. Statistical comparison between approaches was performed using a standard t-test.

Results

A total of n = 144 patient occasions were included. CDS-guided regimens were predicted to achieve vancomycin steady-state troughs in the target range on 70.8% (102/144) of occasions, as compared with 37.5% (54/144) in the clinician-guided arm (P < 0.0001). An AUC24 of ≥400 mg·h/L was achieved on 93% (112/121) of occasions in the CDS-guided arm versus 72% (87/121) of occasions in the clinician-guided arm (P < 0.0001).

Conclusions

In a simulated analysis, the use of a Bayesian CDS tool was better than clinician judgement in recommending vancomycin dosing regimens in which PK/PD targets would be attained in children.
Best practices for data visualization: creating and evaluating a report for an evidence-based fall prevention program
Authors: Khasnabish Srijesa , Burns Zoe , Couch Madeline , Mullin Mary , Newmark Randall , Dykes Patricia C
Published: October 2019

This case report applied principles from the data visualization (DV) literature and feedback from nurses to develop an effective report to display adherence with an evidence-based fall prevention program. We tested the usability of the original and revised reports using a Health Information Technology Usability Evaluation Scale (Health-ITUES) customized for this project. Items were rated on a 5-point Likert scale, strongly disagree (1) to strongly agree (5). The literature emphasized that the ideal display maximizes the information communicated, minimizes the cognitive efforts involved with interpretation, and selects the correct type of display (eg, bar versus line graph). Semi-structured nurse interviews emphasized the value of simplified reports and meaningful data. The mean (standard deviation [SD]) Health-ITUES score for the original report was 3.86 (0.19) and increased to 4.29 (0.11) in the revised report (Mann Whitney U Test, z = −12.25, P < 0.001). Lessons learned from this study can inform report development for clinicians in implementation science.
Thymic epithelial tumor treatment in Japan: analysis of hospital cancer registry and insurance claims data, 2012–2014
Authors: Kanemura Hiroaki , Tamura Tomohide , Nishimura Naoki , Kobayashi Daiki , Higashi Takahiro
Published: October 2019

Introduction

Thymic epithelial tumors are a rare type of neoplasm. Accordingly, it is difficult to perform phase III trials in patients with thymic epithelial tumors, and thus, no standard treatment has been established for these tumors. In this study, we aimed to investigate the current status of thymic epithelial tumor treatment in Japan.

Methods

This retrospective observational study enrolled patients with thymic epithelial tumor whose data were recorded in a nationwide Hospital-based Cancer Registry that was linked with health insurance claims data for the registered patients between 2012 and 2014. The patients’ treatment details were obtained from a health insurance claims database.

Results

A total of 813 patients with thymoma and 547 with thymic carcinoma were included in the analysis. Overall, 549 (67.5%) thymoma patients underwent surgical resection alone. Among patients with thymic carcinoma, 230 (42.0%) underwent initial surgery, and 124 (53.9%) received subsequent radiotherapy and chemotherapy. Chemotherapy regimens varied across the hospitals; overall, 21 and 22 regimens were used to treat thymoma and thymic carcinoma, respectively. Platinum-based combination regimens were predominantly selected for both diseases.

Conclusions

This study revealed the real-world patterns of thymic epithelial tumor treatment in Japan. Although the nature of this study did not enable the determination of optimal treatment strategies, the simultaneous analysis of nationwide registry, insurance, efficacy and prognostic data may contribute to the establishment of a standard treatment strategy for rarely occurring cancers such as thymic epithelial tumor.
Prevalence of zoonotic Bartonella among prairie rodents in Illinois
Authors: Beckmann Sean , Engelbrecht Malcolm , Chavez Fernanda , Rojas Gissel
Published: October 2019

Bartonella is a genus of gram-negative bacteria that includes a variety of human and veterinary pathogens. These pathogens are transmitted from reservoirs to secondary hosts through the bite of arthropod vectors including lice and fleas. Once in the secondary host, the bacteria cause a variety of pathologies including cat-scratch disease, endocarditis, and myocarditis. Reservoirs of these bacteria are numerous and include several species of large mammals, mesocarnivores, and small mammals. Research on reservoirs of these bacteria has focused on western North America, Europe, and Asia, with little focus on the eastern and central United States. We assessed the prevalence of zoonotic Bartonella species among prairie-dwelling rodent species in the midwestern United States. Tissue samples (n = 700) were collected between 2015 and 2017 from five rodent species and screened for the presence of Bartonella DNA via PCR and sequencing of two loci using Bartonella-specific primers. Bartonella were prevalent among all five species, with 13-lined ground squirrels (Ictidomys tridecemlineatus) serving as a likely reservoir of the pathogen B. washoensis, and other rodents serving as reservoirs of the pathogens B. grahamii and B. vinsonii subsp. arupensis. These results demonstrate the value of studies of disease ecology in grassland systems, particularly in the context of habitat restoration and human–vector interactions.
Evaluation of a New Clinical Endpoint for Moderate to Severe Influenza Disease in Children: A Prospective Cohort Study
Authors: Rao Suchitra , Yanni Emad , Moss Angela , Lamb Molly M , Schuind Anne , Bekkat-Berkani Rafik , Innis Bruce L , Cotter Jillian , Mistry Rakesh D , Asturias Edwin J
Published: October 2019

Background

A moderate to severe (M/S) influenza clinical endpoint has been proposed in children, defined as fever >39°C, otitis media, lower respiratory tract infection, or serious extrapulmonary manifestations. The objective of the study was to evaluate the M/S measure against clinically relevant outcomes including hospitalization, emergency room visits, antimicrobial use, and child/parental absenteeism.

Methods

We conducted a prospective observational study of children aged 6 months–8 years at the Children’s Hospital Colorado emergency department (ED) and urgent care site during 2016–2017 and 2017–2018. Children with influenza-like illness (ILI) underwent influenza testing by polymerase chain reaction (PCR); children who tested positive and a subset of matched test-negative controls underwent follow-up at 2 weeks. The primary outcome was the proportion of children who were hospitalized. Secondary outcomes included recurrent ED visits, antimicrobial use, hospital charges, and child/parental absenteeism within 14 days.

Results

Among 1478 children enrolled with ILI, 411 (28%) tested positive for influenza by PCR. Of children with influenza illness, 313 (76%) met the M/S definition. Children with M/S influenza were younger (3.8 years vs 4.8 years), infected with influenza A (59% vs 44%), and more frequently hospitalized (unadjusted risk difference [RD], 6.3%; 95% confidence interval [CI], 2.1–10.4; P = .03) and treated with antibiotics (unadjusted RD, 13.3%; 95% CI, 4.3–22.4; P < .01) compared to those with mild disease.

Conclusions

Children with M/S influenza have a higher risk of hospitalization and antibiotic use compared with mild disease. This proposed definition may be a useful clinical endpoint to study the public health and clinical impact of influenza interventions in children.

Clinical Trials Registration

NCT02979626.
Gene4Denovo: an integrated database and analytic platform for de novo mutations in humans
Authors: Zhao Guihu , Li Kuokuo , Li Bin , Wang Zheng , Fang Zhenghuan , Wang Xiaomeng , Zhang Yi , Luo Tengfei , Zhou Qiao , Wang Lin , Xie Yali , Wang Yijing , Chen Qian , Xia Lu , Tang Yu , Tang Beisha , Xia Kun , Li Jinchen
Published: October 2019

De novo mutations (DNMs) significantly contribute to sporadic diseases, particularly in neuropsychiatric disorders. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) provide effective methods for detecting DNMs and prioritizing candidate genes. However, it remains a challenge for scientists, clinicians, and biologists to conveniently access and analyse data regarding DNMs and candidate genes from scattered publications. To fill the unmet need, we integrated 580 799 DNMs, including 30 060 coding DNMs detected by WES/WGS from 23 951 individuals across 24 phenotypes and prioritized a list of candidate genes with different degrees of statistical evidence, including 346 genes with false discovery rates <0.05. We then developed a database called Gene4Denovo (http://www.genemed.tech/gene4denovo/), which allowed these genetic data to be conveniently catalogued, searched, browsed, and analysed. In addition, Gene4Denovo integrated data from >60 genomic sources to provide comprehensive variant-level and gene-level annotation and information regarding the DNMs and candidate genes. Furthermore, Gene4Denovo provides end-users with limited bioinformatics skills to analyse their own genetic data, perform comprehensive annotation, and prioritize candidate genes using custom parameters. In conclusion, Gene4Denovo conveniently allows for the accelerated interpretation of DNM pathogenicity and the clinical implication of DNMs in humans.
uS3/Rps3 controls fidelity of translation termination and programmed stop codon readthrough in co-operation with eIF3
Authors: Poncová Kristýna , Wagner Susan , Jansen Myrte Esmeralda , Beznosková Petra , Gunišová Stanislava , Herrmannová Anna , Zeman Jakub , Dong Jinsheng , Valášek Leoš Shivaya
Published: October 2019

Ribosome was long considered as a critical yet passive player in protein synthesis. Only recently the role of its basic components, ribosomal RNAs and proteins, in translational control has begun to emerge. Here we examined function of the small ribosomal protein uS3/Rps3, earlier shown to interact with eukaryotic translation initiation factor eIF3, in termination. We identified two residues in consecutive helices occurring in the mRNA entry pore, whose mutations to the opposite charge either reduced (K108E) or increased (R116D) stop codon readthrough. Whereas the latter increased overall levels of eIF3-containing terminating ribosomes in heavy polysomes in vivo indicating slower termination rates, the former specifically reduced eIF3 amounts in termination complexes. Combining these two mutations with the readthrough-reducing mutations at the extreme C-terminus of the a/Tif32 subunit of eIF3 either suppressed (R116D) or exacerbated (K108E) the readthrough phenotypes, and partially corrected or exacerbated the defects in the composition of termination complexes. In addition, we found that K108 affects efficiency of termination in the termination context-specific manner by promoting incorporation of readthrough-inducing tRNAs. Together with the multiple binding sites that we identified between these two proteins, we suggest that Rps3 and eIF3 closely co-operate to control translation termination and stop codon readthrough.
BacFITBase: a database to assess the relevance of bacterial genes during host infection
Authors: Rendón Javier Macho , Lang Benjamin , Tartaglia Gian Gaetano , Burgas Marc Torrent
Published: October 2019

Bacterial infections have been on the rise world-wide in recent years and have a considerable impact on human well-being in terms of attributable deaths and disability-adjusted life years. Yet many mechanisms underlying bacterial pathogenesis are still poorly understood. Here, we introduce the BacFITBase database for the systematic characterization of bacterial proteins relevant for host infection aimed to enable the identification of new antibiotic targets. BacFITBase is manually curated and contains more than 90 000 entries with information on the contribution of individual genes to bacterial fitness under in vivo infection conditions in a range of host species. The data were collected from 15 different studies in which transposon mutagenesis was performed, including top-priority pathogens such as Acinetobacter baumannii and Campylobacter jejuni, for both of which increasing antibiotic resistance has been reported. Overall, BacFITBase includes information on 15 pathogenic bacteria and 5 host vertebrates across 10 different tissues. It is freely available at www.tartaglialab.com/bacfitbase.
Prenatal Nicotine Exposure in Rodents: Why Are There So Many Variations in Behavioral Outcomes?
Authors: Polli Filip Souza , Kohlmeier Kristi Anne
Published: October 2019

Introduction

The World Health Organization (WHO) reported that smoking cessation rates among women have stagnated in the past decade and estimates that hundreds of millions of women will be smokers in the next decade. Social, environmental, and biological conditions render women more susceptible to nicotine addiction, imposing additional challenges to quit smoking during gestation, which is likely why more than 8% of pregnancies in Europe are associated with smoking. In epidemiological investigations, individuals born from gestational exposure to smoking exhibit a higher risk of development of attention-deficit/hyperactive disorder (ADHD) and liability to drug dependence. Among other teratogenic compounds present in tobacco smoke, nicotine actions during neuronal development could contribute to the observed outcomes as nicotine misleads signaling among progenitor cells during brain development. Several experimental approaches have been developed to address the consequences of prenatal nicotine exposure (PNE) to the brain and behavior but, after four decades of studies, inconsistent data have been reported and the lack of consensus in the field has compromised the hypothesis that gestational nicotine exposure participates in cognitive and emotional behavioral deficits.

Aims

In this review, we discuss the most commonly used PNE models with focus on their advantages and disadvantages, their relative validity, and how the different technical approaches could play a role in the disparate outcomes.

Results

We propose methodological considerations, which could improve the translational significance of the PNE models.

Conclusions

Such alterations might be helpful in reconciling experimental findings, as well as leading to development of treatment targets for maladaptive behaviors in those prenatally exposed.

Implications

In this article, we have reviewed the advantages and disadvantages of different variables of the commonly used experimental models of PNE. We discuss how variations in the nicotine administration methods, the timing of nicotine exposure, nicotine doses, and species employed could contribute to the disparate findings in outcomes for PNE offspring, both in behavior and neuronal changes. In addition, recent findings suggest consideration of epigenetic effects extending across generations. Finally, we have suggested improvements in the available PNE models that could contribute to the enhancement of their validity, which could assist in the reconciliation of experimental findings.
Genomic Epidemiology of Major Extraintestinal Pathogenic Escherichia coli Lineages Causing Urinary Tract Infections in Young Women Across Canada
Authors: Fibke Chad D , Croxen Matthew A , Geum Hyun Min , Glass Magdalena , Wong Eugenia , Avery Brent P , Daignault Danielle , Mulvey Michael R , Reid-Smith Richard J , Parmley E Jane , Portt Andrea , Boerlin Patrick , Manges Amee R
Published: October 2019

Background

A few extraintestinal pathogenic Escherichia coli (ExPEC) multilocus sequence types (STs) cause the majority of community-acquired urinary tract infections (UTIs). We examine the genomic epidemiology of major ExPEC lineages, specifically factors associated with intestinal acquisition.

Methods

A total of 385 women with UTI caused by E. coli across Canada were asked about their diet, travel, and other exposures. Genome sequencing was used to determine both ST and genomic similarity. Logistic regression was used to identify factors associated with the acquisition of and infection with major ExPEC STs relative to minor ExPEC STs.

Results

ST131, ST69, ST73, ST127, and ST95 were responsible for 54% of all UTIs. Seven UTI clusters were identified, but genomes from the ST95, ST127, and ST420 clusters exhibited as few as 3 single nucleotide variations across the entire genome, suggesting recent acquisition. Furthermore, we identified a cluster of UTIs caused by 6 genetically-related ST1193 isolates carrying mutations in gyrA and parC. The acquisition of and infection with ST69, ST95, ST127, and ST131 were all associated with increased travel. The consumption of high-risk foods such as raw meat or vegetables, undercooked eggs, and seafood was associated with acquisition of and infection with ST69, ST127, and ST131, respectively.

Conclusions

Reservoirs may aid in the dissemination of pandemic ExPEC lineages in the community. Identifying ExPEC reservoirs may help prevent future emergence and dissemination of high-risk lineages within the community setting.
The Mitochondrial Respiratory Chain Maintains the Photosynthetic Electron Flow in Arabidopsis thaliana Leaves under High-Light Stress
Authors: Yamada Shoya , Ozaki Hiroshi , Noguchi Ko
Published: October 2019

The plant respiratory chain includes the ATP-coupling cytochrome pathway (CP) and ATP-uncoupling alternative oxidase (AOX). Under high-light (HL) conditions, plants experience photoinhibition, leading to a damaged photosystem II (PSII). The respiratory chain is considered to affect PSII maintenance and photosynthetic electron transport under HL conditions. However, the underlying details remain unclear. In this study, we investigated the respiratory chain functions related to PSII maintenance and photosynthetic electron transport in plants exposed to HL stress. We measured the HL-induced decrease in the maximum quantum yield of PSII in the leaves of wild-type and AOX1a-knockout (aox1a) Arabidopsis thaliana plants in which CP was partially inhibited by a complex-III inhibitor. We also calculated PSII photodamage and repair rate constants. Both rate constants changed when CP was partially inhibited in aox1a plants, suggesting that the respiratory chain is related to both processes. Before HL stress, photosynthetic linear electron flow (LEF) decreased when CP was partially inhibited. After HL stress, aox1a in the presence of the CP inhibitor showed significantly decreased rates of LEF. The electron flow downstream from PSII and on the donor side of photosystem I may have been suppressed. The function of respiratory chain is required to maintain the optimal LEF as well as PSII maintenance especially under the HL stress.
Coverage of HIV testing among pregnant women in Nigeria: progress, challenges and opportunities
Authors: Ajayi Ai , Awopegba Oe , Owolabi Eo , Ajala A
Published: October 2019

Objective

This study assessed the progress, opportunities and challenges in scaling up of HIV testing for pregnant women in Nigeria.

Methods

Data were retrieved from the 2016–2017 fifth multiple cluster survey. Adjusted and unadjusted logistic regression models were used to examine demographic factors associated with HIV testing while controlling for geopolitical zones.

Results

At the population level, the coverage of HIV testing among pregnant women increased by 10% points from 32.8 to 42.7% between 2013 and 2017. Also, the coverage of antenatal HIV testing grew by 20 points, from 50.1 to 70.5% over the period. However, women were still more likely to be tested for HIV during pregnancy if they were older than 24 years [adjusted odds ratio (AOR) 1.33, 95% CI 1.04–1.69], had higher education [AOR 6.94, 95% CI 5.07–9.49], resided in urban areas [AOR 1.26, 95% CI 1.07, 1.50] and belong to richest wealth quintile [AOR 7.43, 95% CI 5.72–9.66].

Conclusion

Our findings suggest that progress has been made in scaling up of antenatal coverage of HIV testing. However, the level of HIV testing during pregnancy remains low and far below the 95% national target. Appropriate interventions are needed in resource-poor communities where antenatal care utilization is very low.
Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization
Authors: Zeng Zhen , Zhang Wanting , Qian Yu , Huang Huijun , Wu David J H , He Zhixing , Ye Ding , Mao Yingying , Wen Chengping
Published: October 2019

Objective

To evaluate the telomere length (TL) in patients with RA relative to that in controls and to test whether TL is causally associated with risk of RA.

Methods

Systematic review and meta-analysis of relevant literature was conducted to evaluate the association between TL and RA. Standardized mean differences with 95% CIs of TL in RA patients relative to controls were pooled using fixed or random-effects models. TL-related single-nucleotide polymorphisms were selected from a genome-wide association study of 37 684 individuals, and summary statistics of RA were obtained from a genome-wide association study meta-analysis including 14 361 RA patients and 43 923 controls. Mendelian randomization was performed using the inverse-variance weighted, weighted-median and likelihood-based methods. Sensitivity analyses were performed to test the robustness of the association.

Results

In the meta-analysis of 911 RA patients and 2498 controls, we found that patients with RA had a significantly shorter TL compared with controls (standardized mean differences = −0.50; 95% CI −0.88, −0.11; P = 0.012). In the Mendelian randomization analysis, we found that genetically predicted longer TL was associated with a reduced risk of RA [odds ratio = 0.68; 95% CI 0.54, 0.86; P = 0.002 using the inverse-variance weighted method]. Sensitivity analyses using alternative Mendelian randomization approaches yielded similar findings, suggesting the robustness of the causal association.

Conclusion

Our study provides evidence for a negative causal association of TL with risk of RA. Further studies are warranted to elucidate the underlying mechanism for the role of telomeres in the development of RA.
Far away, so close! Integrative taxonomy reveals a new genus and species of land flatworm (Platyhelminthes: Geoplanidae) from southern South America
Authors: Negrete Lisandro , Do Amaral Silvana Vargas , Ribeiro Giovana Gamino , Wolmann Gonçalves Juliana , Valiati Victor Hugo , Damborenea Cristina , Brusa Francisco , Leal-Zanchet Ana Maria
Published: October 2019

Land flatworms usually show low ability to disperse and high endemicity, displaying many singletons in studies on land planarian assemblages. Thus, many species have been described based on specimens sampled in a single locality and/or on a few specimens. Based on phylogenetic analyses of concatenated COI and 18S rRNA genes and morphological analyses, a new genus and species of geoplaninid land planarian is described from central–east Argentina and southern Brazil. Winsoria gen. nov. shows, among its most outstanding features, a ventral cephalic retractor muscle and a subneural muscle layer that extends throughout the anterior region of the body. In addition, characters of the reproductive system and the phylogenetic analyses support the erection of this new genus. According to molecular phylogenies,Winsoria bipatria sp. nov. is closely related to species of Luteostriata, Supramontana and Issoca, taxa that also possess a cephalic retractor muscle. Despite its disjunct distribution, phylogenetic analyses, genetic divergence and morphological features show that the allopatric populations studied herein belong to a single species. We argue that the occurrence of W. bipatria in localities separated by hundreds of kilometres and a geographical barrier should be explained by passive dispersal.
Levamisole-induced vasculitis
Authors: George Tonya C. , Freet Daniel J. , Cross James M. , Huzar Todd F.
Published: October 2019

Levamisole is a veterinary antihelminthic, chemotherapeutic agent, and immunomodulator that also is used as an adulterant and cutting agent in cocaine distribution. This drug may potentiate the sympathomimetic actions of cocaine and can cause neutropenia, agranulocytosis, purpuric retiform lesions, and skin necrosis. This article describes two cases of suspected levamisole-induced vasculitis. No standardized diagnostic or treatment algorithm exists for this challenging condition. Diagnosis and treatment require a multidisciplinary team approach.
T-Cell–Rich Recurrence of Primary Cutaneous Follicle Center Lymphoma After Systemic Rituximab: A Diagnostic Pitfall
Authors: Santonja Carlos , Prieto-Torres Lucía , Pérez-Sáenz María de los Ángeles , Requena Luis , Rodríguez-Pinilla Socorro-María
Published: October 2019

We report on a 74-year-old man with a cutaneous B-cell follicle center lymphoma, which was treated upfront with systemic rituximab and suffered several local relapses. The first of the local recurrences, 10 months after completion of treatment, was characterized by a dense T-cell infiltrate that obscured a minor population of B-cell lymphoma cells, suggesting a second primary cutaneous T-cell lymphoma. This represents a previously not reported diagnostic pitfall and underscores the importance of performing sequential biopsies when dealing with lymphoma recurrences in this setting.
Maintaining Quality of Life: Electrochemotherapy for Palliative Periorbital Malignancy
Authors: Ullrich Katja , Bisase Brian , Kumar Siva , Malhotra Raman
Published: October 2019

Electrochemotherapy has been used successfully for treatment of recurrent head and neck skin cancers and skin metastasis. It combines both electroporation and chemotherapy. The authors report 4 patients, who all had metastatic periorbital malignancy. These patients were palliative with widespread metastatic malignancy. All patients had either already had multiple procedures or declined surgical resection and preferred less involved measures. The authors report technique and outcomes. Patient 1: 83-year-old man with recurrent malignant melanoma (MM) nodules (BRAF negative) in the left medial orbit and medial canthal area after rhinectomy and previous resections. Patient 2: 72-year-old man with metastatic MM who developed painful and unsightly metastatic nodules on the right and left forehead and the left medial canthus. Patient 3: 93-year-old man with background of widespread multiple myeloma, considered palliative. He developed a left forehead SCC, apparent as a fungating ulcer, which caused significant pain due to perineural invasion. Patient 4: 91-year-old woman with recurrent metastatic sebaceous cell carcinoma of the left lower eyelid obstructing her vision. All patients experienced an improvement in their pain and quality of life. None of the patients developed any significant periorbital inflammation or adverse complications. Electrochemotherapy may be a useful palliative treatment for periorbital tumors. It improves pain and reduces tumor volume. It can be considered for tumors where palliative radiotherapy may be contraindicated.

Electrochemotherapy is a useful palliative treatment for metastases to the periorbital area, improving pain and size of the tumors.
Chronic, Symptomatic Orbital Inflammation Resulting From Retained Bone Wax
Authors: Thangamathesvaran Loka , Mirani Neena , Turbin Roger , Langer Paul D.
Published: October 2019

A 58-year-old man presented with a 9-month history of a chronically draining surgical wound and low-grade periorbital inflammation following a right lateral orbitotomy. Imaging of the right orbit revealed a peculiar lesion in the right lateral orbit that was hypointense on both T1- and T2-weighted MRI with peripheral enhancement. Exploratory orbitotomy and biopsy established the diagnosis of a chronic foreign body inflammatory reaction to bone wax; symptoms resolved following evacuation of the retained foreign material.

A 58-year-old man developed a chronic, symptomatic, inflammatory reaction to bone wax following a lateral orbitotomy; only once previously has symptomatic orbital inflammation following orbital surgery as a result of bone wax been reported.