bluuebunny/crossref_metadata_2025 huggingface dataset:
Autoimmune hepatitis in patients with human immunodeficiency virus infection
Authors: Mubder Mohamad , Azab Mohamed , Jayaraj Mahendran , Cross Chad , Lankarani Daisy , Dhindsa Banreet , Pan Jen-Jung , Ohning Gordon
Published: September 2019

Background:

Liver disease in patients with HIV is common and typically has complex and multifactorial presentations that represent a major cause of morbidity and mortality. Autoimmune hepatitis (AIH) is rarely reported in patient with HIV and the disease course and clinical outcomes for treatment have not been well characterized. We are aiming to determine the patient characteristics, disease prevalence, and treatment outcomes from published articles of patients with HIV and AIH.

Method:

A systematic search of PubMed, Web of Science, and Google Scholar through February 20th, 2019 identified 15 studies that reported the outcomes of AIH in patients with HIV. Because of the small sample sizes and skewed distributions, resampling tests of mean differences using permutation distributions (MAXn = 10,000 permutations) were utilized; analyses were performed using R (v. 3.5.1). Categorical differences were calculated using Fisher exact test for odds ratio = 1 (equal odds), and Cramer V was calculated for effect size; analyses were completed in SPSS (v. 25).

Results:

By reviewing 15 studies reporting a total of 35 patients with AIH and HIV, male patients were found to have significantly higher aspartate transaminase and alanine transaminase levels at time of diagnosis. No other significant findings identified. The CD4 count and viral load did not show significant correlation with AIH diagnosis or its prognosis. All patients but one who presented with severe immune deficiency and responded to highly active anti-retroviral therapy received immunosuppressive treatment without side effects and achieved remission except 2 lost to follow-up and 3 expired.

Conclusion:

Although rare, but AIH can develop in patients with HIV and physicians should consider it in the differential diagnosis for HIV patients presented with abnormal liver function tests, especially after excluding hepatitis C virus and drug-induced liver injury.

Patients with immune deficiency disorders who present with AIH can be treated safely with steroid either as monotherapy or in combination with another immune suppressant therapy.
Using weighted gene co-expression network analysis to identify key modules and hub genes in tongue squamous cell carcinoma
Authors: Yin Ke , Zhang Ying , Zhang Suxin , Bao Yang , Guo Jie , Zhang Guanhua , Li Tianke
Published: September 2019

Background:

Tongue squamous cell carcinoma (TSCC) is one of the most common malignant tumors in head and neck, but its molecular mechanism is not clear.

Methods:

Weighted gene co-expression network analysis (WGCNA) combining with gene differential expression analysis, survival analysis to screen key modules and hub genes related to the progress of TSCC. Gene Set Enrichment Analysis (GSEA) was used to identify biological pathways that might be involved.

Results:

Weighted gene co-expression network was constructed based on dataset GSE34105. The blue module and turquoise module most related to the progress of TSCC were identified by the network. Gene Ontology (GO) enrichment analysis showed that 2 key modules were significantly enriched in apoptosis and immunity related biological processes and pathway. Network topology analysis, gene difference analysis and survival analysis were used to screen 9 hub genes (NOC2L, AIMP2, ANXA2, DIABLO, H2AFZ, MANBAL, PRDX6, SNX14, TIMM23). The expression of hub genes was significantly correlated with the prognosis of TSCC. GSEA showed that the high expression group of hub genes was mainly enriched in olfactory transduction, neuroactive ligand receptor interaction, nicotinate and nicotinamide metabolism, and the low expression group was mainly enriched in base excision repair, cysteine and methionine metabolism, oxidative phosphorylation.

Conclusion:

Two key modules and 9 hub genes screened by WGCNA were closely related to the occurrence and prognosis of TSCC. Hub genes can be used as biomarkers and potential therapeutic targets for the accurate diagnosis and treatment of TSCC in the future.
Efficacy of Shexiang Baoxin Pills for the treatment of unstable angina pectoris
Authors: Chen Huadong , Dong Qianqian , Zheng Xiang
Published: September 2019

Background:

Shexiang Baoxin Pills (SBP) is widely used for the treatment of unstable angina pectoris (UAP) in China. However, the clinical evidence on the efficacy of SBP for the treatment of UAP is not well concluded.

Methods:

Seven electronic databases will be searched for eligible studies: MEDLINE, EMBASE, The Cochrane Library, Wanfang database, Chinese National Knowledge Infrastructure database, VIP database, and Chinese Biological and Medicine database. Data of included studies will be extracted, and quality will be evaluated. Data synthesis will be performed using RevMan software. Subgroup analysis and sensitivity analysis will also be carried out. Publication bias will be evaluated using funnel plot if included studies are sufficient.

Results:

This systemic review and meta-analysis will provide synthesized result of clinical efficacy of SBP for the treatment of UAP.

Conclusions:

This systemic review and meta-analysis will provide high-quality evidence on the clinical efficacy of SBP for the treatment of UAP.

Registration:

PEROSPERO CRD42019124668
Pediatric gastroenteropancreatic neuroendocrine tumor
Authors: Gaiani Federica , de’Angelis Nicola , Minelli Roberta , Kayali Stefano , Carra Maria Clotilde , de’Angelis Gian Luigi
Published: September 2019

Introduction:

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of epithelial neoplasms originating from the diffuse neuroendocrine cell system of the gastrointestinal tract and pancreas. They are very rare, especially in pediatric age, and vary widely in terms of clinical presentation, malignant potential, and prognosis.

Patient concerns:

A 9 years’ old, white female child presented with abdominal pain and diarrhea mixed with bright red blood lasting 2 days followed by hematemesis.

Diagnosis:

Routine laboratory tests revealed microcytic anemia. Upper endoscopy showed a 20-mm polypoid lesion in the posterior wall of the duodenal bulb. Biopsy specimens were taken and histologic analysis showed a well-differentiated neuroendocrine tumor G1, with a ki-67 index <2%, an expression of chromogranine A (CgA), synaptophysin and somatostatin receptor type 2A (SSTR2A). Endoscopic ultrasound showed a 21-mm hypoechoic, hypervascular lesion involving the mucosal, submucosal, and muscular layers and a 15-mm hypoechoic round periduodenal lymph node. Gallium-68-somatostatin receptor positron emission tomography (PET with Ga-DOTATOC) showed one area of tracer uptake in the duodenum and other one near the duodenum compatible with the primary tumor site and a lymph node respectively. All the tests confirmed the diagnosis of a GEP-NET of the duodenal bulb, with a single lymph-node metastasis.

Interventions:

The patient underwent an open duodenal wedge resection.

Outcomes:

The follow-up at 6, 24, and 36 months and then yearly after surgery for a total of 42 months showed no evidence of recurrence.

Conclusion:

Duodenal neuroendocrine tumors represent 1% to 3% of all GEP-NETs. They are rare in adults and extremely rare in children. Therefore, the diagnostic and therapeutic approach should be multidisciplinary, including laboratory, endoscopic, and specific imaging tests and strictly follows guidelines, to avoid misdiagnosis and inadequate treatments. Although the prognosis is benign in most cases, they can present with metastases. Therefore, a careful follow-up is extremely important.
Community-engaged Evidence Synthesis to Inform Public Health Policy and Clinical Practice
Authors: Springs Stacey , Rofeberg Valerie , Brown Sherilyn , Boudreau Steven , Hey Spencer Phillips , Baruch Jay
Published: September 2019

Background:

This case study documents the work of the Rhode Island Arts and Health Advisory Group, which convened in 2016 to develop a set of policy, clinical practice, and research recommendations for implementation by the Rhode Island Department of Health, The Rhode Island State Council on the Arts, and partners. Comprised of artists, clinicians, community members, and patients, the group partnered with researchers to complete an evidence synthesis project of arts-based health care interventions.

Methods:

The group took a community-engaged approach to evidence synthesis, featuring the use of online, and in-person training materials to facilitate the codesign and coexecution of the evidence synthesis protocol. The final evidence map was translated into an online evidence map to facilitate analysis and discussion on arts-based interventions in health care.

Results:

The evidence map informed the development of recommendations for advancing the integration of arts and health in the state. The project evaluation indicated that our community-engaged approach to evidence synthesis promoted engagement as defined by the PCORI Engagement Strategy Rubric (ie, reciprocal relationships, partnership, colearning, transparency, honesty, and trust). Participation also improved community research partners confidence in engaging with the health care system, developed greater empathy and understanding of others in the community, and increased interest in using science or research in advocacy efforts.

Conclusions:

Engaging community partners in evidence synthesis promotes community dialogue and engagement in research, specifically towards: (1) elucidating outcomes of import to patients and communities that are not represented in the medical literature; and (2) identifying comparisons among interventions that resonate with patients and communities.
Clinical Effects and Outcomes After Polymyxin B–Immobilized Fiber Column Direct Hemoperfusion Treatment for Septic Shock in Preterm Neonates*
Authors: Nishizaki Naoto , Hara Taichi , Obinata Kaoru , Nakagawa Mayu , Shimizu Toshiaki
Published: September 2019

Objectives:

To compare the effectiveness and mortality of early-onset sepsis or late-onset sepsis treatments with polymyxin B–immobilized fiber column direct hemoperfusion in terms of effectiveness and mortality in preterm infants with septic shock.

Design:

Retrospective cohort study.

Setting:

Neonatal ICU within a tertiary care hospital.

Patients:

Of 1,115 patients, 49 had blood culture–proven sepsis between January 2013 and December 2018; six and five patients with septic shock had undergone polymyxin B–immobilized fiber column direct hemoperfusion treatment for early-onset sepsis (early-onset sepsis group) and late-onset sepsis (late-onset sepsis group), respectively.

Interventions:

None.

Measurements and Main Results:

Baseline demographic characteristics of both groups were similar. The time from decision to treatment induction was significantly shorter in the early-onset sepsis group than that in the late-onset sepsis group (p = 0.008). The mortality rate after 28 days of treatment and the hospital mortality were significantly lower in the early-onset sepsis group than in the late-onset sepsis group (p = 0.026 and 0.015, respectively). The Pao
2/Fio
2 ratio was significantly higher in the early-onset sepsis group than in the late-onset sepsis group at the end of the treatment (p = 0.035). In addition, median arterial-to-alveolar oxygen tension ratio significantly improved from 0.19 to 0.55, and median blood pressure also significantly improved from 32.5 to 40.0 mm Hg after the treatment in the early-onset sepsis group. Interleukin-6 levels significantly decreased after treatment in the early-onset sepsis group (p = 0.037). The Pediatric Risk of Mortality III score was similar between the early-onset sepsis and late-onset sepsis groups before and after the treatment. Intraventricular hemorrhage events occurred in both groups, but with no significant differences (p = 0.175).

Conclusions:

Polymyxin B–immobilized fiber column direct hemoperfusion treatment for preterm infants with septic shock due to early-onset sepsis is associated with earlier hemodynamic and respiratory status improvements and with lower mortality than that due to late-onset sepsis. Early neonatal septic shock detection and polymyxin B–immobilized fiber column direct hemoperfusion induction may improve the prognosis of affected infants.
Utilization of a Neonatal Early-Onset Sepsis Calculator to Guide Initial Newborn Management
Authors: Leonardi Bianca M. , Binder Margaret , Griswold Katherine J. , Yalcinkaya Gulgun F. , Walsh Michele C.
Published: September 2019

Introduction:

Within our hospital system, all infants born to mothers with chorioamnionitis were directly admitted to the neonatal intensive care unit (NICU) for evaluation and treatment of presumed sepsis for a minimum of 48 hours, regardless of clinical appearance. Implementation of a risk-stratification system for thesWe high-risk infants based on the early onset sepsis (EOS) calculator may decrease NICU admissions and antibiotics exposure in well-appearing neonates.

Methods:

We used The Model for Improvement as a framework for designing this initiative. Participants were inborn infants 35 weeks and older born to mothers with chorioamnionitis and/or fever. Plan Do Study Act (PDSA) cycles were utilized to educate staff, monitor for sepsis, and follow adherence to the calculator in the newborn nursery.

Results:

From June 2015 to June 2016, there were 312 at-risk infants identified and evaluated on the EOS calculator. Of these 312 infants, 228 did not require admission to the NICU based on their risk assessment using the online calculator. Implementation of the Kaiser EOS calculator protocol for at-risk infants decreased NICU admission rates, decreased practitioner practice variability, decreased the number of painful procedures, promoted family bonding, resulted in higher breastfeeding rates at hospital discharge, diminished financial burden, and promoted antibiotic stewardship.

Conclusion:

This study demonstrates that the implementation of the sepsis risk calculator at an academic medical center can decrease the number of asymptomatic infants transferred to the NICU for empiric antibiotic treatment.
Experience With Early Sorafenib Treatment With mTOR Inhibitors in Hepatocellular Carcinoma Recurring After Liver Transplantation
Authors: Invernizzi Federica , Iavarone Massimo , Zavaglia Claudio , Mazza Stefano , Maggi Umberto , Cesarini Lucia , Antonelli Barbara , Airoldi Aldo , Manini Matteo Angelo , Sangiovanni Angelo , Rossi Giorgio , Donato Maria Francesca , Saverio Belli Luca , Lampertico Pietro
Published: September 2019

Background.

Sorafenib (SOR) is currently used for hepatocellular carcinoma (HCC) recurring after liver transplantation (LT) when HCC is unsuitable for surgical/locoregional treatments. We evaluated safety and effectiveness of early introduction of SOR after HCC-recurrence.

Methods.

All patients with HCC-recurrence after LT treated with SOR in 2 centers were included (January 2008 to June 2018). Baseline and on-treatment data were collected.

Results.

Fifty patients early treated with SOR for HCC-recurrence after LT (74% mammalian target of rapamycin inhibitor [mTORi], 54% HCC-treated at baseline) were enrolled. During 7.3 (0.3–88) months of SOR, all patients had at least one adverse event (AE), 56% graded 3–4. SOR was reduced in 68%, being AEs the main cause of reduction, and discontinued in 84% (60% symptomatic progression, 33% AE). Objective response was obtained in 16% and stable disease in 50%. Median time to radiological progression was 6 months (95% confidence Interval [CI], 4-8). Thirty-three patients (69%) died, 94% for HCC progression. Median overall survival (OS) was 18 months (95% CI, 8-27); 5-year OS was 18% (95% CI, 4%-32%). Baseline predictors of OS were SOR+mTORi (hazard ratio [HR], 0.4; 95% CI, 0.2-0.9; P = 0.04), previous curative treatments (HR, 0.3; 95% CI, 0.2-0.7; P = 0.003) and alpha-fetoprotein > 100 ng/mL (HR, 2.5; 95% CI, 1.1-5.0, P = 0.02). At multivariate analysis, HCC curative treatment was the only independent predictor (HR, 0.4; 95% CI 0.2-1.0; P = 0.04).

Conclusions.

Early and combined treatment with SOR and mTORi resulted in a favorable safety profile, while its effectiveness should be confirmed by meta-analysis of previous studies or by larger studies. Curative treatment for HCC resulted the only independent predictor of OS.
Cognitive and Behavioral Changes in Patients Treated With Droxidopa for Neurogenic Orthostatic Hypotension: A Retrospective Review
Authors: McDonell Katherine E. , Shibao Cyndya A. , Biaggioni Italo , Hartman Adam , Robertson David , Claassen Daniel O.
Published: September 2019

Background:

Droxidopa is a norepinephrine precursor that improves symptoms of neurogenic orthostatic hypotension in conditions such as Parkinson disease, multiple system atrophy, and pure autonomic failure by inducing a pressor effect. Unlike other pressor agents, droxidopa crosses the blood-brain barrier; however, its central effects are, as of yet, uncharacterized.

Objective:

We present the results of a retrospective cohort study examining cognitive and behavioral side effects linked to droxidopa therapy.

Methods:

We performed a review of 101 patients who had been treated with droxidopa at an academic tertiary care center and identified cases of cognitive and behavioral changes associated with the therapy.

Results:

We identified six patients who had developed cognitive and behavioral symptoms, including memory difficulties, confusion, mania, and irritability, shortly after droxidopa initiation. All six patients displayed symptoms of synucleinopathy, manifesting with autonomic failure, rapid eye movement sleep behavior disorder, and parkinsonism. Patients had no significant cognitive or behavioral symptoms before droxidopa initiation. Behavioral disturbances were observed early in the droxidopa titration period and at relatively low doses. Symptoms resolved with dose reduction in four patients, and droxidopa was discontinued in two patients due to persistent irritability. No other medical comorbidities or alternative etiologies were identified to explain the symptoms.

Conclusions:

Droxidopa is designed to act peripherally as a pressor agent but may also exert important central effects. We hypothesize that the cognitive and behavioral manifestations observed in the patients with orthostatic hypotension resulted from an “overdose” of key noradrenergic networks linking orbitofrontal and mesolimbic regions.
Middle East respiratory coronavirus (MERS-CoV) spike (S) protein vesicular stomatitis virus pseudoparticle neutralization assays offer a reliable alternative to the conventional neutralization assay in human seroepidemiological studies
Authors: Lester Sandra , Harcourt Jennifer , Whitt Michael , Al-Abdely Hail M. , Midgley Claire M. , Alkhamis Abdulrahim M. , Aziz Jokhdar Hani A. , Assiri Abdullah M. , Tamin Azaibi , Thornburg Natalie
Published: September 2019

Middle East respiratory syndrome coronavirus (MERS-CoV) is a novel zoonotic coronavirus that was identified in 2012. MERS-CoV infection in humans can result in an acute, severe respiratory disease and in some cases multi-organ failure; the global mortality rate is approximately 35 %. The MERS-CoV spike (S) protein is a major target for neutralizing antibodies in infected patients. The MERS-CoV microneutralization test (MNt) is the gold standard method for demonstrating prior infection. However, this method requires the use of live MERS-CoV in biosafety level 3 (BSL-3) containment. The present work describes the generation and validation of S protein-bearing vesicular stomatitis virus (VSV) pseudotype particles (VSV-MERS-CoV-S) in which the VSV glycoprotein G gene has been replaced by the luciferase reporter gene, followed by the establishment of a pseudoparticle-based neutralization test to detect MERS-CoV neutralizing antibodies under BSL-2 conditions. Using a panel of human sera from confirmed MERS-CoV patients, the VSV-MERS-CoV particle neutralization assay produced results that were highly comparable to those of the microneutralization test using live MERS-CoV. The results suggest that the VSV-MERS-CoV-S pseudotype neutralization assay offers a highly specific, sensitive and safer alternative method to detect MERS-CoV neutralizing antibodies in human sera.
Analysis of CRISPR gene drive design in budding yeast
Authors: Yan Yao , Finnigan Gregory C.
Published: September 2019

Control of biological populations remains a critical goal to address the challenges facing ecosystems and agriculture and those posed by human disease, including pests, parasites, pathogens and invasive species. A particular architecture of the CRISPR/Cas biotechnology – a gene drive – has the potential to modify or eliminate populations on a massive scale. Super-Mendelian inheritance has now been demonstrated in both fungi and metazoans, including disease vectors such as mosquitoes. Studies in yeast and fly model systems have developed a number of molecular safeguards to increase biosafety and control over drive systems in vivo, including titration of nuclease activity, anti-CRISPR-dependent inhibition and use of non-native DNA target sites. We have developed a CRISPR/Cas9 gene drive in Saccharomyces cerevisiae that allows for the safe and rapid examination of alternative drive designs and control mechanisms. In this study, we tested whether non-homologous end-joining (NHEJ) had occurred within diploid cells displaying a loss of the target allele following drive activation and did not detect any instances of NHEJ within multiple sampled populations. We also demonstrated successful multiplexing using two additional non-native target sequences. Furthermore, we extended our analysis of ‘resistant’ clones that still harboured both the drive and target selection markers following expression of

Streptococcus pyogenes

Cas9; de novo mutation or NHEJ-based repair could not explain the majority of these heterozygous clones. Finally, we developed a second-generation gene drive in yeast with a guide RNA cassette integrated within the drive locus with a near 100 % success rate; resistant clones in this system could also be reactivated during a second round of Cas9 induction.
Structure–function analysis of the equine hepacivirus 5′ untranslated region highlights the conservation of translational mechanisms across the hepaciviruses
Authors: Lattimer Joseph , Stewart Hazel , Locker Nicolas , Tuplin Andrew , Stonehouse Nicola J. , Harris Mark
Published: September 2019

Equine hepacivirus (EHcV) (now also classified as hepacivirus A) is the closest genetic relative to hepatitis C virus (HCV) and is proposed to have diverged from HCV within the last 1000 years. The 5′ untranslated regions (UTRs) of both HCV and EHcV exhibit internal ribosome entry site (IRES) activity, allowing cap-independent translational initiation, yet only the HCV 5′UTR has been systematically analysed. Here, we report a detailed structural and functional analysis of the EHcV 5′UTR. The secondary structure was determined using selective 2′ hydroxyl acylation analysed by primer extension (SHAPE), revealing four stem–loops, termed SLI, SLIA, SLII and SLIII, by analogy to HCV. This guided a mutational analysis of the EHcV 5′UTR, allowing us to investigate the roles of the stem–loops in IRES function. This approach revealed that SLI was not required for EHcV IRES-mediated translation. Conversely, SLIII was essential, specifically SLIIIb, SLIIId and a GGG motif that is conserved across the Hepaciviridae. Further SHAPE analysis provided evidence that this GGG motif mediated interaction with the 40S ribosomal subunit, whilst a CUU sequence in the apical loop of SLIIIb mediated an interaction with eIF3. In addition, we showed that a microRNA122 target sequence located between SLIA and SLII mediated an enhancement of translation in the context of a subgenomic replicon. Taken together, these results highlight the conservation of hepaciviral translation mechanisms, despite divergent primary sequences.
Gender dependent pharmacotherapy for blocking transition to chronic back pain: a proof of concept randomized trial
Authors: Reckziegel Diane , Tétreault Pascal , Ghantous Mariam , Wakaizumi Kenta , Petre Bogdan , Huang Lejian , Jabakhanji Rami , Abdullah Taha , Vachon-Presseau Etienne , Berger Sara , Baria Alexis , Griffith James W , Baliki Marwan N , Schnitzer Thomas J , Apkarian A Vania
Published: September 2019

Preventing transition to chronic back pain (CBP) is an ideal strategy that would rescue patients from years to a lifetime of suffering with pain. Recent studies suggest involvement of sexually-dimorphic dopaminergic-motivational circuits in the transition to chronic pain (tCBP), and hints the combination of carbidopa/levodopa and naproxen (LDP+NPX) may block tCBP. We tested these concepts in early onset BP, who were stratified by risk for tCBP using brain properties. Those identified as low-risk entered a no-treatment arm. The rest were randomized into a double-blind, placebo and naproxen (PLC+NPX) controlled trial of oral LDP+NPX for 12 weeks, and a post-treatment 12-weeks follow-up. 59 participants completed the study. Both treatments resulted in ∼50% pain relief for ∼75%, sustained post-treatment. LDP+NPX was highly effective in females (>80% pain relief), it modified BP personality, and was related to objective brain functional changes. Although performed in a small group of early onset BP, multiple subjective and objective measures consistently suggest that these long-duration treatments persistently, and gender-dependently, block tCBP.
PolySTest: Robust statistical testing of proteomics data with missing values improves detection of biologically relevant features
Authors: Schwämmle Veit , Hagensen Christina E , Rogowska-Wrzesinska Adelina , Jensen Ole N.
Published: September 2019

Statistical testing remains one of the main challenges for high-confidence detection of differentially regulated proteins or peptides in large-scale quantitative proteomics experiments by mass spectrometry. Statistical tests need to be sufficiently robust to deal with experiment intrinsic data structures and variations and often also reduced feature coverage across different biological samples due to ubiquitous missing values. A robust statistical test provides accurate confidence scores of large-scale proteomics results, regardless of instrument platform, experimental protocol and software tools. However, the multitude of different combinations of experimental strategies, mass spectrometry techniques and informatics methods complicate the decision of choosing appropriate statistical approaches. We address this challenge by introducing PolySTest, a user-friendly web service for statistical testing, data browsing and data visualization. We introduce a new method, Miss Test, that simultaneously tests for missingness and feature abundance, thereby complementing common statistical tests by rescuing otherwise discarded data features. We demonstrate that PolySTest with integrated Miss Test achieves higher confidence and higher sensitivity for artificial and experimental proteomics data sets with known ground truth. Application of PolySTest to mass spectrometry based large-scale proteomics data obtained from differentiating muscle cells resulted in the rescue of 10%-20% additional proteins in the identified molecular networks relevant to muscle differentiation. We conclude that PolySTest is a valuable addition to existing tools and instrument enhancements that improve coverage and depth of large-scale proteomics experiments. A fully functional demo version of PolySTest and Miss Test is available via http://computproteomics.bmb.sdu.dk/Apps/PolySTest.
Multiple features within Sed5p mediate it’s COPI-independent trafficking and Golgi localization
Authors: Gao Guanbin , Banfield David K.
Published: September 2019

Protein retention and the transport of proteins and lipids into and out of the Golgi is intimately linked to the biogenesis and homeostasis of this sorting hub of eukaryotic cells. Of particular importance are membrane proteins that mediate membrane fusion events with and within the Golgi – the Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). In the Golgi of budding yeast cells a single syntaxin - the SNARE Sed5p - oversees membrane fusion within the Golgi. Determining how Sed5p is localized to and trafficked within the Golgi is critical to informing our understanding of the mechanism(s) of biogenesis and homeostasis of this organelle. Here we establish that the Golgi retention and trafficking of Sed5p between the Golgi and the ER is independent of COPI function, the composition of the transmembrane domain, and binding of the Sec1-Munc18 (SM) protein Sly1p. Rather, the steady state localization of Sed5p to the Golgi appears to be primarily conformation-based relying on intra-molecular associations between the Habc domain and SNARE-motif.
Blimp-1 is essential for Th2 cell development and allergic asthma
Authors: He Kun , Hettinga Angela , Kale Sagar Laxman , Hu Sanmei , Xie Markus M. , Dent Alexander L. , Ray Anuradha , Poholek Amanda C.
Published: September 2019

A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung, but dispensable for TFHfunction and IgE production.Mechanistically, Blimp-1 acts through Bcl6, which is necessary to drive GATA3 expression.Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to upregulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10-STAT3-Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.

The transcriptional repressor Blimp-1 acts via a pro-inflammatory IL-10-STAT3 axis as a critical positive regulator of Th2 cells in the lung in response to allergens driving pathophysiology associated with asthma disease.
Understanding the role of urban design in disease spreading
Authors: Brizuela Noel G. , García-Chan Néstor , Pulido Humberto Gutiérrez , Chowell Gerardo
Published: September 2019

Cities are complex systems whose characteristics impact the health of people who live in them. Nonetheless, urban determinants of health often vary within spatial scales smaller than the resolution of epidemiological datasets. Thus, as cities expand and their inequalities grow, the development of theoretical frameworks that explain health at the neighborhood level is becoming increasingly critical. To this end, we developed a methodology that uses census data to introduce urban geography as a leading-order predictor in the spread of influenza-like pathogens. Here, we demonstrate our framework using neighborhood-level census data for Guadalajara (GDL, Western Mexico). Our simulations were calibrated using weekly hospitalization data from the 2009 A/H1N1 influenza pandemic and show that daily mobility patterns drive neighborhood-level variations in the basic reproduction number R0, which in turn give rise to robust spatiotemporal patterns in the spread of disease. To generalize our results, we ran simulations in hypothetical cities with the same population, area, schools and businesses as GDL but different land use zoning. Our results demonstrate that the agglomeration of daily activities can largely influence the growth rate, size and timing of urban epidemics. Overall, these findings support the view that cities can be redesigned to limit the geographic scope of influenza-like outbreaks and provide a general mathematical framework to study the mechanisms by which local and remote health consequences result from characteristics of the physical environment.

Author summary

Environmental, social and economic factors give rise to health inequalities among the inhabitants of a city, prompting researchers to propose ’smart’ urban planning as a tool for public health. Here, we present a mathematical framework that relates the spatial distributions of schools and economic activities to the spatiotemporal spread of influenza-like outbreaks. First, we calibrated our model using city-wide data for Guadalajara (GDL, Western Mexico) and found that a person’s place of residence can largely influence their role and vulnerability during an epidemic. In particular, the higher contact rates of people living near major activity hubs can give rise to predictable patterns in the spread of disease. To test the universality of our findings, we ’redesigned’ GDL by redistributing houses, schools and businesses across the city and ran simulations in the resulting geographies. Our results suggest that, through its impact on the agglomeration of economic activities, urban planning may be optimized to inhibit epidemic growth. By predicting health inequalities at the neighborhood-level, our methodology may help design public health strategies that optimize resources and target those who are most vulnerable. Moreover, it provides a mathematical framework for the design and analysis of experiments in urban health research.
Delayed antibiotic exposure induces population collapse in enterococcal communities with drug-resistant subpopulations
Authors: Hallinen Kelsey M. , Karslake Jason , Wood Kevin B.
Published: September 2019

Bacteria exploit a diverse set of defenses to survive exposure to antibiotics. While the molecular and genetic underpinnings of antibiotic resistance are increasingly understood, less is known about how these molecular events influence microbial dynamics on the population scale. In this work, we show that the dynamics ofE. faecaliscommunities exposed to antibiotics can be surprisingly rich, revealing scenarios where–for example–increasing population size or delaying drug exposure can promote population collapse. Specifically, we combine experiments in computer-controlled bioreactors with simple mathematical models to reveal density-dependent feedback loops that couple population growth and antibiotic efficacy when communities include drug-resistant (β-lactamase producing) subpopulations. The resulting communities exhibit a wide range of behavior, including population survival, population collapse, or one of two qualitatively distinct bistable behaviors where survival is favored in either small or large populations. These dynamics reflect competing density-dependent effects of different subpopulations, with growth of drug-sensitive cells increasing but growth of drug-resistant cells decreasing effective drug inhibition. Guided by these results, we experimentally demonstrate how populations receiving immediate drug influx may sometimes thrive, while identical populations exposed to delayed drug influx (and lower average drug concentrations) collapse. These results illustrate that the spread of drug resistant determinants—even in a simplified single-species communities—may be governed by potentially counterintuitive dynamics driven by population-level interactions.
Robustness and the evolution of length control strategies in the type III secretion system and flagellar hook
Authors: Nariya Maulik K. , Mallela Abhishek , Shi Jack J. , Deeds Eric J.
Published: September 2019

Bacteria construct many structures, like the flagellar hook and the type III secretion system, that aid in crucial processes such as locomotion and pathogenesis. Experimental work has suggested two competing mechanisms bacteria could use to regulate length in these structures: the “ruler” mechanism and the “substrate switching” mechanism. In this work, we constructed a mathematical model of length control based on the ruler mechanism, and found that the predictions of this model are consistent with experimental data not just for the scaling of the average length with the ruler protein length, but also the variance. Interestingly, we found that the ruler mechanism allows for the evolution of needles with large average lengths without the concomitant large increase in variance that occurs in the substrate switching mechanism. These findings shed new light on the trade-offs that may have lead to the evolution of different length control mechanisms in different bacterial species.
Deviations from dynamic equilibrium in ecological communities worldwide
Authors: Kalyuzhny Michael , Flather Curtis H. , Shnerb Nadav M. , Kadmon Ronen
Published: September 2019

Ecological communities are assembled by colonization and extinction events, that may be regulated by ecological niches1–5. The most parsimonious explanation of local community assembly is the Dynamic Equilibrium (DE) model, which assumes that community dynamics is shaped by random colonization and extinctions events, effectively ignoring the effects of niches1, 6. Despite its empirical success in explaining diversity patterns1, 5, 7, it is unknown to what extent the assembly dynamics of communities around the globe are consistent with this model. Using a newly developed methodology, we show that in 4989 communities from 49 different datasets, representing multiple taxa, biomes and locations, changes in richness and composition are larger than expected by DE. All the fundamental assumptions of DE are violated, but the large changes in species richness and composition primarily stem from the synchrony in the dynamics of different species. These results indicate that temporal changes in communities are predominantly driven by shared responses of co-occurring species to environmental changes, rather than by inter-specific competition. This finding is in sharp contrast to the long-term recognition of competition as a primary driver of species assembly8–12. While ecological niches are often thought to stabilize species diversity and composition4, 13, 14, we found that they promote large changes in ecological communities.
Methylome-Wide Association Study of Central Adiposity Implicate Genes Involved in Immune and Endocrine Systems
Authors: Justice Anne E , Chittoor Geetha , Gondalia Rahul , Melton Phillip E , Lim Elise , Grove Megan L. , Whitsel Eric A. , Liu Ching-Ti , Cupples L. Adrienne , Fernandez-Rhodes Lindsay , Guan Weihua , Bressler Jan , Fornage Myriam , Boerwinkle Eric , Li Yun , Demerath Ellen , Heard-Costa Nancy , Levy Dan , Stewart James D , Baccarelli Andrea , Hou Lifang , Conneely Karen , Mori Trevor , Beilin Lawrence J. , Huang Rae-Chi , Gordon-Larsen Penny , Howard Annie Green , North Kari E
Published: September 2019

We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist- to-hip ratio, and waist-to-height ratio adjusted for body mass index, in 2684 African American adults in the Atherosclerosis Risk in Communities study. We validated significantly associated Cytosine-phosphate-Guanine methylation sites (CpGs) among adults using the Women’s Health Initiative and Framingham Heart Study participants (combined N=5743) and generalized associations in adolescents from The Raine Study (N=820). We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and 2 in adolescents, including CpG site associations nearTXNIP, ADCY7, SREBF1, andRAP1GAP2that had not previously been associated with obesity-related traits.
Mechanisms that allow cortical preparatory activity without inappropriate movement
Authors: Darlington Timothy R. , Lisberger Stephen G.
Published: September 2019

We reveal a novel mechanism that explains how preparatory activity can evolve in motor-related cortical areas without prematurely inducing movement. The smooth eye movement region of the frontal eye fields (FEFSEM) is a critical node in the neural circuit controlling smooth pursuit eye movement. Preparatory activity evolves in FEFSEM during fixation in parallel with an objective measure of visual-motor gain. We propose that the use of FEFSEM output as a gain signal allows for preparation to progress in the pursuit system without causing movement. We also show that preparatory modulation of firing rate in FEFSEM progresses in a way that predicts movement, providing evidence against the “movement-null” space hypothesis of how preparatory activity can progress without movement. Finally, there is partial reorganization of FEFSEM population activity between preparation and movement. We propose that this reorganization allows for a directionally non-specific component of preparatory visual-motor gain enhancement in the pursuit system.
A diet-dependent enzyme from the human gut microbiome promotes Th17 cell accumulation and colitis
Authors: Alexander Margaret , Ang Qi Yan , Nayak Renuka R. , Bustion Annamarie E. , Upadhyay Vaibhav , Pollard Katherine S. , Turnbaugh Peter J.
Published: September 2019

Aberrant activation of Th17 cells by the gut microbiota contributes to autoimmunity; however, the mechanisms responsible and their diet-dependence remain unclear. Here, we show that the autoimmune disease-associated gut ActinobacteriumEggerthella lentaincreases intestinal Th17 cells and worsens colitis in aRorc-dependent and strain-variable manner. A single genomic locus predicted Th17 accumulation. A gene within this locus, encoding the Cgr2 enzyme, was sufficient to increase Th17 cells. Levels ofcgr2were increased in stool from patients with rheumatoid arthritis compared to healthy controls. Dietary arginine blockedE. lenta-induced Th17 cells and colitis. These results expand the mechanisms through which bacteria shape mucosal immunity and demonstrate the feasibility of dissecting the complex interactions between diet, the gut microbiota, and autoimmune disease.

One Sentence Summary

An autoimmune disease-associated bacterium triggers disease due to a diet-dependent enzyme that regulates mucosal immunity.
Diet alters micronutrient pathways in the gut and placenta that regulate fetal growth and development in pregnant mice
Authors: Palladino Elia , Van Mieghem Tim , Connor Kristin L.
Published: September 2019

Maternal malnutrition and micronutrient deficiencies can alter fetal development. However, the mechanisms underlying these relationships are poorly understood. We used a systems-physiology approach to investigate diet-induced effects on maternal gut microbes and folate/inositol transport in the maternal/fetal gut and placenta. Female mice were fed a control diet (CON) diet, undernourished (UN, restricted by 30% of CON intake) or a high fat diet (HF, 60% kcals fat) during pregnancy to model normal pregnancy, fetal growth restriction, or maternal metabolic dysfunction, respectively. At gestational day 18.5 we assessed circulating folate levels by microbiological assay, relative abundance of gut lactobacilli by G3PhyloChip™, and folate/inositol transporters in placenta and maternal/fetal gut by qPCR/immunohistochemistry. UN and HF-fed mothers had lower plasma folate concentrations vs. CON. Relative abundance of three lactobacilli taxa were higher in HF vs. UN and CON. HF-fed mothers had higher gut proton coupled folate transporter (Pcft) and reduced folate carrier 1 (Rfc1), and lower sodium myo-inositol co-transporter 2 (Smit2), mRNA expression vs. UN and CON. HF placentae had increased folate receptor beta (Frβ) expression vs. UN. mRNA expression of Pcft, folate receptor alpha (Frα) and Smit2 was higher in gut of HF fetuses vs. UN and CON. Transporter protein expression was not different between groups. Maternal malnutrition alters abundance of select gut microbes and folate/inositol transporters, which may influence maternal micronutrient status and delivery to the fetus, impacting pregnancy/fetal outcomes.
Learning Divisive Normalization in Primary Visual Cortex
Authors: Burg Max F. , Cadena Santiago A. , Denfield George H. , Walker Edgar Y. , Tolias Andreas S. , Bethge Matthias , Ecker Alexander S.
Published: September 2019

Divisive normalization (DN) is a prominent computational building block in the brain that has been proposed as a canonical cortical operation. Numerous experimental studies have verified its importance for capturing nonlinear neural response properties to simple, artificial stimuli, and computational studies suggest that DN is also an important component for processing natural stimuli. However, we lack quantitative models of DN that are directly informed by measurements of spiking responses in the brain and applicable to arbitrary stimuli. Here, we propose a DN model that is applicable to arbitrary input images. We test its ability to predict how neurons in macaque primary visual cortex (V1) respond to natural images, with a focus on nonlinear response properties within the classical receptive field. Our model consists of one layer of subunits followed by learned orientation-specific DN. It outperforms linear-nonlinear and wavelet-based feature representations and makes a significant step towards the performance of state-of-the-art convolutional neural network (CNN) models. Unlike deep CNNs, our compact DN model offers a direct interpretation of the nature of normalization. By inspecting the learned normalization pool of our model, we gained insights into a long-standing question about the tuning properties of DN that update the current textbook description: we found that within the receptive field oriented features were normalized preferentially by features with similar orientation rather than non-specifically as currently assumed.

Author summary

Divisive normalization (DN) is a computational building block throughout sensory processing in the brain. We currently lack an understanding of what role this normalization mechanism plays when processing complex stimuli like natural images. Here, we use modern machine learning methods to build a general DN model that is directly informed by data from primary visual cortex (V1). Contrary to high-predictive deep learning models, our DN-based model’s parameters offer a straightforward interpretation of the nature of normalization. Within the receptive field, we found that neurons responding strongly to a specific orientation are preferentially normalized by other neurons that are highly active for similar orientations, rather than being normalized by all neurons as it is currently assumed by textbook models.