bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular insights on CALX-CBD12 inter-domain dynamics from MD simulations, RDCs and SAXS
Authors: de Souza Degenhardt Maximilia F. , Vitale Phelipe A. M. , Abiko Layara A. , Zacharias Martin , Sattler Michael , Oliveira Cristiano L. P. , Salinas Roberto K.
Published: December 2020

Na+/Ca2+exchangers (NCX) are secondary active transporters that couple the translocation of Na+with the transport of Ca2+in the opposite direction. The exchanger is an essential Ca2+extrusion mechanism in excitable cells. It consists of a transmembrane domain and a large intracellular loop that contains two Ca2+-binding domains, CBD1 and CBD2. The two CBDs are adjacent to each other and form a two-domain Ca2+-sensor called CBD12. Binding of intracellular Ca2+to CBD12 activates the NCX but inhibits the Na+/Ca2+exchanger ofDrosophila, CALX. NMR spectroscopy and SAXS studies showed that CALX and NCX CBD12 constructs display significant inter-domain flexibility in the Apo state, but assume rigid inter-domain arrangements in the Ca2+-bound state. However, detailed structure information on CBD12 in the Apo state is missing. Structural characterization of proteins formed by two or more domains connected by flexible linkers is notoriously challenging and requires the combination of orthogonal information from multiple sources. As an attempt to characterize the conformational ensemble of CALX-CBD12 in the Apo state, we applied molecular dynamics (MD) simulations, NMR (1H-15N RDCs) and Small-Angle X-Ray Scattering (SAXS) data in a combined modelling strategy that generated atomistic information on the most representative conformations. This joint approach demonstrated that CALX-CBD12 preferentially samples closed conformations, while the wide-open inter-domain arrangement characteristic of the Ca2+-bound state is less frequently sampled. These results are consistent with the view that Ca2+binding shifts the CBD12 conformational ensemble towards extended conformers, which could be a key step in the Na+/Ca2+exchangers’ allosteric regulation mechanism. The present strategy, combining MD with NMR and SAXS, provides a powerful approach to select representative structures from ensembles of conformations, which could be applied to other flexible multi-domain systems.

SIGNIFICANCE

The conformational ensemble of CALX-CBD12, the main Ca2+-sensor ofDrosophila’s Na+/Ca2+exchanger, was characterized by a combination of MD simulations with SAXS and NMR data using the EOM approach. This analysis showed that this two-domain construct experiences opening-closing motions, providing molecular information about CALX-CBD12 in the Apo state. Ca2+-binding shifts the conformational ensemble towards extended conformers. These findings are consistent with a model according to which Ca2+modulation of CBD12 plasticity is a key step in the Ca2+-regulation mechanism of the full-length exchanger.
The polybasic cleavage site in the SARS-CoV-2 spike modulates viral sensitivity to Type I IFN and IFITM2
Authors: Winstone Helena , Lista Maria Jose , Reid Alisha , Pickering Suzanne , Doores Katie J , Swanson Chad , Neil Stuart J D
Published: December 2020

The cellular entry of severe acute respiratory syndrome-associated coronaviruses types 1 and 2 (SARS-CoV-1 and -2) requires sequential protease processing of the viral spike glycoprotein (S). The presence of a polybasic cleavage site in SARS-CoV-2 S at the S1/S2 boundary has been suggested to be a factor in the increased transmissibility of SARS-CoV-2 compared to SARS-CoV-1 by facilitating maturation of the S precursor by furin-like proteases in the producer cells rather than endosomal cathepsins in the target. We investigate the relevance of the polybasic cleavage site in the route of entry of SARS-CoV-2 and the consequences this has for sensitivity to interferons, and more specifically, the IFN-induced transmembrane (IFITM) protein family that inhibit entry of diverse enveloped viruses. We found that SARS-CoV-2 is restricted predominantly by IFITM2 and the degree of this restriction is governed by route of viral entry. Removal of the cleavage site in the spike protein renders SARS-CoV-2 entry highly pH- and cathepsin-dependent in late endosomes where, like SARS-CoV-1 S, it is more sensitive to IFITM2 restriction. Furthermore, we find that potent inhibition of SARS-CoV-2 replication by type I but not type II IFNs is alleviated by targeted depletion of IFITM2 expression. We propose that the polybasic cleavage site allows SARS-CoV-2 to mediate viral entry in a pH-independent manner, in part to mitigate against IFITM-mediated restriction and promote replication and transmission. This suggests therapeutic strategies that target furin-mediated cleavage of SARS-CoV-2 S may reduce viral replication through the activity of type I IFNs.

IMPORTANCE

The furin cleavage site in the S protein is a distinguishing feature of SARS-CoV-2 and has been proposed to be a determinant for the higher transmissibility between individuals compared to SARS-CoV-1. One explanation for this is that it permits more efficient activation of fusion at or near the cell surface rather than requiring processing in the endosome of the target cell. Here we show that SARS-CoV-2 is inhibited by antiviral membrane protein IFITM2, and that the sensitivity is exacerbated by deletion of the furin cleavage site which restricts viral entry to low pH compartments. Furthermore, we find that IFITM2 is a significant effector of the antiviral activity of type I interferons against SARS-CoV-2 replication. We suggest one role of the furin cleavage site is to reduce SARS-CoV-2 sensitivity to innate immune restriction, and thus may represent a potential therapeutic target for COVID-19 treatment development.
Mutation of a conserved Gln residue does not abolish desensitization of acid-sensing ion channel 1
Authors: Rook Matthew L , Miaro Megan , Couch Tyler , Kneisley Dana L , Musgaard Maria , MacLean David M.
Published: December 2020

Desensitization is a common feature of ligand-gated ion channels although the molecular cause varies widely between channel types. Mutations that substantially reduce or abolish desensitization have been described for many ligand-gated ion channels including glutamate, GABA, glycine and nicotinic receptors but not for acid-sensing ion channels (ASICs) until recently. Mutating Gln276 to a glycine in human ASIC1a was reported to mostly abolish desensitization at both the macroscopic and single channel levels, potentially providing a valuable tool for subsequent studies. However, we find that in both human and chicken ASIC1 the effect of Q276G is modest. In chicken ASIC1, the equivalent Q277G slightly reduces desensitization when using pH 6.5 as a stimulus but desensitizes essentially like wild type when using more acidic pH values. In addition, steady-state desensitization is intact, albeit right-shifted, and recovery from desensitization is accelerated. Molecular dynamics simulations indicate that the Gln277 side chain participates in a hydrogen bond network that might stabilize the desensitized conformation. Consistent with this, destabilizing this network with the Q277N or Q277L mutations largely mimics the Q277G phenotype. In human ASIC1a, Q276G does not substantially reduce desensitization but surprisingly slows entry to and exit from the desensitized state, thus requiring longer agonist applications to reach equilibrium. Our data reveal that while the Q/G mutation does not substantially impair desensitization as previously reported, it does point to unexpected differences between chicken and human ASICs and the need for careful scrutiny before using this mutation in future studies.
Patient-derived cancer organoid tracking with widefield one-photon redox imaging to assess treatment response
Authors: Gil Daniel A. , Deming Dustin , Skala Melissa C.
Published: December 2020

Motivation

Accessible tools are needed for rapid, non-destructive imaging of patient-derived cancer organoid (PCO) treatment response to accelerate drug discovery and streamline treatment planning for individual patients.

Aim

Segment and track individual PCOs with widefield one-photon redox imaging to extract morphological and metabolic variables of treatment response.

Approach

Redox imaging of the endogenous fluorophores, NAD(P)H and FAD, was used to monitor the metabolic state and morphology of PCOs. Redox imaging was performed on a widefield one-photon epifluorescence microscope to evaluate drug response in two colorectal PCO lines. An automated image analysis framework was developed to track PCOs across multiple time points over 48 hours. Variables quantified for each PCO captured metabolic and morphological response to drug treatment, including the optical redox ratio and organoid area.

Results

The optical redox ratio (NAD(P)H/(FAD+NAD(P)H)) was independent of PCO morphology pre-tieatment. Drugs that induced cell death decreased the optical redox ratio and growth rate compared to control. Multivariate analysis of redox and morphology variables identified distinct PCO sub-populations. Single-organoid tracking improved sensitivity to drug treatment compared to pooled organoid analysis.

Conclusion

Widefield one-photon redox imaging can monitor metabolic and morphological changes on a single organoid-level, providing an accessible, non-destructive tool to screen drugs in patient-matched samples.
Projecting the combined healthcare burden of seasonal influenza and COVID-19
Authors: Du Zhanwei , Fox Spencer J. , Ingle Tanvi , Pignone Michael P. , Meyers Lauren Ancel
Published: December 2020

The overlapping 2020-2021 influenza season and COVID-19 pandemic may overwhelm hospitals throughout the Northern Hemisphere. Using a mathematical model, we project that COVID-19 burden will dwarf that of influenza. If non-pharmacological mitigation efforts fail, increasing influenza vaccination coverage by 30% points would avert 54 hospitalizations per 100,000 people.
A unified evolutionary origin for the ubiquitous protein transporters SecY and YidC
Authors: Lewis Aaron J. O. , Hegde Ramanujan S.
Published: December 2020

Cells use transporters to move protein across membranes, but the origins of the most ancient transporters are unknown. Here, we analyse the ubiquitous protein-conducting channel SecY. Features conserved by its two duplicated halves suggest that their common ancestor was an antiparallel homodimeric channel. Structural searches with SecY’s halves detect exceptional similarity with the only other ubiquitous protein transporter, YidC. Their shared fold comprises a three-helix bundle interrupted by a helical hairpin. In YidC this hairpin is cytoplasmic and facilitates substrate delivery, whereas in SecY it is transmembrane and forms the substrate-binding lateral gate helices. In both, the three-helix bundle forms a protein-conducting hydrophilic groove, delimited by a conserved hydrophobic residue. We propose that SecY originated as a homodimeric YidC homolog. Many YidC homologs now use this interface to heterodimerise with a conserved partner. Unification of the two ubiquitous protein transporters would reconstruct a key step in the evolution of cells.
Three-color single-molecule imaging reveals conformational dynamics of dynein undergoing motility
Authors: Niekamp Stefan , Stuurman Nico , Zhang Nan , Vale Ronald D.
Published: December 2020

The motor protein dynein undergoes coordinated conformational changes of its domains during motility along microtubules. Previous single-molecule studies analyzed the motion of the AAA rings of the dynein homodimer, but not the distal microtubule binding domains (MTBD) that step along the track. Here, we simultaneously tracked two MTBDs and one AAA ring of a single dynein, as it undergoes hundreds of steps with nanometer precision using three-color imaging. We show that the AAA ring and the MTBDs do not always step simultaneously and can take different sized steps. This variability in the movement between AAA ring and MTBD results in an unexpectedly large number of conformational states of dynein during motility. Extracting data on conformational transition biases, we could accurately model dynein stepping in silico. Our results reveal that the flexibility between major dynein domains is critical for dynein motility.
Factors Associated with Longitudinal Psychological and Physiological Stress in Health Care Workers During the COVID-19 Pandemic
Authors: Hirten Robert P. , Danieletto Matteo , Tomalin Lewis , Choi Katie Hyewon , Zweig Micol , Golden Eddye , Kaur Sparshdeep , Helmus Drew , Biello Anthony , Pyzik Renata , Calcogna Claudia , Freeman Robert , Sands Bruce E , Charney Dennis , Bottinger Erwin P , Keefer Laurie , Suarez-Farinas Mayte , Nadkarni Girish N. , Fayad Zahi A.
Published: December 2020

Introduction

The Coronavirus Disease 2019 (COVID-19) pandemic has resulted in psychological distress in health care workers (HCWs). There is a need to characterize which HCWs are at increased risk of psychological sequela from the pandemic.

Methods

HCWs across seven hospitals in New York City were prospectively followed in an ongoing observational digital study using the custom Warrior Watch Study App. Participants wore an Apple Watch for the duration of the study measuring HRV throughout the follow up period. Surveys were obtained daily.

Results

Three hundred and sixty-one HCWs were enrolled. Multivariable analysis found New York City COVID-19 case count to be significantly associated with increased longitudinal stress (p=0.008). A non-significant decrease in stress (p=0.23) was observed following COVID-19 diagnosis, though there was a borderline significant increase following the 4-week period after a COVID-19 diagnosis via nasal PCR (p=0.05). Baseline emotional support, baseline quality of life and baseline resilience were associated with decreased longitudinal stress (p<0.001). Baseline resilience and emotional support were found to buffer against stressors, with a significant reduction in stress during the 4-week period after COVID-19 diagnosis observed only in participants in the highest tertial of emotional support and resilience (effect estimate −0.97, p=0.03; estimate −1.78, p=0.006). A significant trend between New York City COVID-19 case count and longitudinal stress was observed only in the high tertial emotional support group (estimate 1.22, p=0.005), and was borderline significant in the high and medium resilience tertials (estimate 1.29, p=0.098; estimate 1.14, p=0.09). Participants in the highest tertial of baseline emotional support and resilience had significantly reduced amplitude and acrophase of the circadian pattern of longitudinally collected heart rate variability.

Conclusion

Our findings demonstrate that low resilience, emotional support, and quality of life identify HCWs at risk of high perceived longitudinal stress secondary to the COVID-19 pandemic and have a distinct physiological stress profile. Assessment of HCWs for these features can identify and permit allocation of psychological support to these at-risk individuals as the COVID-19 pandemic and its psychological effects continue in this vulnerable population.
Dynamic regulation of hierarchical heterogeneity in Acute Myeloid Leukemia serves as a tumor immunoevasion mechanism
Authors: Pospori Constandina , Grey William , Anton Sara Gonzalez , Gibson Shayin , Georgiou Christiana , Birch Flora , Stevens Georgia , Williams Thomas , Khorshed Reema , Haltalli Myriam , Skoufou-Papoutsaki Maria-Nefeli , Sloan Katherine , Encabo Hector Huerga , Hopkins Jack , Christodoulidou Chrysi , Stampoulis Dimitris , Hearn-Yeates Francesca , Gribben John , Stauss Hans J. , Chakraverty Ronjon , Bonnet Dominique , Lo Celso Cristina
Published: December 2020

Acute Myeloid Leukemia, a hematological malignancy with poor clinical outcome, is composed of hierarchically heterogeneous cells. We examine the contribution of this heterogeneity to disease progression in the context of anti-tumor immune responses and investigate whether these responses regulate the balance between stemness and differentiation in AML. Combining phenotypic analysis with proliferation dynamics and fate-mapping of AML cells in a murine AML model, we demonstrate the presence of a terminally differentiated, chemoresistant population expressing high levels of PDL1. We show that PDL1 upregulation in AML cells, following exposure to IFNγ from activated T cells, is coupled with AML differentiation and the dynamic balance between proliferation, versus differentiation and immunosuppression, facilitates disease progression in the presence of immune responses. This microenvironment-responsive hierarchical heterogeneity in AML may be key in facilitating disease growth at the population level at multiple stages of disease, including following bone marrow transplantation and immunotherapy.
Multistability and consequent phenotypic plasticity in AMPK-Akt double negative feedback loop in cancer cells
Authors: Chedere Adithya , Hari Kishore , Kumar Saurav , Rangarajan Annapoorni , Jolly Mohit Kumar
Published: December 2020

Adaptation and survival of cancer cells to various stress and growth factor conditions is crucial for successful metastasis. A double-negative feedback loop between two serine/threonine kinases AMPK and Akt can regulate the adaptation of breast cancer cells to matrix-deprivation stress. This feedback loop can generate majorly two phenotypes or cell states: matrix detachment-triggered pAMPKhigh/ pAktlowstate, and matrix (re)attachment-triggered pAkthigh/ pAMPKlowstate. However, whether these two cell states can exhibit phenotypic plasticity and heterogeneity in a given cell population, i.e., whether they can co-exist and undergo spontaneous switching to generate the other subpopulation, remains unclear. Here, we develop a mechanism-based mathematical model that captures the set of experimentally reported interactions among AMPK and Akt. Our simulations suggest that the AMPK-Akt feedback loop can give rise to two co-existing phenotypes (pAkthigh/ pAMPKlowand pAMPKhigh/pAktlow) in specific parameter regimes. Next, to test the model predictions, we segregated these two subpopulations in MDA-MB-231 cells and observed that each of them was capable of switching to another in adherent conditions. Finally, the predicted trends are supported by clinical data analysis of TCGA breast cancer and pan-cancer cohorts that revealed negatively correlated pAMPK and pAkt protein levels. Overall, our integrated computational-experimental approach unravels that AMPK-Akt feedback loop can generate multistability and drive phenotypic switching and heterogeneity in a cancer cell population.
Fusobacterium nucleatumfacilitates cetuximab resistance in colorectal cancer via the PI3K/AKT and JAK/STAT3 pathways
Authors: Han Hu , Li Yan , Qin Wan , Wang Lu , Yin Han , Su Beibei , Yuan Xianglin
Published: December 2020

Infectious pathogens contribute to about 20% of the total tumor burden.Fusobacterium nucleatum(Fn) has been associated with the initiation, progression, and therapy resistance in colorectal cancer (CRC). The over-abundance ofFnhas been observed in patients with right-sided CRC than in those with left-sided CRC. While theKRAS/NRAS/BRAFwild-type status of the CRC conferred better response to cetuximab in patients with left-sided CRC than with right-sided CRC. However, treatment failure remains the leading cause of tumor relapse and poor clinical outcome in patients with CRC. Here, we have studied the association ofFnto cetuximab resistance. Our functional studies indicate thatFnfacilitates resistance of CRC to cetuximabin vitroandin vivo. Moreover,Fnwas found to target the PI3K/AKT and JAK/STAT3 pathways, which altered the response to cetuximab therapy. Therefore, assessing the levels and targetingFnand the associated signaling pathways may allow modulating the treatment regimen and improve prognoses of CRC patients.
Live monitoring of ROS-induced cytosolic redox changes with roGFP2-based sensors in plants
Authors: Ugalde José Manuel , Fecker Lara , Schwarzländer Markus , Müller-Schüssele Stefanie J. , Meyer Andreas J.
Published: December 2020

Plant cells produce reactive oxygen species (ROS) as by-products of oxygen metabolism and for signal transduction. Depending on their concentration and their site of production, ROS can cause oxidative damage within the cell, and must be effectively scavenged. Detoxification of the most stable ROS, hydrogen peroxide (H2O2), via the glutathione-ascorbate pathway may transiently alter the glutathione redox potential (EGSH). Changes inEGSHcan thus be considered as a proxy of the oxidative load in the cell. Genetically encoded probes based on roGFP2 enable extended opportunities forin vivomonitoring of H2O2andEGSHdynamics. Here, we report detailed protocols for live monitoring of both parameters in the cytosol with the probes Grx1-roGFP2 forEGSHand roGFP2-Orp1 for H2O2, respectively. The protocols have been adapted for live cell imaging with high lateral resolution on a confocal microscope and for multiparallel measurements in whole organs or intact seedlings in a fluorescence microplate reader. Elicitor-induced ROS generation is used as an example for illustration of the opportunities for dynamic ROS measurements that can easily be transferred to other scientific questions and model systems.
Impact of mHealth interventions on antenatal and postnatal care utilization in low and middle-income countries: A Systematic Review and Meta-Analysis
Authors: Kant Ravi , Yadav Poonam , Kishore Surekha , Barnwal Shruti , Kumar Rajesh , Khapre Meenakshi
Published: December 2020

Objective

To evaluate the effectiveness of mHealth interventions on antenatal and postnatal care utilization in low and middle-income countries.

Design

Systematic review and meta-analysis

Setting

Studies from low and middle-income countries were included for analysis.

Participants

We searched the literature through major electronic databases such as PubMed, MEDLINE, Embase, Cochrane, Scopus, CINAHL, Clinical key, Google Scholar, Ovid databases with selected keywords, and explored the reference list of articles. Meta-analysis was performed in RevMan 5.4 software; p-value < 0.05 was considered statistically significant. The effect of variables was measured in the Odds ratio with a fixed-effect model. Six published interventional studies were selected as per the eligibility and PICO framed for the systematic review and meta-analysis. Search restricted to articles in the English language, online published, and preprint articles till September 2020.

Primary and secondary outcome measures

We evaluated the effectiveness of mHealth intervention on antenatal care utilization, including four antenatal check-ups, iron-folic acid supplementation, two tetanus toxoid immunizations, and postnatal care utilization, which includes postnatal check-ups of delivered mothers.

Results

Results have been presented in the form of a forest plot. Findings of this meta-analysis depicted the significant increase in four or more antenatal care attendance (OR=1.89, 95% CI-1.49-2.19), TT immunization (OR=1.63 (95% CI-1.17-2.27), compliance to iron supplementation (OR=1.88, 95% CI-1.18-3.00) and postnatal care attendance (OR=2.54 (95% CI-2.15-2.99) among those pregnant mothers who received mHealth intervention compared to control group.

Conclusion

This meta-analysis concluded that m-health has the potential to increase the utilization of full antenatal care and postnatal care compared to standard care, although the level of evidence is moderate.

Trial registration

CRD42020204618, PROSPERO, International prospective register of systematic reviews

Article Summary

Strengths and limitations of this study

This meta-analysis creates an evidence for the effectiveness of mHealth with pooled data of interventional studies with limited sample sizes.

Technology is changing, but even with limited support like SMS, there was an improvement in antenatal and postnatal service utilization.

Sensitivity analysis identified possible reasons for heterogeneity among studies.

Studies included from LMICs so results can be generalized for the respective population.

mHealth as an intervention is a broad term that created heterogeneity also.
SPaRTAN, a computational framework for linking cell-surface receptors to transcriptional regulators
Authors: Ma Xiaojun , Somasundaram Ashwin , Qi Zengbiao , Singh Harinder , Osmanbeyoglu Hatice Ulku
Published: December 2020

The identity and functions of specialized cell types are dependent on the complex interplay between signaling and transcriptional networks. We present SPaRTAN (Single-cell Proteomic and RNA based Transcription factor Activity Network), a computational method to link cell-surface receptors to transcription factors (TFs) by exploiting cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) datasets with cis-regulatory information. SPaRTAN is applied to immune cell types in the blood to predict the coupling of signaling receptors with cell context-specific TFs. The predictions are validated by prior knowledge and flow cytometry analyses. SPaRTAN is then used to predict the signaling coupled TF states of tumor infiltrating CD8+T cells in malignant peritoneal and pleural mesotheliomas. SPaRTAN greatly enhances the utility of CITE-seq datasets to uncover TF and cell-surface receptor relationships in diverse cellular states.

Significance

Recently single-cell technologies such as CITE-seq have been developed that enable simultaneous quantitative analysis of cell-surface receptor expression with transcriptional states. To date, these datasets have not been used to systematically develop cell-context-specific maps of the interface between signaling and transcriptional regulators orchestrating cellular identity and function. We developed a computational framework, SPaRTAN (Single-cell Proteomic and RNA based Transcription factor Activity Network) that integrates single-cell proteomic and transcriptomic data based on CITE-seq with cis-regulatory information. We applied our method to publicly available (PBMCs) and new CITE-seq datasets (mesothelioma). Our predicted TF activity and cell-surface receptor relationships are validated by prior knowledge as well as experimental testing. SPaRTAN reveals many previously unidentified surface-receptor associated TFs.
20 µs-resolved high-throughput X-ray photon correlation spectroscopy on a 500k pixel detector enabled by data-management workflow
Authors: Zhang Qingteng , Dufresne Eric M. , Nakaye Yasukazu , Jemian Pete R. , Sakumura Takuto , Sakuma Yasutaka , Ferrara Joseph D. , Maj Piotr , Hassan Asra , Bahadur Divya , Ramakrishnan Subramanian , Khan Faisal , Veseli Sinisa , Sandy Alec R. , Schwarz Nicholas , Narayanan Suresh
Published: December 2020

The performance of the new 52 kHz frame rate Rigaku XSPA-500k detector was characterized on beamline 8-ID-I at the Advanced Photon Source at Argonne for X-ray photon correlation spectroscopy (XPCS) applications. Due to the large data flow produced by this detector (0.2 PB of data per 24 h of continuous operation), a workflow system was deployed that uses the Advanced Photon Source data-management (DM) system and high-performance software to rapidly reduce area-detector data to multi-tau and two-time correlation functions in near real time, providing human-in-the-loop feedback to experimenters. The utility and performance of the workflow system are demonstrated via its application to a variety of small-angle XPCS measurements acquired from different detectors in different XPCS measurement modalities. The XSPA-500k detector, the software and the DM workflow system allow for the efficient acquisition and reduction of up to ∼109 area-detector data frames per day, facilitating the application of XPCS to measuring samples with weak scattering and fast dynamics.
Integrated care effectiveness for adults with co-occurring disorders
Authors: Mooss Angela , Myatt Joyce , Goldman Jennifer , Alexander Joey-Ann
Published: December 2020

Purpose

This study examined effectiveness of an integrated care program on emergency department visits within a longitudinal sample of patients with both primary care and behavioral health diagnoses.

Design/methodology/approach

Patients with co-occurring disorders enrolled in an integrated care clinic and were followed over time to determine whether participation in the clinic, including engagement in wellness/peer services, predicted decreases in Emergency Department (ED) use. Associations between socio-demographic characteristics of patients and ED use were also analyzed.

Findings

After 6 months, clinic patients had decreases in ED use that continued for twelve months, albeit to a lesser degree. Demographics and program services were not related to ED use; however, multiple associations existed between high ED utilizers, severe mental illness (SMI), substance use disorders (SUD) and non-retention in services.

Research limitations/implications

The study lacked a comparison group and there was no distinction between avoidable and unavoidable ED visits. A small sample size across time points led to inconclusive post hoc findings.

Originality/value

This study explored effectiveness of primary care integration into a behavioral health clinic for persons with multiple morbidities. Although initial decreases in ED visits were present, results indicate that these models may not be effective for persons with SMI or SMI/SUD who are already high ED users. This study provides support for integrated care in reducing ED use among persons with multiple morbidities and calls for further research on designing effective integrated models for persons with SMI and SUD.
Exosomal miR‐3180‐3p inhibits proliferation and metastasis of non‐small cell lung cancer by downregulating FOXP4
Authors: Chen Tengfei , Liu Yali , Chen Jun , Zheng Huifei , Chen Qiuyun , Zhao Jun
Published: December 2020

Background

Non‐small cell lung cancer (NSCLC) is one of the most malignant cancers worldwide and its pathogenesis is not completely clear. In this study, we explored the functions and mechanisms of exosomes transferring miR‐3180‐3p in NSCLC progression.

Methods

The expression levels of miR‐3180‐3p in NSCLC tissues and paracarcinoma tissues was obtained from the GEO database (GEO: GSE53882). Exosomes derived from A549 cells were identified. Proliferation, migration and invasion were measured after treatment with exosomal miR‐3180‐3p or transfection using miR‐3180‐3p mimics. The relationship between miR‐3180‐3p and forkhead box P4 (FOXP4) was predicted using a bioinformatic tool and measured using a dual‐luciferase reporter gene assay and western blotting. Finally, a mouse xenograft model of NSCLC cells was established to verify the function of exosomal miR‐3180‐3p in vivo.

Results

We found that miR‐3180‐3p decreased in both NSCLC cell lines and patient tissues. Overexpression of miR‐3180‐3p or treatment with exosomal miR‐3180‐3p significantly suppressed cell proliferation and metastasis in NSCLC cell lines. Subsequently, we found miR‐3180‐3p downregulated FOXP4 protein expression levels. Furthermore, the volumes and weights of nude mouse tumors expressing exosomal miR‐3180‐3p were significantly reduced.

Conclusions

Exosomal miR‐3180‐3p suppresses NSCLC progression by downregulating FOXP4 expression.

Key points

Significant findings of the study

We found that exosomal miR‐3180‐3p suppressed NSCLC progression and also identified a miR‐3180‐3p target gene. These findings provide a foundation to determine innovative therapeutic strategies.

What this study adds

This study contributes to research investigating exosomal containing miRNAs.
Magnocellular and Parvocellular Mediated Luminance Contrast Discrimination in Severe Alcohol Use Disorder
Authors: Creupelandt Coralie , Maurage Pierre , Lenoble Quentin , Lambot Carine , Geus Christophe , D’Hondt Fabien
Published: December 2020

Background

Severe alcohol use disorder (SAUD) is associated with widespread cognitive impairments, including low‐level visual processing deficits that persist after prolonged abstinence. However, the extent and characteristics of these visual deficits remain largely undetermined, impeding the identification of their underlying mechanisms and influence on higher‐order processing. In particular, little work has been conducted to assess the integrity of the magnocellular (MC) and parvocellular (PC) visual pathways, namely the 2 main visual streams that convey information from the retina up to striate, extrastriate, and dorsal/ventral cerebral regions.

Methods

We investigated achromatic luminance contrast processing mediated by inferred MC and PC pathways in 33 patients with SAUD and 32 matched healthy controls using 2 psychophysical pedestal contrast discrimination tasks that promote responses of inferred MC or PC pathways. We relied on a staircase procedure to assess participants’ ability to detect small changes in luminance within an array of 4 gray squares that were either continuously presented (steady pedestal, MC‐biased) or briefly flashed (pulsed pedestal, PC‐biased).

Results

We replicated the expected pattern of MC and PC contrast responses in healthy controls. We found preserved dissociation of MC and PC contrast signatures in SAUD but higher MC‐mediated mean contrast discrimination thresholds combined with a steeper PC‐mediated contrast discrimination slope compared with healthy controls.

Conclusion

These findings indicate altered MC‐mediated contrast sensitivity and PC‐mediated contrast gain, confirming the presence of early sensory disturbances in individuals with SAUD. Such low‐level deficits, while usually overlooked, might influence higher‐order abilities (e.g., memory, executive functions) in SAUD by disturbing the “coarse‐to‐fine” tuning of the visual system, which relies on the distinct functional properties of MC and PC pathways and ensures proper and efficient monitoring of the environment.
Plastic ingestion is an underestimated cause of death for southern hemisphere albatrosses
Authors: Roman Lauren , Butcher Richelle Grace , Stewart David , Hunter Stuart , Jolly Megan , Kowalski Phil , Hardesty Britta Denise , Lenting Baukje
Published: December 2020

Albatrosses are among the world's most imperiled vertebrates, with 73% of species threatened with extinction. Ingestion of plastic is a well‐recognized threat among three North Pacific species, but lesser known in the southern hemisphere, where it is considered a minor threat. As plastic entering the ocean is increasing while albatross populations decline, the threat of ocean plastic to albatross populations may be underestimated. We present case studies of 107 beach‐cast albatrosses of twelve species, received by wildlife hospitals in Australia and New Zealand, and estimate plastic ingestion and mortality rates for albatrosses in the southern hemisphere. Ingested plastic was present in 5.6% of individuals, and the cause of death in half of these cases. We estimate ingestion of plastic may cause 3.4–17.5% of nearshore mortalities and is worth consideration as a substantial threat to albatross populations. We provide clinical findings and “checklist” methodologies for identifying potential cases of foreign‐body gastrointestinal obstruction. We suggest practical policy responses, empowering decision makers to reduce albatross mortality from anthropogenic sources.
Ski promotes proliferation and inhibits apoptosis in fibroblasts under high‐glucose conditions via the FoxO1 pathway
Authors: Peng Yan , Xiong Ren‐Ping , Zhang Zhuo‐Hang , Ning Ya‐Lei , Zhao Yan , Tan Si‐Wei , Zhou Yuan‐Guo , Li Ping
Published: December 2020

Objectives

The present study clarified the role and signalling pathway of Ski in regulating proliferation and apoptosis in fibroblasts under high‐glucose (HG) conditions.

Materials and Methods

The proliferation and apoptosis of rat primary fibroblasts were assessed using EdU incorporation and TUNEL assays. The protein and phosphorylation levels of the corresponding factors were measured using immunofluorescence staining and Western blotting. Immunoprecipitation was used to determine the interactions between Ski and FoxO1 or Ski and HDAC1. The Ski protein was overexpressed via recombinant adenovirus transfection, and FoxO1 and HDAC1 were knocked down using targeted small‐interfering RNA.

Results

The present study found that HG inhibited fibroblast proliferation, increased apoptosis and reduced Ski levels in rat primary fibroblasts. Conversely, increasing Ski protein levels alleviated HG‐induced proliferation inhibition and apoptosis promotion. Increasing Ski protein levels also increased Ski binding to FoxO1 to decrease FoxO1 acetylation, and interfering with FoxO1 caused loss of the regulatory effect of Ski in fibroblasts under HG. Increasing Ski protein levels decreased FoxO1 acetylation via HDAC1‐mediated deacetylation.

Conclusions

Therefore, these findings confirmed for the first time that Ski regulated fibroblast proliferation and apoptosis under HG conditions via the FoxO1 pathway.
Cross‐national comparison of social isolation and mortality among older adults: A 10‐year follow‐up study in Japan and England
Authors: Saito Masashige , Aida Jun , Cable Noriko , Zaninotto Paola , Ikeda Takaaki , Tsuji Taishi , Koyama Shihoko , Noguchi Taiji , Osaka Ken , Kondo Katsunori
Published: December 2020

Aim

Existing evidence links social isolation with poor health. To examine differences in the mortality risk by social isolation, and in socio‐economic correlates of social isolation, we analyzed large‐scale cohort studies in Japan and England.

Methods

Participants were drawn from the Japan Gerontological Evaluation Study (JAGES) and the English Longitudinal Study of Ageing (ELSA). We analyzed the 10‐year mortality among 15 313 JAGES participants and 5124 ELSA respondents. Social isolation was measured by two scales, i.e., scoring the frequency of contact with close ties, and a composite measurement of social isolation risk. We calculated the population attributable fraction, and Cox regression models with multiple imputations were used to estimate hazard ratios (HRs) for mortality due to social isolation.

Results

The proportion of those with contact frequency of less than once a month was 8.5% in JAGES and 1.3% in ELSA. Males, older people, those with poor self‐rated health, and unmarried people were significantly associated with social isolation in both countries. Both scales showed that social isolation among older adults had a remarkably higher risk for premature death (less frequent contact with others in JAGES: hazard ratio [HR] = 1.18, 95% confidence interval [CI]: 1.05–1.33, in ELSA: HR = 1.27, 95% CI: 0.85–1.89; and high isolation risk score in JAGES: HR = 1.30, 95% CI: 1.12–1.50, in ELSA: HR = 2.05, 95% CI: 1.52–2.73). The population attributable fraction showed less frequent contact with close ties was attributed to about 18 000 premature deaths annually in Japan, in contrast with about 1800 in England.

Conclusions

Negative health impacts of social isolation were higher among older Japanese compared with those in England. Geriatr Gerontol Int 2021; 21: 209–214.
How politicians see their relationship with top bureaucrats: Revisiting classical images
Authors: Baekgaard Martin , Blom‐Hansen Jens , Serritzlew Søren
Published: December 2020

The relationship between politicians and bureaucrats is an enduring concern in political science. Central to this debate, Aberbach, Putnam, and Rockman (APR) in 1981 developed four images to characterize political‐bureaucratic relations. We argue that the one‐dimensional focus on roles in their images comes with important limitations. To deal with these limitations, we collect survey responses from 3,384 local politicians from four countries on seven dimensions of the political‐bureaucratic relationship. We then use cluster analysis to develop six images bottom‐up. Five of our images are largely consistent with APR's image II and III. Yet, they differ in the extent to which politicians trust the bureaucracy, consider them loyal, and see them as an important source of information. A sixth image is not consistent with any of APR's images. We find that both systemic (country, municipality size) and individual factors (ideology, position, seniority) contribute to differences in images. Overall, our images suggest that political‐bureaucratic relations vary more between and within political systems than suggested by APR's images.
Septic arthritis due to Neisseria gonorrhoea in Western Australia
Authors: Nossent Johannes , Raymond Warren , Keen Helen , Preen David B. , Inderjeeth Charles A.
Published: December 2020

Background

A high prevalence of gonococcal infections has been reported from remote parts of Western Australia, but the occurrence of disseminated infection leading to arthritis has not been studied.

Aims

To investigate the frequency, risk factors and long‐term outcome of gonococcal arthritis (GA) in Western Australia (WA).

Methods

A population‐based data linkage study of patients with a hospital‐based diagnosis of GA in WA between 1990 and 2014. Demographics, standardised incidence rates per million and comorbidity accrued before (lookback 186 months, interquartile range (IQR) 86–267) and after the index hospital contact for GA (follow up 100 months, IQR 60–209) are presented as frequency (%), median (IQR) or rates /1000 months.

Results

In total, 98 patients were diagnosed with GA. The annual incidence of GA increased from 1.35 to 2.10 per million between 1990 and 2014, but the rate of GA complicating all gonococcal infections was stable around 0.25%. Female patients with GA (54%; n = 53/98) were younger (24 vs 38 years) and more frequently identified as indigenous (88% vs 49%) than male patients (46%; n = 45/98; P = 0.002). Female patients had higher rates of prior infections (15.5 vs 8.1 per 1000 months; P = 0.002) and diabetes mellitus (15.9% vs 2.5%; P = 0.03) and a longer hospital stay (10 vs 8 days; P = 0.02). GA recurrence rate during follow up was low (2%), but a broad range of comorbidities developed contributing to a 14% crude death rate.

Conclusions

GA stably complicates 0.25% of gonococcal infections in WA with young indigenous females and middle‐aged non‐indigenous males most affected. Prior infectious disease and diabetes mellitus are potential risk factors for GA in females. GA recurs rarely, but its development reflects a high risk of morbidity and mortality over the following 10 years.
Circular RNA in cardiovascular disease: Expression, mechanisms and clinical prospects
Authors: Tang Ying , Bao Jinghui , Hu Jiahui , Liu Leiling , Xu Dan‐Yan
Published: December 2020

Circular RNAs (circRNAs) are a group of covalently closed, endogenous, non‐coding RNAs, which exist widely in human tissues including the heart. Increasing evidence has shown that cardiac circRNAs play crucial regulatory roles in cardiovascular diseases (CVDs). In this review, we aimed to provide a systemic understanding of circRNAs with a special emphasis on the cardiovascular system. We have summarized the current research on the classification, biogenesis and properties of circRNAs as well as their participation in the pathogenesis of CVDs. CircRNAs are conserved, stable and have specific spatiotemporal expression; thus, they have been accepted as a potential diagnostic marker or an incremental prognostic biomarker for CVDs.
Arabidopsis U‐box E3 ubiquitin ligase PUB11 negatively regulates drought tolerance by degrading the receptor‐like protein kinases LRR1 and KIN7
Authors: Chen Xuexue , Wang Tingting , Rehman Amin Ur , Wang Yu , Qi Junsheng , Li Zhen , Song Chunpeng , Wang Baoshan , Yang Shuhua , Gong Zhizhong
Published: December 2020

Both plant receptor‐like protein kinases (RLKs) and ubiquitin‐mediated proteolysis play crucial roles in plant responses to drought stress. However, the mechanism by which E3 ubiquitin ligases modulate RLKs is poorly understood. In this study, we showed that Arabidopsis PLANT U‐BOX PROTEIN 11 (PUB11), an E3 ubiquitin ligase, negatively regulates abscisic acid (ABA)‐mediated drought responses. PUB11 interacts with and ubiquitinates two receptor‐like protein kinases, LEUCINE RICH REPEAT PROTEIN 1 (LRR1) and KINASE 7 (KIN7), and mediates their degradation during plant responses to drought stress in vitro and in vivo. pub11 mutants were more tolerant, whereas lrr1 and kin7 mutants were more sensitive, to drought stress than the wild type. Genetic analyses show that the pub11 lrr1 kin7 triple mutant exhibited similar drought sensitivity as the lrr1 kin7 double mutant, placing PUB11 upstream of the two RLKs. Abscisic acid and drought treatment promoted the accumulation of PUB11, which likely accelerates LRR1 and KIN7 degradation. Together, our results reveal that PUB11 negatively regulates plant responses to drought stress by destabilizing the LRR1 and KIN7 RLKs.
Large‐scale diversity reassessment, evolutionary history, and taxonomic revision of the green macroalgae family Udoteaceae (Bryopsidales, Chlorophyta)
Authors: Lagourgue Laura , Payri Claude E.
Published: December 2020

Udoteaceae is a morphologically diverse family of the order Bryopsidales. Despite being very widespread geographically, this family is little known as compared with the closely related Halimedaceae or Caulerpaceae. Using the most extensive Udoteaceae collection to date and a multilocus genetic data set (tufA, rbcL, and 18S rDNA), we reassessed the species diversity of the family, as well as the phylogenetic relationships, the diagnostic morphoanatomical characters, and evolutionary history of its genera, toward a proposed taxonomic revision. Our approach included a combination of molecular and morphological criteria, including species delimitation methods, phylogenetic reconstruction, and mapping of trait evolution. We successfully delimited 62 species hypotheses, of which 29 were assigned (existing) species names and 13 represent putative new species. Our results also led us to revise the genera Udotea s.s., Rhipidosiphon s.s., and Chlorodesmis s.s., to validate the genus Rhipidodesmis, and to propose three new genera: Glaukea gen. nov., Ventalia gen. nov., and Udoteopsis gen. nov. We also identified two large species complexes, which we refer to as the “Penicillus–Rhipidosiphon–Rhipocephalus–Udotea complex” and the “Poropsis–Penicillus–Rhipidodesmis complex”. Using a time‐calibrated phylogeny, we estimated the origin of the family Udoteaceae at Late Triassic (ca. 216 Ma), whereas most of the genera originated during Paleogene. Our morphological inference results indicated that the thallus of the Udoteaceae ancestor was likely entirely corticated and calcified, composed of a creeping axis with a multisiphonous stipe and a pluristromatic flabellate frond. The frond shape, cortication, and calcification are still symplesiomorphies for most extant Udoteaceae genera and represent useful diagnostic characters.
Sleep in older adolescents. Results from a large cross‐sectional, population‐based study
Authors: Saxvig Ingvild West , Bjorvatn Bjørn , Hysing Mari , Sivertsen Børge , Gradisar Michael , Pallesen Ståle
Published: December 2020

The aim of the present study was to describe sleep patterns in a large and representative sample of Norwegian adolescents. The sample included 4,010 first‐year high school students, aged 16–17 years (54% female), who completed a web‐based survey on sleep patterns. The process of going to sleep was addressed as a two‐step sequence of (a) shuteye latency (interval from bedtime to shuteye time) and (b) sleep onset latency (interval from shuteye time to sleep onset). Results showed that 84.8% of the adolescents failed to obtain the recommended amount of sleep (8+ h) on schooldays, and 49.4% obtained less than 7 h. Mean bedtime on schooldays was 10:33 PM, with rise time 8:19 h later (time in bed). The adolescents reported long school‐day shuteye latency (43 min), limiting sleep opportunity to 7:36 h. Sleep onset latency was 32 min and mean school‐day sleep duration was only 6:43 h. On free days, 26.3% of the adolescents obtained less than 8 h of sleep, and 11.7% obtained less than 7 h. Mean bedtime was 00:33 AM, time in bed was 10:35 h, shuteye latency was 39 min and sleep onset latency was 24 min. Mean free‐day sleep duration was 8:38 h. There were sex differences in several sleep parameters, including shuteye latency. The results indicate that the majority of Norwegian adolescents fail to obtain the recommended amount of sleep (8+ h) on schooldays. Long shuteye latency appears to be a main driver for short school‐day sleep duration in adolescents.