bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment
Authors: Nicolas-Boluda Alba , Vaquero Javier , Barrin Sarah , Kantari-Mimoun Chahrazade , Ponzo Matteo , Renault Gilles , Deptuła Piotr , Pogoda Katarzyna , Bucki Robert , Cascone Ilaria , Courty Jose , Fouassier Laura , Gazeau Florence , Donnadieu Emmanuel
Published: May 2020

Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing 5 preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase (LOX) was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.
A novel essential RNA-binding protein complex inTrypanosoma brucei
Authors: Bajak Kathrin , Leiss Kevin , Clayton Christine , Erben Esteban
Published: May 2020

ZC3H5 is an essential cytoplasmic trypanosome protein with a single Cx7Cx5Cx3H zinc finger domain. We here show that ZC3H5 forms a complex with three other proteins, encoded by genes Tb927.11.4900, Tb927.8.1500 and Tb927.7.3040. ZC3H5 interacts directly with Tb927.11.4900, which in turn interacts with Tb927.7.3040. Tb927.11.4900 has a circularly permuted GTPase domain, which is required for the Tb927.7.3040 interaction. RNA immunoprecipitation revealed that ZC3H5 is preferentially associated with poorly translated, low-stability mRNAs, the 5’-untranslated regions and coding regions of which are enriched in the motif (U/A)UAG(U/A). Tethering of ZC3H5, or other complex components, to a reporter repressed its expression. However, depletion of ZC3H5in vivodid not increase the abundance of ZC3H5-bound mRNAs: instead, counter-intuitively, there were very minor decreases in a few targets, and marked increases in the abundances of very stable mRNAs encoding ribosomal proteins. Depletion also resulted in an increase in monosomes at the expense of large polysomes, and appearance of “halfmer” disomes containing two 80S subunits and one 40S subunit. We speculate that the ZC3H5 complex might be implicated in quality control during the translation of sub-optimal open reading frames; complex assembly might be regulated by GTP hydrolysis and GTP-GDP exchange.
Insights into rumen microbial biosynthetic gene cluster diversity through genome-resolved metagenomics
Authors: Anderson Christopher L. , Fernando Samodha C.
Published: May 2020

Ruminants are critical to global food security as they transform lignocellulosic biomass into high-quality protein products. The rumen microbes ferment feed to provide necessary energy and nutrients for the ruminant host. However, we still lack insight into the metabolic processes encoded by most rumen microbial populations. In this study, we implemented metagenomic binning approaches to recover 2,809 microbial genomes from cattle, sheep, moose, deer, and bison. By clustering genomes based on average nucleotide identity, we demonstrate approximately one-third of the metagenome-assembled genomes (MAGs) to represent species not present in current reference databases and rumen microbial genome collections. Combining these MAGs with other rumen genomic datasets permitted a phylogenomic characterization of the biosynthetic gene clusters (BGCs) from 8,160 rumen microbial genomes, including the identification of 5,346 diverse gene clusters for nonribosomal peptide biosynthesis. A subset ofPrevotellaandSelenomonasBGCs had higher expression in steers with lower feed efficiency. Moreover, the microdiversity of BGCs was fairly constant across types of BGCs and cattle breeds. The reconstructed genomes expand the genomic representation of rumen microbial lineages, improve the annotation of multi-omics data, and link microbial populations to the production of secondary metabolites that may constitute a source of natural products for manipulating rumen fermentation.
In vivoCRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer
Authors: Chen Zeyu , Arai Eri , Khan Omar , Zhang Zhen , Ngiow Shin Foong , He Yuan , Huang Hua , Manne Sasikanth , Cao Zhendong , Baxter Amy E. , Cai Zhangying , Freilich Elizabeth , Ali Mohammed A. , Giles Josephine R. , Wu Jennifer E. , Greenplate Allison R. , Kurachi Makoto , Nzingha Kito , Ekshyyan Viktoriya , Wen Zhuoyu , Speck Nancy A. , Battle Alexis , Berger Shelley L. , Wherry E. John , Shi Junwei
Published: May 2020

Improving effector activity of antigen specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TF), the transcriptional coordination of TEFFbiology remains poorly understood. We developed anin vivoT cell CRISPR screening platform and identified a novel mechanism restraining TEFFbiology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFFresponses without compromising memory or exhaustion precursors. Fli1 restrained TEFFlineage differentiation by binding tocis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs allowing more efficient Runx3-driven TEFFbiology. CD8 T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8 T cell transcriptional landscape from excessive ETS:RUNX-driven TEFFcell differentiation. Moreover, genetic deletion of Fli1 improves TEFFdifferentiation and protective immunity in infections and cancer.
RdRp mutations are associated with SARS-CoV-2 genome evolution
Authors: Eskier Doğa , Karakülah Gökhan , Suner Aslı , Oktay Yavuz
Published: May 2020

COVID-19, caused by the novel SARS-CoV-2 virus, started in China in late 2019, and soon became a global pandemic. With the help of thousands of viral genome sequences that have been accumulating, it has become possible to track the evolution of viral genome over time as it spread across the world. An important question that still needs to be answered is whether any of the common mutations affect the viral properties, and therefore the disease characteristics. Therefore, we sought to understand the effects of mutations in RNA-dependent RNA polymerase (RdRp), particularly the common 14408C>T mutation, on mutation rate and viral spread. By focusing on mutations in the slowly evolving M or E genes, we aimed to minimize the effects of selective pressure. Our results indicate that 14408C>T mutation increases the mutation rate, while the third-most common RdRp mutation, 15324C>T, has the opposite effect. It is possible that 14408C>T mutation may have contributed to the dominance of its co-mutations in Europe and elsewhere.
A replication-competent vesicular stomatitis virus for studies of SARS-CoV-2 spike-mediated cell entry and its inhibition
Authors: Dieterle M. Eugenia , Haslwanter Denise , Bortz Robert H. , Wirchnianski Ariel S. , Lasso Gorka , Vergnolle Olivia , Abbasi Shawn A. , Fels J. Maximilian , Laudermilch Ethan , Florez Catalina , Mengotto Amanda , Kimmel Duncan , Malonis Ryan J. , Georgiev George , Quiroz Jose , Barnhill Jason , Pirofski Liise-anne , Daily Johanna P. , Dye John M. , Lai Jonathan R. , Herbert Andrew S. , Chandran Kartik , Jangra Rohit K.
Published: May 2020

There is an urgent need for vaccines and therapeutics to prevent and treat COVID-19. Rapid SARS-CoV-2 countermeasure development is contingent on the availability of robust, scalable, and readily deployable surrogate viral assays to screen antiviral humoral responses, and define correlates of immune protection, and to down-select candidate antivirals. Here, we describe a highly infectious recombinant vesicular stomatitis virus bearing the SARS-CoV-2 spike glycoprotein S as its sole entry glycoprotein that closely resembles the authentic agent in its entry-related properties. We show that the neutralizing activities of a large panel of COVID-19 convalescent sera can be assessed in high-throughput fluorescent reporter assay with rVSV-SARS-CoV-2 S and that neutralization of the rVSV and authentic SARS-CoV-2 by spike-specific antibodies in these antisera is highly correlated. Our findings underscore the utility of rVSV-SARS-CoV-2 S for the development of spike-specific vaccines and therapeutics and for mechanistic studies of viral entry and its inhibition.
Glyphosate Inhibits Melanization and Increases Susceptibility to Infection in Insects
Authors: Smith Daniel F. Q. , Camacho Emma , Thakur Raviraj , Barron Alexander J. , Dong Yuemei , Dimopoulos George , Broderick Nichole A. , Casadevall Arturo
Published: May 2020

Melanin, a black-brown pigment found throughout all kingdoms of life, has diverse biological functions including: UV protection, thermoregulation, oxidant scavenging, arthropod immunity, and microbial virulence. Given melanin’s broad roles in the biosphere, particularly in insect immune defenses, it is important to understand how exposure to ubiquitous environmental contaminants affects melanization. Glyphosate – the most widely used herbicide globally – inhibits melanin production, which could have wide-ranging implications in the health of many organisms, including insects. Here, we demonstrate that glyphosate has deleterious effects on insect health in two evolutionary distant species,Galleria mellonella(Lepidoptera: Pyralidae) andAnopheles gambiae(Diptera: Culicidae), suggesting a broad effect in insects. Glyphosate reduced survival ofG. mellonellacaterpillars following infection with the fungusCryptococcus neoformansand decreased the size of melanized nodules formed in hemolymph, which normally help eliminate infection. Glyphosate also increased the burden of the malaria- causing parasitePlasmodium falciparuminA. gambiaemosquitoes, altered uninfected mosquito survival, and perturbed the microbial composition of adult mosquito midguts. Our results show that glyphosate’s mechanism of melanin inhibition involves antioxidant synergy and disruption of the reaction oxidation-reduction balance Overall, these findings suggest that glyphosate’s environmental accumulation could render insects more susceptible to microbial pathogens due to melanin inhibition, immune impairment, and perturbations in microbiota composition, potentially contributing to declines in insect populations.
Endogenous viral element-derived piRNAs are not required for production of ping-pong-dependent piRNAs from Diaphorina citri densovirus
Authors: Nigg Jared C. , Kuo Yen-Wen , Falk Bryce W.
Published: May 2020

Partial integrations of DNA and non-retroviral RNA virus genomes, termed endogenous viral elements (EVEs), are abundant in arthropod genomes and often produce PIWI-interacting RNAs (piRNAs) speculated to target cognate viruses through the ping-pong cycle, a post-transcriptional RNA silencing mechanism. Here we describe a Diaphorina citri densovirus (DcDV)-derived EVE in the genome ofDiaphorina citri. We found that this EVE gives rise to DcDV-specific primary piRNAs and is unevenly distributed amongD. citripopulations. Unexpectedly, we found that DcDV is targeted by ping-pong-dependent viral piRNAs (vpiRNAs) inD. citrilacking the DcDV-derived EVE, while four naturally infecting RNA viruses ofD. citriare not targeted by vpiRNAs. Furthermore, a recombinant Cricket paralysis virus containing a portion of the DcDV genome corresponding to the DcDV-derived EVE was not targeted by vpiRNAs during infection inD. citriharboring the EVE. These results represent the first report of ping-pong-dependent vpiRNAs outside of mosquitoes.
Notch family members follow stringent requirements for intracellular domain dimerization at sequence-paired sites
Authors: Crow Jacob J. , Albig Allan R.
Published: May 2020

Notch signaling is essential for multicellular life, regulating core functions such as cellular identity, differentiation, and fate. These processes require highly sensitive systems to avoid going awry, and one such regulatory mechanism is through Notch intracellular domain dimerization. Select Notch target genes contain sequence-paired sites (SPS); motifs in which two Notch transcriptional activation complexes can bind and interact through Notch’s ankyrin domain, resulting in enhanced transcriptional activation. This mechanism has been mostly studied through Notch1, and to date, the abilities of the other Notch family members have been left unexplored. Through the utilization of minimalized, SPS-driven luciferase assays, we were able to test the functional capacity of Notch dimers. Here we show that each family member is capable of dimerization-induced signaling, following the same stringent requirements as seen with Notch1. Interestingly, we identified a mechanical difference between canonical and cryptic SPSs, leading to differences in their dimerization-induced regulation. Finally, we profiled the Notch family members’ SPS gap distance preferences and found that they all prefer a 16-nucleotide gap, with little room for variation. In summary, this work highlights the potent and highly specific nature of Notch dimerization and refines the scope of this regulatory function.
Functional selective FPR1 signaling in favor of an activation of the neutrophil superoxide generating NOX2-complex
Authors: Lind Simon , Dahlgren Claes , Holmdahl Rikard , Olofsson Peter , Forsman Huamei
Published: May 2020

Two formyl peptide receptors (FPR1 and FPR2), abundantly expressed by neutrophils, regulate both pro-inflammatory tissue recruitment of neutrophils and resolution of inflammatory reactions. This dual functionality of the FPRs, opens for a possibility to develop receptor selective therapeutics as mechanism for novel anti-inflammatory treatments. In line with this, high throughput screening studies have identified numerous FPR ligands belonging to different structural classes, but a potent FPR1 agonist with defined biased signaling and functional selectivity has not yet been reported. In this study, we used an FPR1 selective small compound agonist (RE) that represents a chemical entity developed from NOX2 activators identified from our earlier screening studies (WO2012127214). This FPR1 agonist potently activates neutrophils to produce reactive oxygen species (ROS, EC50~1 nM), whereas it is a weaker chemoattractant than the prototype FPR1 agonist fMLF. At the signaling level, RE has a strong bias towards the PLC-PIP2-Ca2+pathway and ERK1/2 activation but away from β-arrestin recruitment and the ability to recruit neutrophils chemotactically. In addition, FPR1 when activated by RE could cross-regulate other receptor-mediated neutrophil functions. In comparison to the peptide agonist fMLF, RE is more resistant to oxidization-induced inactivation by the MPO-H2O2-halide system. In summary, this study describes as a novel FPR1 agonist displaying a biased signaling and functional selectivity when activating FPR1 in human blood neutrophils. RE could possibly be a useful tool compound not only for further mechanistic studies of the regulatory role of FPR1 in inflammationin vitroandin vivo, but also for developing FPR1specific drug therapeutics.
CONTAIN: An open-source shipping container laboratory optimised for automated COVID-19 diagnostics
Authors: Walker Kenneth T. , Donora Matthew , Thomas Anthony , Phillips Alexander James , Ramgoolam Krishma , Pilch Kjara S , Oberacker Phil , Jurkowski Tomasz Piotr , Gosman Rares Marius , Fleiss Aubin , Perkins Alex , MacKenzie Neil , Zuckerman Mark , Danovi Davide , Steiner Helene , Meany Thomas
Published: May 2020

The COVID-19 pandemic has challenged diagnostic systems globally. Expanding testing capabilities to conduct population-wide screening for COVID-19 requires innovation in diagnostic services at both the molecular and industrial scale. No report to-date has considered the complexity of laboratory infrastructure in conjunction with the available molecular assays to offer a standardised solution to testing. Here we present CONTAIN. A modular biosafety level 2+ laboratory optimised for automated RT-qPCR COVID-19 testing based on a standard 40ft shipping container. Using open-source liquid-handling robots and RNA extraction reagents we demonstrate a reproducible workflow for RT-qPCR COVID-19 testing. With five OT2 liquid handlers, a single CONTAIN unit reaches a maximum daily testing capacity of 2400 tests/day. We validate this workflow for automated RT-qPCR testing, using both synthetic SARS-CoV-2 samples and patient samples from a local NHS hospital. Finally, we discuss the suitability of CONTAIN and its flexibility in a range of diagnostic testing scenarios including high-density urban environments and mobile response units.

Visual abstract
Self-activated photoblinking of nitrogen vacancy centers in nanodiamonds (sandSTORM): A method for rapid single molecule localization microscopy with unlimited observation time
Authors: Narayanasamy Kaarjel K. , Price Joshua C. , Mesquita-Riberio Raquel , Mather Melissa L. , Jayasinghe Izzy
Published: May 2020

Stochastic optical reconstruction microscopy (STORM) is one of the most commonly used super-resolution microscopy techniques. Popular implementations of STORM utilize aromatic fluorophores and consist of a number of intrinsic limitations such the finite photostability of the dyes, the reliance upon non-physiological redox buffers and speed which is ultimately limited by the ‘off’-rates of the photoblinking. Self-activated nanodiamond-based STORM (sandSTORM) has been developed as an accelerated STORM protocol which harvests the rapid, high quantum-yield and sustained photoblinking of nanodiamonds (ND). Photoluminescence emanating from the stochastic charge-state interconversion of Nitrogen Vacancy (NV) centers between NV0and NV-is localized using conventional STORM-optimized hardware and image processing protocols over an unlimited duration of imaging. This produces super-resolution images of matching resolution at ∼ 3-times the speed and ∼ 100 times less light exposure to the sample compared to traditional STORM. The enabling NDs have been used to map arrays of ryanodine receptor in skeletal muscle tissues via immunolabelling and directly visualize the internal spaces of living neurons via endocytosis of NDs. This paper details the physical basis of sandSTORM, factors which optimize its performance, and key characteristics which make it a powerful STORM protocol suitable for imaging nanoscale sub-cellular structures.
Discovery of potent inhibitors of PLproCoV2 by screening a library of selenium-containing compounds
Authors: Węglarz-Tomczak Ewelina , Tomczak Jakub M. , Giurg Mirosław , Burda-Grabowska Małgorzata , Brul Stanley
Published: May 2020

A collection of twelve organoselenium compounds, structural analogues of antioxidant drug ebselen were screened for inhibition of the papain-like protease (PLpro) from the acute respiratory syndrome coronavirus 2 (SARS-CoV-2, CoV2). This cysteine protease, being responsible for the hydrolysis of peptide bonds between specific amino acids, plays a critical role in CoV2 replication and in assembly of new viral particles within human cells. The activity of the PLproCoV2 is essential for the progression of coronavirus disease 2019 (COVID-19) and it constitutes a key target for the development of anti-COVID-19 drugs. Here, we identified four strong inhibitors that bind favorably to the PLproCoV2 with theIC50in the nanomolar range.
Software entrepreneurs’ competencies based on business growth
Authors: Sudirman Iman , Siswanto Joko , Aisha Atya Nur
Published: May 2020

Purpose

This study aims to identify the competencies of small- and medium-sized enterprises’ (SMEs) entrepreneurs in the software sector and the perceived level of attainment in each competency. It also examines whether these competencies and their levels affect business turnover and growth (in terms of business scale and duration).

Design/methodology/approach

To accomplish this purpose, the study took a quantitative approach, involving a survey of 33 SME entrepreneurs, which was then processed using statistical tests, including chi-square test, Kruskal–Wallis test and ordinal regression.

Findings

There were four findings of the study. Firstly, software SME entrepreneurs need 17 competencies, with high levels of soft competencies being required and average levels of technical competencies. Secondly, there are significant differences in perceived levels of customer service orientation (p = 0.089) depending on the scale of the business and in perceived levels of project management (p = 0.087) depending on the duration of the business. Thirdly, customer service orientation (p = 0.031) and project management (p = 0.01) both have a significant influence on business revenues. Fourthly, there were significant gaps in perceived levels of competency (p < 0.05) in achievement orientation, customer service orientation and project management.

Originality/value

There is existing research that conducts competency mappings at the managerial level in large-scale organizations; however, this sort of research in relation to SME entrepreneurs is still lacking. The present study seeks to fill this gap. It also maps integrated entrepreneurial competencies, including soft and technical competencies; a focus that is lacking in previous studies.
Experimental investigation on influence of electrode vibrations on hardness and microstructure of 1018 mild steel weldments
Authors: Bade Venkata Suresh , P. Srinivasa Rao , P. Govinda Rao
Published: May 2020

Purpose

The purpose of this study is to explore the importance of vibrations during welding process. In recent years, welding has gained its supremacy in the field of production. The main set back of the welding process is induced residual stresses, which is a major cause for many welding defects. These defects can be minimized by post-weld heat treatment methods, which is a time consuming and laborious process. In the recent past, a technique of exciting the weld-pool by vibrating the work-pieces was also adopted to minimize the above-mentioned stresses. A novel technique of electrode vibration is another effective way of transferring the vibrations to the weld-pool to influence the induced residual stress.

Design/methodology/approach

In this research, the electrode is vibrated with the help of an electric motor. The specimens were prepared as per American Society for Testing and Materials standards and welded with varying frequencies and voltages. The weldments are tested for hardness along the weld bead and heat affected zone, also the microstructure of the fusion zone is analyzed.

Findings

It is observed that there is an improvement in the hardness because of the grain refinement, which is a result of proper excitation of the weld-pool. It is observed that there is an improvement in hardness test up to 28.69% when compared with the conventional welding process. The peak value of hardness is observed at a frequency of 4,450 Hz. This is because of fine grain structure at this frequency, which is observed through the microstructure analysis.

Originality/value

A novel technique is introduced to refine the weld-pool through electrode vibrations. To improve the hardness of the welded joints, vibrations play a major role by refining the grain structure. The vibrations are imparted with the help of a special equipment attached to the electrode.
Modelling how resource competition among snail hosts affects the mollusciciding frequency and intensity needed to control human schistosomes
Authors: Malishev Matthew , Civitello David J.
Published: May 2020

Ecological interactions among intermediate hosts or vectors of human pathogens can enhance or hinder control efforts. However, we currently lack quantitative frameworks to predict how interactions among host physiology, ecology and control effort shape human disease risk.

We explore this approach for human schistosomiasis, a major, historically neglected tropical disease. A recent re‐emphasis on snail host control using molluscicides highlights the need to re‐evaluate the ecological mechanisms driving emergence of schistosome cercariae, the life stage that directly infects humans.

We integrate physiology, resource competition and control using individual‐based models based on general metabolic theory, Dynamic Energy Budget theory, to simulate human infectious schistosome density under molluscicide scenarios varying in frequency and intensity throughout a 150‐day transmission season. Without molluscicide control, our model predicts intense resource competition among hosts and large and early parasite peaks under algae and detritus resources. Consistent monthly control, as recommended by the WHO, can work if intense, that is, >90% host mortality. In contrast, one‐off, intense and early mollusciciding induces large delayed rebounds in parasites by releasing the few remaining snails from resource competition.

Our simulations confirm the WHO recommendation that frequent mollusciciding can disrupt transmission, but contradict recent suggestions for infrequent mollusciciding, for example, annually, which can backfire because relaxed resource competition among hosts stimulates parasite production. Our results identify resource competition as a key ecological mechanism driving parasite population intensity for schistosome habitats across ecosystems.

Our results show resource ecology models can identify peaks in parasite density. More generally, resource competition among hosts may complicate efforts to control infected snail host densities in the field and thus disease risk through culling or mortality‐based interventions. Connecting individuals to community and disease dynamics with resource ecology can inform better field control strategies and help managers avoid unintended consequences for human health.

A free Plain Language Summary can be found within the Supporting Information of this article.
Applications of weighted association networks applied to compositional data in biology
Authors: Espinoza Josh L. , Shah Naisha , Singh Suren , Nelson Karen E. , Dupont Chris L.
Published: May 2020

Next‐generation sequencing technologies have generated, and continue to produce, an increasingly large corpus of biological data. The data generated are inherently compositional as they convey only relative information dependent upon the capacity of the instrument, experimental design and technical bias. There is considerable information to be gained through network analysis by studying the interactions between components within a system. Network theory methods using compositional data are powerful approaches for quantifying relationships between biological components and their relevance to phenotype, environmental conditions or other external variables. However, many of the statistical assumptions used for network analysis are not designed for compositional data and can bias downstream results. In this mini‐review, we illustrate the utility of network theory in biological systems and investigate modern techniques while introducing researchers to frameworks for implementation. We overview (1) compositional data analysis, (2) data transformations and (3) network theory along with insight on a battery of network types including static‐, temporal‐, sample‐specific‐ and differential‐networks. The intention of this mini‐review is not to provide a comprehensive overview of network methods, rather to introduce microbiology researchers to (semi)‐unsupervised data‐driven approaches for inferring latent structures that may give insight into biological phenomena or abstract mechanics of complex systems.
A retrospective stenting study on superior vena cava syndrome caused by lung cancer
Authors: Wei Sen , Liu Jinghao , Li Xin , Song Zuoqing , Dong Ming , Zhao Honglin , Zhao Qingchun , Chen Gang , Chen Jun
Published: May 2020

Background

Superior vena cava syndrome (SVCS) is a common condition predominantly caused by lung cancer. The presence of symptoms of SVCS, such as elevated intracranial pressure and laryngeal edema, indicates an unfavorable prognosis for lung cancer patients. Superior vena cava (SVC) stenting is the first‐line treatment for SVCS. In this study, we retrospectively analyzed SVCS cases treated with stenting in our center to explore the safety and effectiveness of stenting in the treatment of SVCS.

Methods

We reviewed 16 patients with SVCS caused by lung cancer who were treated at our center with endovascular stenting between 2016 and 2018. Patient information such as age, sex, type of lung cancer, obstruction condition, complications, survival time, and postoperative treatments are summarized.

Results

There were no treatment‐related complications in the perioperative period in any of the patients. Examination at postoperative day 2 indicated that the accompanying SVCS symptoms had improved in all patients. The median survival of patients treated along with combined postoperative chemotherapy and antivascular targeted therapy reached seven months (1–18 months).

Conclusions

SVC stenting is effective as a first‐line treatment modality for patients with SVCS caused by lung cancer. In combination with other treatment modalities, it can significantly alleviate symptoms and reduce complications, and thus it plays an important role in the treatment of patients with SVCS caused by lung cancer.
Weed control in natural grasslands: A case study using a perennial native forb from the South American Campos
Authors: Quiñones Dellepiane Amparo , Lattanzi Fernando A. , Saldain Néstor E. , Lezama Felipe
Published: May 2020

Management of native weeds in natural grasslands is a challenging task. Often, recommendations are based on short‐term studies of the response of weed cover and density to different control methods. However, perennial species well adapted to disturbances typically recover from commonly used control techniques. In this long‐term study, we focused on a rosette native to the South American Campos: Eryngium horridum Malme (Apiaceae). This plant is strongly avoided by cattle due to its spiny leaves and tends to form dense patches, reducing the available grazing area. We aimed at understanding how key demographic processes, such as size‐related plant survival and seedling establishment, are affected by different control treatments. For this, E. horridum cover, density and size structure were assessed over three years in response to mechanical, chemical and integrated (mechanical + chemical) control methods. In a field experiment, we used a weighted rim and a wiper applicator with 2,4‐D + picloram for the mechanical and chemical control, respectively. Cover was reduced by control treatments (‘control phase’), but this was not sustained in the long term (‘recovery phase’). Regardless of the method used, control success was closely related to effects on population size structure. Mortality was high and rapid in large rosettes, which effectively led to a rapid and widespread cover reduction in all control treatments. However, only herbicide reduced rosette density delaying the recovery phase. Seedling density was low during the experimental period and scarcely affected by treatments. We conclude that cover reduction depends on removing all large rosettes, but recovery is related both to the size of the remaining pool of small rosettes and to the ability of buried rhizomes to resprout. Finally, we highlight the importance of finding a balance between productive goals and biodiversity conservation. In that context, integrated control successfully reduced cover, delayed recovery and minimised the amount of herbicide used.

Abstract in Spanish is available with online material.
Genotype concordance and polygenic risk score estimation across consumer genetic testing data
Authors: Batra Prag , Huang Kuan‐lin
Published: May 2020

The consumer genomics industry is steadily growing and delivering genetic information to over 10 million individuals. Yet, the implications of using data from different services remain unclear. We investigated the genotyped sites, concordance, and genetic risk estimation using data from three consumer services—two single nucleotide polymorphism (SNP)‐array based and one sequencing based. In an N‐of‐one setting, we found the three services genotyped predominantly distinct sets of sites. While there was a high concordance between overlapping sites of the two SNP‐array services (99.6%), there was a lower concordance between these services and a low‐pass whole‐genome service (73.0%). The discrepancy between the three sets of data resulted in different APOE genotypes and genetic risk scores of Alzheimer's disease. Our results demonstrate genotype results across consumer genomics platforms may lead to different genetic risk estimates, highlighting the need for careful quality control and interpretation.
Cervical length surveillance for predicting spontaneous preterm birth in women with uterine anomalies: A cohort study
Authors: Hughes Kelly M. , Kane Stefan C. , Haines Terrence P. , Sheehan Penelope M.
Published: May 2020

Introduction

Uterine anomalies occur in an estimated 5% of women and have been shown to confer a higher risk of spontaneous preterm birth (SPTB). A sonographically short cervix (<25 mm) is a risk indicator for SPTB, although its predictive utility has been little studied in this specific high‐risk population. We aimed to assess the pregnancy outcomes and predictive ability of short cervix in a cohort of women with uterine anomalies attending a high‐risk antenatal clinic.

Material and methods

This historical cohort study assessed all pregnancies in women with congenital uterine anomalies referred to the Preterm labor Clinic at the Royal Women’s Hospital, Melbourne, Australia, between 2004 and 2013. Logistic and linear regressions and receiver‐operator curves were used to examine associations between cervical length and preterm birth.

Results

SPTB (<37 weeks’ gestation) occurred in 23% of the 86 pregnancies (n = 20); rates by subgroup were: unicornuate uterus 60% (n = 3/5), uterus didelphys 40% (n = 6/15), bicornuate uterus 18% (n = 9/51), septate uterus 13% (n = 2/15). Preterm prelabor rupture of membranes occurred in 55% of spontaneous preterm births and was not independently associated with the presence of cervical cerclage or ureaplasma urealyticum. Short cervical length was associated with SPTB in women with septate uterus. Short cervix at 24 weeks (not at 16 or 20 weeks) was moderately predictive of SPTB < 34 weeks.

Conclusions

Women with uterine anomalies are at increased risk of spontaneous preterm birth, particularly those with unicornuate uterus or uterus didelphys, but cervical surveillance did not identify these cases. Short cervix may be associated with SPTB in women with septate uterus. Preterm prelabor rupture of membranes occurred in 55% of SPTB. More research is required into etiology to help determine appropriate monitoring and treatment.
More positive group memberships are associated with greater resilience in Royal Air Force (RAF) personnel
Authors: White Craig A. , Slater Matthew J. , Turner Martin J. , Barker Jamie B.
Published: May 2020

In the current project, we examined how perceived group memberships (number, and characteristics, of), social and relational identification, and social identity leadership are associated with resilience in Royal Air Force (RAF) personnel. Based on social identity theorizing, we hypothesized positive associations between the number of groups, perceptions of their characteristics (e.g., positivity), and how they relate to each other (i.e., compatibility) and resilience (H1). We also hypothesized positive associations between both social identity leadership (H2) and resilience, and social and relational identification (H3) and resilience. Two hundred and forty‐three personnel from 18 RAF bases completed an identity mapping exercise and measures of leadership, social and relational identification, and resilience. Our findings highlighted the importance of the association between positive group memberships and resilience, and social identification and resilience. Counter to our hypothesis, belonging to more groups was negatively associated with resilience, and there were non‐significant relationships between three principles of social identity leadership and resilience, with embedding identity being significantly negatively associated with resilience. In support of social identity theorizing, the number of positive groups was positively associated with resilience, as was social identification. These findings indicate that, for RAF personnel, it is belonging to positive groups, both within and outside work, along with social identification, that is positively associated with resilience.
Patients with chronic prostatitis/chronic pelvic pain syndrome show T helper type 1 (Th1) and Th17 self‐reactive immune responses specific to prostate and seminal antigens and diminished semen quality
Authors: Motrich Ruben D. , Breser María L. , Molina Rosa I. , Tissera Andrea , Olmedo José J. , Rivero Virginia E.
Published: May 2020

Objectives

To assess the presence of self‐reactive immune responses to seminal and prostate antigens (PAg), biomarkers of inflammation of the male genital tract, and semen quality parameters in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

Patients, Subjects and Methods

Peripheral blood and semen samples were collected from patients with CP/CPPS and age‐matched healthy control volunteers. We analysed the lymphoproliferative responses of peripheral blood mononuclear cells (PBMC) to different seminal plasma (SP)‐derived and purified PAg, serum autoantibodies specific to PAg, leucocyte subpopulations, and inflammatory cytokines in semen, sperm apoptosis/necrosis, and semen quality parameters.

Results

Significantly greater PBMC proliferative responses specific to PAg, with elevated secretion of interferon (IFN)γ and interleukin (IL)‐17, were detected in the patients with CP/CPPS vs the controls. Moreover, the patients with CP/CPPS had significantly greater serum immunoglobulin G immune reactivity to SP proteins, such as prostate‐specific antigen and prostatic acid phosphatase, than the controls. Inflammation of the male genital tract was exemplified by high levels of IFNγ, IL‐17, IL‐1β and IL‐8, as well as higher counts of leukocytes, mainly CD4 T lymphocytes and macrophages, in the semen. In addition, this local inflammation was associated with an overall diminished semen quality, i.e., reduced sperm concentration, motility and viability; and higher levels of sperm apoptosis/necrosis in patients with CP/CPPS vs controls.

Conclusion

Patients with CP/CPPS show T helper type 1 (Th1) and Th17 immune responses specific to PAg associated with chronic inflammation of the male genital tract and reduced semen quality. These immune responses may underlie the induction and development of chronic pelvic pain and inflammation of the male genital tract, which in turn could alter normal prostate functioning and impair semen quality.
N‐benzhydryl quinuclidine compounds are a potent and Src kinase‐independent inhibitor of NALCN channels
Authors: Hahn Suyun , Kim So Woon , Um Ki Bum , Kim Hyun Jin , Park Myoung Kyu
Published: May 2020

Background and Purpose

NALCN is a Na+ leak, GPCR‐activated channel that regulates the resting membrane potential and neuronal excitability. Despite numerous possible roles for NALCN in both normal physiology and disease processes, lack of specific blockers hampers further investigation.

Experimental Approach

The effect of N‐benzhydryl quinuclidine compounds on NALCN channels was demonstrated using whole‐cell patch‐clamp recordings in HEK293T cells overexpressing NALCN and acutely isolated nigral dopaminergic neurons that express NALCN endogenously. Src kinase activity was measured using a Src kinase assay kit, and voltage and current‐clamp recordings from nigral dopaminergic neurons were used to measure NALCN currents and membrane potentials.

Key Results

N‐benzhydryl quinuclidine compounds inhibited NALCN channels without affecting TRPC channels, another important route for Na+ leak. In HEK293T cells overexpressing NALCN, N‐benzhydryl quinuclidine compounds potently suppressed muscarinic M3 receptor‐activated NALCN currents. Structure–function relationship studies suggest that the quinuclidine ring with a benzhydryl group imparts the ability to inhibit NALCN currents regardless of Src family kinases. Moreover, N‐benzhydryl quinuclidine compounds inhibited not only GPCR‐activated NALCN currents but also background Na+ leak currents and hyperpolarized the membrane potential in native midbrain dopaminergic neurons that express NALCN endogenously.

Conclusion and Implications

These findings suggest that N‐benzhydryl quinuclidine compounds have a pharmacological potential to directly inhibit NALCN channels and could be a useful tool to investigate functions of NALCN channels.
Open‐channel blocking action of volatile anaesthetics desflurane and sevoflurane on human voltage‐gated Kv1.5 channel
Authors: Fukushima Yutaka , Kojima Akiko , Mi Xinya , Ding Wei‐Guang , Kitagawa Hirotoshi , Matsuura Hiroshi
Published: May 2020

Background and Purpose

Volatile anaesthetics have been shown to differentially modulate mammalian Shaker‐related voltage‐gated potassium (Kv1.x) channels. This study was designed to investigate molecular and cellular mechanisms underlying the modulatory effects of desflurane or sevoflurane on human Kv1.5 (hKv1.5) channels.

Experimental Approach

Thirteen single‐point mutations were constructed within pore domain of hKv1.5 channel using site‐directed mutagenesis. The effects of desflurane or sevoflurane on heterologously expressed wild‐type and mutant hKv1.5 channels were examined by whole‐cell patch‐clamp technique. A computer simulation was conducted to predict the docking pose of desflurane or sevoflurane within hKv1.5 channel.

Key Results

Both desflurane and sevoflurane increased hKv1.5 current at mild depolarizations but decreased it at strong depolarizations, indicating that these anaesthetics produce both stimulatory and inhibitory actions on hKv1.5 channels. The inhibitory effect of desflurane or sevoflurane on hKv1.5 channels arose primarily from its open‐channel blocking action. The inhibitory action of desflurane or sevoflurane on hKv1.5 channels was significantly attenuated in T480A, V505A, and I508A mutant channels, compared with wild‐type channel. Computational docking simulation predicted that desflurane or sevoflurane resides within the inner cavity of channel pore and has contact with Thr479, Thr480, Val505, and Ile508.

Conclusion and Implications

Desflurane and sevoflurane exert an open‐channel blocking action on hKv1.5 channels by functionally interacting with specific amino acids located within the channel pore. This study thus identifies a novel molecular basis mediating inhibitory modulation of hKv1.5 channels by desflurane and sevoflurane.
Q&A
Authors: Lovelady Brett , Schwartz Bob
Published: May 2020

Creating innovative design for products and brands that have come to define popular culture, Brett Lovelady is internationally renowned for his inspired approach to design.

In a career that has encompassed work with non‐profit organizations, advocacy groups, and for‐profit companies, Bob Schwartz has been a design leader who has brought innovation, design thinking, and a focus on human factors to decades of industrial design success.
Preliminary support for using the Atypicality Scale from the Behavior Assessment System for Children, Second Edition, to screen for psychosis‐spectrum disorders within a college counselling centre
Authors: Thompson Elizabeth C. , DeLuca Joseph S. , Petti Emily , Rakhshan Rouhakhtar Pamela , Schiffman Jason
Published: May 2020

Aim

Evidence supports the use of brief psychosis‐spectrum screeners for identifying individuals at risk for psychosis. Screening has not been well‐studied in help‐seeking college samples. This study investigated the use of the Behavior Assessment System for Children, Second Edition (BASC‐2) Atypicality Scale as a psychosis‐spectrum screening tool within a university counselling centre.

Methods

Atypicality scores from the BASC‐2 were compared to interview‐based assessment, the Structured Interview for Psychosis‐risk Syndromes (SIPS), to explore associations across the measures and evaluate the scale's ability to identify individuals who meet criteria for a psychosis‐spectrum diagnosis.

Results

Forty‐three participants completed the BASC‐2 and SIPS, and 23 were SIPS‐positive. Compared to the SIPS‐negative group, the SIPS‐positive group had significantly higher Atypicality scores. Exploratory results indicated that Atypicality scores identified SIPS‐positive individuals with an overall accuracy of 72% (78% sensitivity, 65% specificity).

Conclusion

The Atypicality Scale may be an appropriate first‐line psychosis‐spectrum screening tool in college counselling centres.
Situational analysis of prevailing practices in the management of first‐episode psychosis in Chennai, India
Authors: Dhandapani Vijaya Raghavan , Ramachandran Padmavati , Mohan Greeshma , Chandrasekaran Sangeetha , Paul Vimala , Pattabiraman Ramakrishnan , Mohan Mohapradeep , Iyer Srividya , Rangaswamy Thara , Singh Swaran Preet
Published: May 2020

Aim

This paper aims to examine how existing mental health within the city of Chennai, India manages first‐episode psychosis, to determine lacunae and barriers in providing effective early intervention and to make appropriate recommendations to improve the care of first‐episode psychosis patients.

Methods

Interviews were held with 15 health professionals to capture information on current practices and facilities available for the management of first‐episode psychosis.

Results

No specialized clinic or services were available for individuals with first‐episode psychosis in Chennai, except one. Pharmacotherapy was the main treatment modality with psychological support to patients and families. Most common drugs used were Risperidone, Olanzapine, and Haloperidol in their recommended doses. General practitioners and paediatricians, due to inadequate training in mental health, referred patients with psychosis to mental health professionals.

Conclusions

Equipping the existing mental health services to manage FEP and training all health professionals on psychosis will improve FEP management in Chennai.