bluuebunny/crossref_metadata_2025 huggingface dataset:
High incidence of pulmonary thromboembolism in hospitalized SARS-CoV-2 infected patients
Authors: El-Qutob D , Alvarez L , García-Sidro P , Robustillo M , Barreda I , Nieto M , Pin M , Carrera-Hueso FJ
Published: March 2021

Introduction

SARS-CoV-2 infected patients present thrombotic complications caused by direct endothelial cells injury of the microvessels. Pulmonary thromboembolism (PE) has been reported by Computed Tomography pulmonary angiogram (CTPA) in patients with COVID-19 pneumonia with high D-dimer levels.

Objectives

We present the characteristics of SARS-CoV-2 infected patients diagnosed of PE by CTPA in our hospital. We also present the comparison of these findings with non-infected patients with PE data.

Methods

Patients 18 years of age or older with SARS-CoV2 virus infection, and patients with suspected infection at beginning of admission but with negative PCR, were studied with CTPA for suspicion of VTE, during their hospitalization.

Results

During the study period, 52 CTPA were performed in our hospital, sixteen in SARS-CoV-2 infected patients. No significant differences in age (p=0.43) and sex (p=0.31) were found between the two groups, infected and non-infected patients. In the infected group, the patients who had PE had a much lower median age (47.8 years) than those without PE (73.3 years). No differences between infected and non-infected patients were detected in the diagnosis of PE with CTPA, 28.6% versus 27.8% (p=1.00). Overall patient mortality was 1.9%; one patient died (6.3%) in the infected group, and none in the non-infected group (p=0.31).

Conclusion

A considerable incidence of PE diagnosed by CTPA in SARS-CoV-2 infected patients has been observed, despite thrombo-prophylaxis.
Mitigating Covid-19 aerosol infection risk in school buildings: the role of natural ventilation, classroom volume, occupancy
Authors: Zivelonghi Alessandro , Lai Massimo
Published: March 2021

Issues linked to aerosol physics within school buildings and related infection risk still lack a proper recognition in school safety regulations. In this theoretical work we try to shed more light on the critical role of air ventilation, classroom volume, occupancy, and face mask types (surgical vs ffp2) in controlling airborne transmission risk in educational settings. Limited spaces available in many schools require to precisely assess the occupancy/volume ratio in each classroom and to investigate the specific risk levels from aerosolization of viral loads from infective sources. Moreover, most schools are not provided with mechanical HVAC systems. Fundamental questions are therefore: how the specific classroom volume affects the long-range contagion risk in a given classroom? is linear social distancing the right way to assess a volumetric risk problem? How effective are other countermeasures like reduced speaking volume or equipping teachers with microphones? We present here the results of a numerical analysis based on the Gammaitoni-Nucci infection risk model and the consolidated Wells-Riley like approach, with SARS-CoV2 input data and geometric data from a typical high-school classroom in Italy. We investigated separately the case of infective asymptomatic student and infective asymptomatic teacher as source of viral quanta, taking into account thermal gradient effects on the air ventilation rates. First recommendations based on the volumetric nature of aerosol risk are suggested to extend the linear social distancing approach applied so far. Finally we discuss the concept of “cumulative infection risk” over multiple lesson+break cycles in Wells-Riley-like infection models. We believe that any attempt to proper model infection risk in closed environments with cycled changes of the source and the susceptible individuals, should carefully consider this point, particularly when modelling air ventilation breaks in classrooms.
Light Enhanced Cognitive Behavioral Therapy (CBT+) for Insomnia and Fatigue During Chemotherapy for Breast Cancer: A Randomized Controlled Trial
Authors: Bean Helena R. , Diggens Justine , Ftanou Maria , Alexander Marliese , Stafford Lesley , Bei Bei , Francis Prudence A. , Wiley Joshua F.
Published: March 2021

Study Objectives

Sleep problems are common during chemotherapy for breast cancer (BC). We evaluated whether combined brief cognitive behavioral and bright light therapy (CBT+) is superior to treatment as usual with relaxation audio (TAU+) for insomnia symptoms and sleep efficiency (primary outcomes).

Methods

We randomized women receiving intravenous chemotherapy, stratified by tumor stage and insomnia severity index (ISI), to 6-weeks CBT+ or TAU+. CBT+ included one in-person session, one telephone call, seven emails, and 20 minutes bright light each morning. TAU+ comprised usual treatment and two emails with relaxation audio tracks. Patient-reported outcomes were assessed at baseline, midpoint (week 3), post (week 6) and 3-month follow-up.

Results

Women (N = 101) were randomly assigned to CBT+ or TAU+. Insomnia symptoms declined significantly more from baseline to post with CBT+ versus TAU+ (−5.06 vs -1.93, P = .009; effect size [ES] = .69). At 3-month follow-up, both groups had improved insomnia symptoms but did not differ (ES = .18, P = .56). CBT+ had higher patient-reported sleep efficiency than TAU+ after the start of intervention (P = .05) and more improvement in fatigue (ES = .59, P = .013) and daytime sleep-related impairment (ES = .61, P = .009) from baseline to post.

Conclusions

CBT+ had a clinically significant impact on insomnia and fatigue with moderate effect sizes. Results support offering cognitive behavioral therapy for insomnia and bright light therapy during chemotherapy for breast cancer to help manage sleep and fatigue.

Clinical trial information

Registered with the Australian New Zealand Clinical Trials Registry (http://anzctr.org.au/), Registration Number: ACTRN12618001255279

Statement of Significance

Poor sleep is prevalent after cancer diagnosis, especially during chemotherapy. Although cognitive behavioral therapy for insomnia (CBT-I) has been shown to be effective, including in cancer survivors, chemotherapy is unique with significant, ongoing, exogenous factors disrupting sleep (e.g., pain, nausea, and steroids used to manage side effects from chemotherapy). We showed statistically and clinically significant improvements in insomnia and fatigue symptoms in the CBT-I plus bright light therapy (CBT+) treatment condition compared to the control in women receiving chemotherapy for stage 1–4 breast cancer. Waiting until cancer treatment completion may result in prolonging poor sleep and our findings suggest is not necessary. Future studies are needed to evaluate whether combined CBT+ is superior to CBT-I or light alone.
Introducing the 4Ps Model of Transitioning to Distance Learning: a convergent mixed methods study conducted during the COVID-19 pandemic
Authors: Otaki Farah , Zaher Shroque , Plessis Stefan Du , Lakhtakia Ritu , Zary Nabil , Inuwa Ibrahim
Published: March 2021

Significant concern has been raised regarding the effect of COVID-19 on medical education. The aim of this study was to shed light on the distance learning experiences of medical students and their instructors. A convergent mixed methods approach was utilized. Qualitative and quantitative data was collected using a survey.

The percentage of the total average of satisfaction among stakeholders was 76.4%. The qualitative analysis revealed several themes. This study introduced the 4Ps Model of Transitioning to Distance Learning. It would be useful to leverage the lessons-learned to tailor blended medical programs, with a reasonable mélange of experiences. The study also contributes to the mixed methods research through showcasing a means of adapting it to evaluate critical situations reliably and rapidly.
Ventilation procedures to minimize the airborne transmission of viruses at schools
Authors: Stabile L. , Pacitto A. , Mikszewski A. , Morawska L. , Buonanno G.
Published: March 2021

Reducing the transmission of SARS-CoV-2 through indoor air is the key challenge of the COVID-19 pandemic. Crowded indoor environments, such as schools, represent possible hotspots for virus transmission since the basic non-pharmaceutical mitigation measures applied so far (e.g. social distancing) do not eliminate the airborne transmission mode. There is widespread consensus that improved ventilation is needed to minimize the transmission potential of airborne viruses in schools, whether through mechanical systems or ad-hoc manual airing procedures in naturally ventilated buildings. However, there remains significant uncertainty surrounding exactly what ventilation rates are required, and how to best achieve these targets with limited time and resources. This paper uses a mass balance approach to quantify the ability of both mechanical ventilation and ad-hoc airing procedures to mitigate airborne transmission risk in the classroom environment. For naturally-ventilated classrooms, we propose a novel feedback control strategy using CO2 concentrations to continuously monitor and adjust the airing procedure. Our case studies show how such procedures can be applied in the real world to support the reopening of schools during the pandemic. Our results also show the inadequacy of relying on absolute CO2 concentration thresholds as the sole indicator of airborne transmission risk.
A short ERK5 isoform modulates nucleocytoplasmic shuttling of active ERK5 and associates with poor survival in breast cancer
Authors: Miranda Mariska , Saunus Jodi M. , Akgül Seçkin , Marjaneh Mahdi Moradi , Kutasovic Jamie R. , Shi Wei , Chatterjee Oishee , Casciello Francesco , Rozali Esdy , Handoko Herlina Y. , Wiegmans Adrian P. , Liu Tianqing , Lee Jason S. , Day Bryan W. , Edwards Stacey L. , French Juliet D. , Reed Amy E. McCart , Chenevix-Trench Georgia , Khanna Kum Kum , Simpson Peter T. , Lakhani Sunil R. , Al-Ejeh Fares
Published: March 2021

Background

The nucleocytoplasmic shuttling of ERK5 has gained recent attention as a regulator of its diverse roles in cancer progression but the exact mechanisms for this shuttling are still under investigation.

Methods

Usingin vitro, in vivoandin silicostudies, we investigated the roles of shorter ERK5 isoforms in regulating the nucleocytoplasmic shuttling of active phosphorylated-ERK5 (pERK5). Retrospective cohorts of primary and metastatic breast cancer cases were used to evaluate the association of the subcellular localization of pERK5 with clinicopathological features.

Results

Extranuclear localization of pERK5 was observed during cell migrationin vitroand at the invasive fronts of metastatic tumorsin vivo. The nuclear and extranuclear cell fractions contained different isoforms of pERK5, which are encoded by splice variants expressed in breast and other cancers in the TCGA data. One isoform, isoform-3, lacks the C-terminal transcriptional domain and the nuclear localization signal. The co-expression of isoform-3 and full-lengthERK5associated with high epithelial-to-mesenchymal transition (EMT) and poor patient survival. Experimentally, expressing isoform-3 with full-length ERK5 in breast cancer cells increased cell migration, drove EMT and led to tamoxifen resistance. In breast cancer patient samples, pERK5 showed variable subcellular localizations where its extranuclear localization associated with aggressive clinicopathological features, metastasis, and poor survival.

Conclusion

Our studies support a model of ERK5 nucleocytoplasmic shuttling driven by splice variants in an interplay between mesenchymal and epithelial states during metastasis. Using ERK5 as a biomarker and a therapeutic target should account for its splicing and context-dependent biological functions.

Graphical Abstract

ERK5 isoform-3 expression deploys active ERK5 (pERK5) outside the nucleus to facilitate EMT and cell migration. In cells dominantly expressing isoform-1, pERK5 shuttles to the nucleus to drive cell expansion.
Molecular phylogeny of Puerto Rico Bank dwarf geckos (Squamata: Sphaerodactylidae:Sphaerodactylus)
Authors: Reynolds R. Graham , Miller Aryeh H. , Ríos-Franceschi Alejandro , Huffine Clair A. , Fredette Jason , Angeli Nicole F. , Vega-Castillo Sondra I. , Revell Liam J. , Puente-Rolón Alberto R.
Published: March 2021

Abstract

The genusSphaerodactylusis a very species-rich assemblage of sphaerodactylid lizards that has undergone a level of speciation in parallel to that of the well-knownAnolislizards. Nevertheless, molecular phylogenetic research on this group consists of a handful of smaller studies of regional focus (e.g., western Puerto Rico, the Lesser Antilles) or large-scale analyses based on relatively limited sequence data. Few medium-scale multi-locus studies exist— for example, studies that encompass an entire radiation on an island group. Building upon previous work done in Puerto RicanSphaerodactylus, we performed multi-locus sampling ofSphaerodactylusgeckos from across the Puerto Rico Bank. We then used these data for phylogeny estimation with near-complete taxon sampling. We focused on sampling the widespread nominal speciesS. macrolepisand in so doing, we uncovered a highly divergent and morphologically distinct lineage ofSphaerodactylus macrolepisfrom Puerto Rico, Culebra, and Vieques islands, which we recognize asS. grandisquamis(Stejneger, 1904) on the basis of molecular and morphological characters.S. grandisquamisco-occurs withS. macrolepisonly on Culebra Island but is highly genetically differentiated and morphologically distinct.Sphaerodactylus macrolepisis now restricted to the eastern Puerto Rico Bank, from Culebra east through the Virgin Islands and including the topotypic population on St. Croix. We include additional discussion of the evolutionary history and historical biogeography of theSphaerodactylusof the Puerto Rican Bank in the context of these new discoveries.
Evaluation and Optimization of High-Field Asymmetric Waveform Ion Mobility Spectrometry for Multiplexed Quantitative Site-specific N-glycoproteomics
Authors: Fang Pan , Ji Yanlong , Silbern Ivan , Viner Rosa , Oellerich Thomas , Pan Kuan-Ting , Urlaub Henning
Published: March 2021

The heterogeneity and complexity of glycosylation hinder the depth of site-specific glycoproteomics analysis. High-field asymmetric-waveform ion-mobility spectrometry (FAIMS) has shown to improve the scope of bottom-up proteomics. The benefits of FAIMS for quantitative N glycoproteomics have not been investigated yet. In this work, we optimized FAIMS settings for N-glycopeptide identification, with or without the tandem mass tag (TMT) label. The optimized FAIMS approach significantly increased the identification of site-specific N glycopeptides derived from the purified IgM protein or human lymphoma cells. We explored in detail the changes in FAIMS mobility caused by N glycopeptides with different characteristics, including TMT labeling, charge state, glycan type, peptide sequence, glycan size and precursor m/z. Importantly, FAIMS also improved multiplexed N glycopeptide quantification, both with the standard MS2 acquisition method and with our recently developed Glyco-SPS-MS3 method. The combination of FAIMS and Glyco-SPS-MS3 provided the highest quantitative accuracy and precision. Our results demonstrate the advantages of FAIMS for improved mass-spectrometry-based qualitative and quantitative N glycoproteomics.
Synergy of culture-dependent molecular identification and whole-community metabarcode sequencing for characterizing the microbiota of arable crop residues
Authors: Laval Valérie , Kerdraon Lydie , Barret Matthieu , Liabot Anne-Lise , Marais Coralie , Boudier Benjamin , Balesdent Marie-Hélène , Saux Marion Fischer-Le , Suffert Frédéric
Published: March 2021

This study is the first to compare culture-dependent (strain isolation plus molecular identification) and culture-independent (whole-community metabarcode sequencing) approaches for characterizing the microbiota of crop residues. We investigated the diversity of fungal and bacterial communities in wheat and oilseed rape residues, using two different culture-dependent strategies to cover the maximum diversity for each kingdom: broad substrate sampling coupled with low-throughput isolation and diversity analysis for fungi, and reduced substrate sampling coupled with high-throughput isolation and diversity analysis for bacteria. The proportion of cultivable microorganisms was neither as low as the ‘1%’ paradigm long associated with the rhizosphere microflora, nor as high as the 50% sometimes reported for the phyllosphere microflora. It was, thus, intermediate between the values for soil and plants. This finding is consistent with residues being considered to constitute an ecotone, at the interface between soil and phyllosphere. Isolation and metabarcoding provided consistent complementary information: they revealed close community profiles, leading to the identification of several common and specific amplicon sequence variants (ASVs). The power of the culture-independent approach was thus confirmed. By contrast the culture-dependent approach was less weak than anticipated. Firstly, it provided complementary information about microbial diversity, with several ASVs not retrieved by metabarcoding being identified after isolation in the community-based culture collection. Secondly, this approach made it possible to preserve and test different taxa either individually or after the creation of synthetic communities, for deciphering the ecological functions of communities beyond merely descriptive aspects.
Genome-wide Association Study of Pancreatic Fat: The Multiethnic Cohort Adiposity Phenotype Study
Authors: Streicher Samantha A , Lim Unhee , Park S. Lani , Li Yuqing , Sheng Xin , Hom Victor , Xia Lucy , Pooler Loreall , Shepherd John , Loo Lenora WM , Darst Burcu F , Highland Heather M , Polfus Linda M , Bogumil David , Ernst Thomas , Buchthal Steven , Franke Adrian A , Setiawan Veronica Wendy , Tiirikainen Maarit , Wilkens Lynne R , Haiman Christopher A , Stram Daniel O , Cheng Iona , Marchand Loïc Le
Published: March 2021

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = −0.67, P = 4.50×10-8) and rs7996760 on chromosome 6q14 (Beta = −0.90, P = 4.91×10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also suggestively associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89-1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region betweenGSX1andPLUT, and rs79967607 is in intron 1 ofEPM2A.PLUT,a linkRNA, regulates transcription of an adjacent gene,PDX1, that controls beta-cell function in the mature pancreas, andEPM2Aencodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.
Experimental sexual selection affects the evolution of physiological and life history traits
Authors: Garlovsky Martin D. , Holman Luke , Brooks Andrew L. , Novicic Zorana K. , Snook Rhonda R.
Published: March 2021

Sexual selection and sexual conflict are expected to affect all aspects of the phenotype, not only traits that are directly involved in reproduction. Here, we show coordinated evolution of multiple physiological and life history traits in response to long-term experimental manipulation of the mating system in populations ofDrosophila pseudoobscura. Development time was extended under polyandry relative to monogamy in both sexes, potentially due to higher investment in traits linked to sexual selection and sexual conflict. Individuals (especially males) evolving under polyandry had higher metabolic rates and locomotor activity than those evolving under monogamy. Polyandry individuals also invested more in metabolites associated with increased endurance capacity and efficient energy metabolism and regulation, namely lipid and glycogen. Finally, polyandry males were less desiccation- and starvation-resistant than monogamy males, suggesting trade-offs between resistance and sexually selected traits. Our results provide experimental evidence that mating systems can impose selection that influences the evolution of non-sexual phenotypes such as development, activity, metabolism, and nutrient homeostasis.
Antibacterial activity ofBalanites aegyptiacaOil Extract onStaphylococcus aureusandEscherichia coli
Authors: Khanam Sabina , Zakari’yau Galadima Fatima
Published: March 2021

Africa is very rich with biodiversity resources, vegetation and it is estimated about 40,000- 45,000 species of different flora. A very large number of plant species are medicinally used for the treatment of various diseases.Balanites aegyptiacaalso called “desert date” indeed a plant with amazing benefits for human,Balanites aegyptiacawas popularly known to have added value and hope for person who went to pursue it for health. In Nigeria, there are evidences of serious bacterial infections with Gram-positive and Gram-negativeStaphylococcus aureusandEscherichia colirespectively.Balanites aegypticais used to treat so many illnesses including laxative, diarrhea, hemorrhoid, stomach aches, jaundice, yellow fever, syphilis and epilepsy. TheBalanite aegypticasample was sun dried for easy removal of the seed from the shell; it was washed to remove un-wanted particles and was dried off then pounded fine powder using mortar and pestle.Antibacterial activity of theBalanites aegypticaoil at different concentrations onstaphylococcus aureusandEscherichia colibacteria and different meters in diameter of the zones was observed.The results shows significant effect of Balanites oil on bacteria by observing the presence of clear spaces known as the zone of inhibitions in the experiments.
Integrating transcription factor abundance with chromatin accessibility in human erythroid lineage commitment
Authors: Baskar Reema , Chen Amy F. , Favaro Patricia , Reynolds Warren , Mueller Fabian , Borges Luciene , Jiang Sizun , Park Hyun Shin , Kool Eric T. , Greenleaf William J. , Bendall Sean C.
Published: March 2021

We present InTAC-seq, a method for simultaneous quantification of genome-wide open chromatin and intracellular protein abundance in fixed cells. Using InTAC we directly observe variation in chromatin accessibility and transcription factor motif occupancy driven by differences in transcription factor protein abundance. By purifying bone marrow progenitor cells based on GATA1 protein expression, we establish its role in both functional and epigenetic restriction of erythroid cell identity in human hematopoiesis.
Innate triggering and antiviral effector functions of activin A
Authors: Al-Hourani K. , Ramamurthy N , Marchi E , Eichinger RM , Lee LN , Fabris P , Klenerman P , Drakesmith H.
Published: March 2021

First-line defence against viral infection is contingent upon rapid detection of conserved viral structural and genomic motifs by germline-encoded pattern recognition receptors, followed by activation of the type I IFN system and establishment of an intracellular antiviral state. Novel antiviral functions of bone morphogenetic protein and related activin cytokines, acting in conjunction with, and independently of, type I IFN, have recently been described. Activin A mediates multiple innate and adaptive immune functions – including antiviral effects. However, how such effects are mediated and how activin might be triggered by viral infection have not been defined. Here we addressed this in vivo and in vitro, in humans and mice.

Transcriptomic analyses delineated strikingly congruent patterns of gene regulation in hepatocytes stimulated with recombinant activin A and IFNαin vitro. Activin A mRNA, encoded byINHBA, is induced upon activation of RIG-I, MDA5 and TLR7/8 viral nucleic acid sensorsin vitro, across multiple cell lines and in human peripheral blood mononuclear cells.In vivo, infection of mice with influenza A also upregulatedInhbamRNA in the lung; this local upregulation ofInhbais retained in MAVS knockout mice, indicating a role for non-RIG-I-like receptors in its induction. Activin induction and signalling were also detectable in patients with chronic viral hepatitis.

Together, these data suggest Activin A is triggered in parallel with type I IFN responses and can trigger related antiviral effector functions. This model has implications for the development of targeted antiviral therapies, in addition to revealing novel facets of activin biology.
Plant immune system activation is necessary for efficient interaction with auxin secreting beneficial bacteria
Authors: Tzipilevich Elhanan , Benfey Philip N.
Published: March 2021

Plants continuously monitor the presence of microorganisms through their immune system to establish an adaptive response. Unlike immune recognition of pathogenic bacteria, how beneficial bacteria interact with the plant immune system is not well understood. Analysis of colonization ofArabidopsis thalianaby auxin producing beneficial bacteria revealed that activation of the plant immune system is necessary for efficient bacterial colonization and auxin secretion. A feedback loop is established in which bacterial colonization triggers an immune reaction and production of reactive oxygen species, which, in turn, stimulate auxin production by the bacteria. Auxin promotes bacterial survival and efficient root colonization, allowing the bacteria to inhibit fungal infection and promote plant health.
Dimeric form of SARS-CoV-2 polymerase
Authors: Jochheim Florian A. , Tegunov Dimitry , Hillen Hauke S. , Schmitzova Jana , Kokic Goran , Dienemann Christian , Cramer Patrick
Published: March 2021

The coronavirus SARS-CoV-2 uses an RNA-dependent RNA polymerase (RdRp) to replicate and transcribe its genome. Structures of the RdRp revealed a monomeric enzyme composed of the catalytic subunit nsp12, two copies of subunit nsp8, and one copy of subunit nsp7. Here we report an alternative, dimeric form of the coronavirus polymerase and resolve its structure at 4.8 Å resolution. In this structure, the two RdRps contain only one copy of nsp8 and dimerize via their nsp7 subunits to adopt an antiparallel arrangement. We speculate that the RdRp dimer facilitates template switching during production of sub-genomic RNAs for transcription.
SPECT/CT imaging, biodistribution and radiation dosimetry of a177Lu-DOTA-integrin αvβ6 cystine knot peptide in a pancreatic cancer xenograft model
Authors: Sachindra Sachindra , Hellberg Teresa , Exner Samantha , Prasad Sonal , Beindorff Nicola , Rogalla Stephan , Kimura Richard , Gambhir Sanjiv Sam , Wiedenmann Bertram , Grötzinger Carsten
Published: March 2021

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant neoplasms, as many cases go undetected until they reach an advanced stage. Integrin αvβ6 is a cell surface receptor overexpressed in PDAC. Consequently, it may serve as a target for the development of probes for imaging diagnosis and radioligand therapy. Engineered cystine knottin peptides specific for integrin αvβ6 have recently been developed showing high affinity and stability. This study aimed to evaluate an integrin αvβ6-specific knottin molecular probe containing the therapeutic radionuclide177Lu for targeting of PDAC.

Methods

The expression of integrin αvβ6 in PDAC cell lines BxPC3 and Capan2 was analyzed using RT-qPCR and immunofluorescence. In vitro competition and saturation radioligand binding assays were performed to calculate the binding affinity of the DOTA-coupled tracer loaded with and without lutetium to BxPC3 and Capan2 cell lines. To evaluate tracer accumulation in the tumor and organs, SPECT/CT, biodistribution and dosimetry projections were carried out using a Capan2 xenograft tumor mouse model.

Results

RT-qPCR and immunofluorescence results showed high expression of integrin αvβ6 in BxPC3 and Capan2 cells. A competition binding assay revealed high affinity of the tracer with IC50values of 1.69 nM and 9.46 nM for BxPC3 and Capan2, respectively. SPECT/CT and biodistribution analysis of the conjugate177Lu-DOTA-integrin αvβ6 knottin demonstrated accumulation in Capan2 xenograft tumors (3.13 ± 0.63 %IA/g at day 1 post injection) with kidney uptake at 19.2 ± 2.5 %IA/g, declining much more rapidly than in tumors.

Conclusion

177Lu-DOTA-integrin αvβ6 knottin was found to be a high-affinity tracer for PDAC tumors with considerable tumor accumulation and moderate, rapidly declining kidney uptake. These promising results warrant a preclinical treatment study to establish therapeutic efficacy.
Deep Learning Predicts Patterns of Cardiotoxicity in a High-Content Screen Using Induced Pluripotent Stem Cell–Derived Cardiomyocytes
Authors: Grafton Francis , Ho Jaclyn , Ranjbarvaziri Sara , Farshidfar Farshad , Budan Ana , Steltzer Stephanie , Maddah Mahnaz , Loewke Kevin E. , Green Kristina , Patel Snahel , Hoey Tim , Mandegar Mohammad A.
Published: March 2021

Drug-induced cardiotoxicity and hepatotoxicity are major causes of drug attrition. To decrease late-stage drug attrition, pharmaceutical and biotechnology industries need to establish biologically relevant models that use phenotypic screening to predict drug-induced toxicity. In this study, we sought to rapidly detect patterns of cardiotoxicity using high-content image analysis with deep learning and induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). We screened a library of 1280 bioactive compounds and identified those predicted to have cardiotoxic liabilities using a single-parameter score based on deep learning. Compounds with major predicted cardiotoxicity included DNA intercalators, ion channel blockers, epidermal growth factor receptor, cyclin-dependent kinase, and multi-kinase inhibitors. We also screened a diverse library of molecules with unknown targets and identified chemical frameworks with predicted cardiotoxic liabilities. By using this screening approach during target discovery and lead optimization, we can de-risk early-stage drug discovery. We show that the broad applicability of combining deep learning with iPSC technology is an effective way to interrogate cellular phenotypes and identify drugs that protect against diseased phenotypes and deleterious mutations.

GRAPHICAL ABSTRACT

CONTRIBUTION TO THE FIELD

In this article, Grafton and colleagues use induced pluripotent stem cell technology and deep learning to train a neural network capable of detecting patterns of cardiotoxicity. To identify bioactive and chemical classes that lead to cardiotoxicity, they combine the neural network with high-content screening of 2560 compounds. The methods described in this study can be used to de-risk early-stage drug development, triage hits, and identify drugs that protect against disease. This screening paradigm will serve as a useful resource for drug discovery and phenotypic interrogation of stem cells and stem cell–derived cell types.
Viability markers for determination of desiccation tolerance and critical stages during dehydration inSelaginellaspecies
Authors: Alejo-Jacuinde Gerardo , Kean-Galeno Tania , Martínez-Gallardo Norma , Tejero-Díez J. Daniel , Mehltreter Klaus , Délano-Frier John P. , Oliver Melvin J. , Simpson June , Herrera-Estrella Luis
Published: March 2021

Plants can tolerate some degree of dehydration but below a threshold of water content most plants die. However, some species display specific physiological, biochemical, and molecular responses that allow survival to desiccation. Some of these responses are activated at critical stages during water loss and could represent the difference between desiccation tolerance (DT) and death. Here, we report the development of a simple and reproducible system to determine DT inSelaginellaspecies. This system is based on the use of excised tissue (explants), exposed to a dehydration agent inside small containers, rather than whole plants making it faster, better controlled, and potential use under field conditions. We also report that the triphenyltetrazolium chloride test is a simple and accurate assay to determine tissue viability. The explant system is particularly useful to identify critical points during the dehydration process and was applied to identify novel desiccation-tolerantSelaginellaspecies. Our data suggest that desiccation-sensitiveSelaginellaspecies have a change in viability when dehydrated to 40% RWC, indicating the onset of a critical condition at this water content. Comparative studies at these critical stages could provide a better understanding of DT mechanisms and unravel insights into the key responses to survive desiccation.

Highlight

In this article, we developed a simple and efficient system to determine desiccation tolerance and critical stages during the dehydration process inSelaginellathat can be applied to other plant species.
β-arrestin-mediated Angiotensin II type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension
Authors: Ma Zhiyuan , Viswanathan Gayathri , Sellig Mason , Jassal Chanpreet , Choi Issac , Xiong Xinyu , Nazo Nour , Rajagopal Sudarshan
Published: March 2021

Objectives

The goal of this study was to test whether a β-arrestin-biased agonist of the angiotensin II (AngII) type 1 receptor (AT1R), which acts as a vasodilator while not blocking cellular proliferation, would have positive effects compared to a balanced agonist, angiotensin II (AngII), or an antagonist, losartan, in pulmonary arterial hypertension (PAH).

Background

PAH is a disease of abnormal pulmonary vascular remodeling whose treatment has focused on targeting vasoactive substances, such as inhibiting endothelin signaling and promoting prostacyclin signaling. PAH medical therapies are thought to primarily act as vasodilators, although they may also have effects on pulmonary vascular remodeling. There are a number of reports that blocking AT1R signaling can be beneficial in preclinical models of PAH. The AT1R is a G protein-coupled receptor (GPCR) that promotes vasoconstriction through heterotrimeric G proteins but also signals via β-arrestins, which promote cardioprotective effects and vasodilation.

Methods

We compared the effects of a β-arrestin-biased AT1R agonist, TRV120023 (TRV023), to a balanced agonist (AngII) and an antagonist (losartan) in preclinical PAH models.

Results

In acute infusion studies, AngII increased right ventricular (RV) pressures while TRV023 did not. However, with chronic infusion in monocrotaline (MCT) PAH rats, TRV023 failed to improve hemodynamics or survival compared to AngII, while losartan significantly improved survival. Both TRV023 and AngII enhanced proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) from PAH patients, which was associated with the promotion of proliferative MAP kinase signaling.

Conclusions

β-arrestin-mediated AT1R signaling promotes vascular remodeling and worsens PAH, and suggests that the primary benefit of current PAH therapies is through pulmonary vascular reverse remodeling and not vasodilation.
Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction
Authors: Pattabiraman Goutham , Bell-Cohn Ashlee J. , Murphy Stephen F. , Mazur Daniel J. , Schaeffer Anthony J. , Thumbikat Praveen
Published: March 2021

Intraurethral inoculation of mice with uropathogenicE. coli(CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and in CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells and the histamine 1 receptor in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain (MLC)-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.

NEW AND NOTEWORTHY

LUTS-associated BPH is derived from a combination of immune activation, extracellular matrix remodeling, hyperplasia, and smooth muscle cell contraction in prostates of men. Using a mouse model, we describe the importance of mast cells in regulating these multiple facets involved in the pathophysiology of LUTS. Mast cell inhibition alleviates both pathology and urinary dysfunction in this model suggesting the potential for mast cell inhibition as a therapeutic that prevents and reverses pathology and associated symptomology.
Insular cortex corticotropin-releasing factor integrates stress signaling with social decision making
Authors: Rieger Nathaniel S. , Varela Juan A. , Ng Alexandra , Granata Lauren , Djerdjaj Anthony , Brenhouse Heather C. , Christianson John P.
Published: March 2021

Impairments in social cognition manifest in a variety of psychiatric disorders, making the neurobiological mechanisms underlying social decision making of particular translational importance. The insular cortex is consistently implicated in stress-related social and anxiety disorders, which are associated with diminished ability to make and use inferences about the emotions of others to guide behavior. We investigated how corticotropin releasing factor (CRF), a neuromodulator evoked by both self and social stressors, influenced the insula. In acute slices from male and female rats, CRF depolarized insular pyramidal neurons. In males, but not females, CRF suppressed presynaptic GABAergic inhibition leading to greater excitatory synaptic efficacy in a CRF receptor 1 (CRF1) and cannabinoid receptor 1 (CB1) dependent fashion. In males only, insular CRF increased social investigation, and CRF1and CB1antagonists interfered with social decision making. To investigate the molecular and cellular basis for the effect of CRF we examined insular CRF1and CB1mRNAs and found greater total insula CRF1mRNA in females but greater CRF1and CB1mRNA colocalization in male insular cortex glutamatergic neurons which suggest complex, sex-specific organization of CRF and endocannabinoid systems. Together these results reveal a new sex-specific mechanism by which stress and affect contribute to social decision making.
Untangling the cell immune response dynamic for severe and critical cases of SARS-CoV-2 infection
Authors: Blanco-Rodríguez Rodolfo , Du Xin , Hernández-Vargas Esteban
Published: March 2021

COVID-19 is a global pandemic leading high death tolls worldwide day by day. Clinical evidence suggests that COVID-19 patients can be classified as non-severe, severe and critical cases. In particular, studies have highlighted the relationship between the lymphopenia and the severity of the illness, where CD8+T cells have the lowest levels in critical cases. In this work, we aim to elucidate the key parameters that define the course of the disease deviating from severe to critical case. To this end, several mathematical models are proposed to represent the dynamic of the immune response in patients with SARS-CoV-2 infection. The best model had a good fit to reported experimental data, and in accordance with values found in the literature. Our results suggest that a rapid proliferation of CD8+T cells is decisive in the severity of the disease.
Proteasome homeostasis is essential for a robust cauliflower mosaic virus infection
Authors: Shukla Aayushi , Ustun Suayib , Hafrén Anders
Published: March 2021

The ubiquitin-proteasome system (UPS) is essential for the maintenance and shifts in protein homeostasis, and thereby forms a founding pillar in virtually all cellular processes including plant immunity and viral infections. According to its importance in fine-tuning the complex plant immune response, proteasomal defects result in divergent outcomes including both resistance and susceptibility phenotypes in response to viruses. The final outcome will largely depend on the specific virus and its specific co-adaptation with the UPS as well as the immune system. Here, we show that cauliflower mosaic virus (CaMV) relies on the proteasome for robust infection. The proteasome system is induced during infection via SA and supports systemic accumulation of the virus as well as plant growth performance during infection. This establishes the UPS as a win-win pathway for the plant and the virus, and together with our demonstration of a proteasome-suppressing viral effector, the intimacy between the proteasome and CaMV is fortified.
Translocation of chloroplast NPR1 to the nucleus in retrograde signaling for adaptive response to salt stress in tobacco
Authors: Seo So Yeon , Park Ky Young
Published: March 2021

Chloroplasts play a pivotal role in biotic and abiotic stress responses, accompanying changes in the cell reduction/oxidation (redox) state. Chloroplasts are an endosymbiotic organelle that sends retrograde signals to the nucleus to integrate with environmental changes. This study showed that salt stress causes the rapid accumulation of the nonexpressor of pathogenesis-related genes 1 (NPR1) protein, a redox-sensitive transcription coactivator that elicits many tolerance responses in chloroplasts and the nucleus. The transiently accumulated chloroplast NPR1 protein was translocated to the nucleus in a redox-dependent manner under salinity stress. In addition, immunoblotting and fluorescence image analysis showed that chloroplast-targeted NPR1-GFP fused with cTP (chloroplast transit peptide from RbcS) was localized in the nucleus during the responses to salt stress. Chloroplast functionality was essential for retrograde translocation, in which the stomules and cytoplasmic vesicles participated. Treatments with H2O2and an ethylene precursor enhanced this retrograde translocation. Compared to each wild-type plant, retrograde signaling-related gene expression was severely impaired in thenpr1-1mutant in Arabidopsis, but enhanced transiently in theNPR1-Oxtransgenic tobacco line. Therefore, NPR1 might be a retrograde signaling hub that improves a plant’s adaptability to changing environments.
Ezh2 mediates epigenetic regulation of osteoclastogenesis and bone remodeling in mice
Authors: Chen Jin-Ran , Lazarenko Oxana P. , Gai Dongzheng , Li Can , Blackburn Michael L. , Zhan Fenghuang
Published: March 2021

Osteoclasts derived from hematopoietic stem cells control bone resorption. Identifying novel molecules that can epigenetically regulate osteoclastogenesis has been an important basic and clinical issue. The polycomb group (PcG) protein enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase is associated with epigenetic regulation of numerous cellular processes, it is not yet clear on its involvement in bone cell development and homeostasis. Here, we crossed LysM-Cre mice with Ezh2flox/floxmice to delete Ezh2 in myeloid cell lineage mature macrophages. Conditional deletion of Ezh2 in macrophages resulted in significant increases in postnatal bone growth in the first 6 months of life, but tibia length and body weight gains were not different in knockout mice compared with their wild type controls. Significantly decreased osteoclastogenesis but increased bone mass without osteopetrosis were found in Ezh2 conditional knockout (CKO) mice. In contrast to female mice, one floxed Ezh2 gene copy recombinant with LysM-Cre+(Ezh2flox/+LysM-Cre+) produced increased bone mass in young adult male mice compared with control mice (Ezh2flox/flox, LysM-Cre+and wild type). Inflammatory milieu in bone was significantly lower in both male and female CKO mice compared with their respective controls. Deletion of Ezh2 in macrophages triggered increased gene expression of osteoclast suppressors, IRF8, MafB and Arg1 due to decreased Ezh2-induced trimethylation of H3K27me3. Conversely, NFATc1 and Cathepsin k expression were decreased. These findings suggest that pre-osteoclastic cell differentiation is under epigenetic control of osteoclast suppressive gene expression via an Ezh2-dependent mechanisms.
Microenvironment evolution and SCC behavior of subsea pipeline within disbonded coating crevice in a seawater environment under cathodic protection
Authors: Zhang Wei , Liu Hongqun , Hu Minglei , Wu Wei
Published: March 2021

Purpose

This paper aims to make clear the sensitive zone of subsea pipeline to stress corrosion cracking (SCC) under a disbonded coating.

Design/methodology/approach

The change of microenvironment under a disbonded coating in artificial seawater was analyzed by using a rectangular crevice cell. The SCC behavior of subsea pipeline was studied by slow strain rate tensile tests.

Findings

The microenvironment at the crevice bottom exhibits obvious acidification, Cl- aggregation and cathodic protection potential (CP) rise. Accordingly, the susceptibility of X70 steels to SCC is high due to the intensive anodic dissolution effect. At the opening, hydrogen atom can access into the steel and induce hydrogen embrittlement effect on account of the applied over-protected CP potential, resulting in a relatively high susceptibility to SCC. The corrosiveness of the microenvironment at crevice middle, however, is mild with proper CP potential; thus, the susceptibility of X70 steel to SCC here is lower than that obtained at the opening and the crevice bottom.

Originality/value

A rectangular crevice cell is built to survey the microenvironment evolution under a disbonded coating in situ. The sensitive zone of subsea pipeline to SCC under a disbonded coating is clarified.
Family firm CEOs: human capital and career success
Authors: Blanco Maria Rita , Sastre-Castillo Miguel Angel , Montoro-Sanchez Maria Angeles
Published: March 2021

Purpose

This article explores the influence of education and experience on the time to the top in family and non-family CEOs who work for Latin American family firms.

Design/methodology/approach

In order to achieve these objectives, this study draws upon human capital theory as well as career and family firm literature. The careers of 129 CEOs of family firms who form part of the América Economía ranking were analyzed and quantitative methods were used.

Findings

In Latin American family firms, family CEOs reach the top faster than their non-family counterparts. In addition, the influence of human capital variables on the way to the top differs between the two groups. For family CEOs, obtaining a graduate degree delays the way to the top, while for non-family ones, it reduces the time to the top. As regards experience, for promoted family CEOs, the greater the percentage of the career spent in the organization they lead, the shorter the time to the top. No support was found for either the influence of having worked for just one firm or having had elite graduate education abroad, in multilatina CEOs.

Practical implications

Individual career management suggestions for future CEOs as well as specific guidelines for talent managers are proposed

Originality/value

This is the first study to explore the influence of human capital indicators on the time to the top in Latin American family firm CEOs.