bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early steps of embryo implantation are regulated by exchange of extracellular vesicles between the embryo and the endometrium
Authors: Szuszkiewicz Joanna , Myszczynski Kamil , Reliszko Zaneta P , Heifetz Yael , Kaczmarek Monika M 
Published: May 2022

AbstractIn early pregnancy, as the embryo arrives in the uterus, intensive communication between the embryo and uterus begins. Hundreds of molecules are known to be involved, but despite numerous findings, full understanding of the complexity of the embryo–maternal dialog remains elusive. Recently, extracellular vesicles, nanoparticles able to transfer functionally active cargo between cells, have emerged as important players in cell–cell communication, and as such, they have gained great attention over the past decade also in reproductive biology. Here we use a domestic animal model (Sus scrofa) with an epitheliochorial, superficial type of placentation because of its advantage in studding uterine luminal fluid extracellular vesicles. We show that during early pregnancy, the uterine lumen is abundant with extracellular vesicles that carry a plethora of miRNAs able to target genes involved in embryonic and organismal development. These extracellular vesicles, upon the delivery to primary trophoblast cells, affect genes governing development as well as cell-to-cell signaling and interactions, consequently having an impact on trophoblast cell proliferation, migration, and invasion. We conclude that exchange of a unique population of extracellular vesicles and their molecular cargo at the maternal–embryo interface is the key to the success of embryo implantation and pregnancy.
The capsid precursor protein of astrovirus VA1 is proteolytically processed intracellularly
Authors: Aguilera-Flores Catalina , López Tomás , Zamudio Fernando , Sandoval-Jaime Carlos , Pérezc Edmundo I. , López Susana , DuBois Rebecca , Arias Carlos F. 
Published: May 2022

ABSTRACTHuman astrovirus VA1 has been associated with neurological disease in immunocompromised patients, and its recent propagation in cell culture has opened the possibility to study its biology. Unlike classical human astroviruses, VA1 growth was found to be independent of trypsin during virus replication in vitro. In this work, we show that despite its independence on trypsin activation for cell infection, the VA1 capsid precursor protein, of 86 kDa (VP86), is processed intracellularly, and this proteolytic processing is important for astrovirus VA1 infectivity. Antibodies raised against different regions of the capsid precursor showed that the polyprotein can be processed starting at either its amino-or carboxy-terminal end, and they allowed us to identify that proteins of about 33 (VP33) and 38 (VP38) kDa constitute the core and the spike proteins of the mature infectious virus particles, respectively. The amino-terminal end of the spike protein was found to be Thr-348. Whether the protease involved in intracellular cleavage of the capsid precursor is of viral or cellular origin remains to be determined, but the cleavage is independent of caspases. Also, trypsin is able to degrade the capsid precursor but has no effect on VP34 and VP38 proteins when assembled into virus particles. These studies provide the basis for advancement of the knowledge of astrovirus VA1 cell entry and replication.IMPORTANCEHuman astrovirus VA1 has been associated with neurological disease in immunocompromised patients. Its recent propagation in cell culture has facilitated the study of its biology. In this work, we show that despite the ability of this virus to grow in the absence of trypsin, a marked feature of human classical astroviruses, the capsid precursor protein of astrovirus VA1 is cleaved intracellularly to yield the mature infectious particles, formed by two polypeptides, VP33 that constitutes the core domain of the virus particle, and V38 that forms the spike of the virus. These studies provide a platform to advance our knowledge on astrovirus VA1 cell entry and replication.
‘Erythritol’, a safe natural sweetener exhibits multi-stage anti-malarial activity by blocking Plasmodium falciparum membrane transporter ‘aquaporin’
Authors: Kumari Jyoti , Kumar Vikash , Behl Ankita , Sah Raj Kumar , Garg Swati , Pati Soumya , Samby Kirandeep , Burrows Jeremy , Mohandas Narla , Singh Shailja 
Published: May 2022

AbstractThe increased resistance of human malaria parasite Plasmodium falciparum to currently used drugs necessities the development of novel anti-malarials. In the present study, we examine the potential of erythritol, a sugar substitute, for therapeutic intervention that target a multifunctional transporter protein Plasmodium aquaglyceroporin (PfAQP) responsible for maintaining hydro-homeostasis. We show that erythritol effectively inhibited growth and progression of asexual blood stage malaria parasite by suppressing invasion and egress processes. It inhibited the liver stage (sporozoites) and transmission stage parasite (gametocytes) development that suggest its multi-stage, transmission-blocking potential. Interestingly, erythritol inhibited in vivo growth of malaria parasite in mouse experimental model. It was more effective in inhibiting parasite growth both in vivo and in vitro when tested together with a known anti-malarial ‘artesunate’. No Evans blue staining in treated mice indicated erythritol mediated protection of blood–brain barrier integrity in mice infected with P. berghei. Additionally, erythritol showed cytokine-modulating effect which suggest its direct effect on the host immune system. Our results of cellular thermal shift assay and ammonia detection assay demonstrate that erythritol binds with PfAQP and reduce the amount of ammonia release across the parasite respectively. We performed functional complementation assays which suggest that PfAQP expression in yeast mutant restores its growth in hyperosmotic conditions but showed reduced growth in the presence of erythritol, suggesting erythritol as an inhibitor of PfAQP. Overall, our data bestow erythritol as a promising new lead compound with an attractive antimalarial profile and could possibly be combined with known drugs without losing its efficacy.
Implementation strategies for telemental health: a systematic review
Authors: Appleton Rebecca , Barnett Phoebe , San Juan Norha Vera , Tuudah Elizabeth , Lyons Natasha , Parker Jennie , Roxburgh Emily , Spyridonidis Spyros , Tamworth Camilla , Worden Minnie , Yilmaz Melisa , Sevdalis Nick , Lloyd-Evans Brynmor , Needle Justin J , Johnson Sonia 
Published: May 2022

AbstractBackgroundThe COVID-19 pandemic resulted in a rapid shift from traditional face-to-face care provision towards delivering mental health care remotely through telecommunications, often referred to as telemental health care. However, the manner and extent of telemental health implementation have varied considerably across settings and areas, and substantial barriers are encountered. There is, therefore, now a need to identify what works best for service users and staff and establish the key mechanisms for efficient integration into routine care.ObjectiveWe aimed to identify investigations of pre-planned strategies intended to achieve or improve effective and sustained implementation of telemental health approaches, and to evaluate how different strategies influence implementation outcomes.MethodsA systematic review was conducted, with five databases searched for relevant literature using any methodological approach, published between January 2010 and July 2021. Studies were eligible for inclusion if they took place in secondary or tertiary mental health services and focused on pre-planned strategies for achieving or improving delivery of mental health care through remote communication between mental health professionals or between mental health professionals and service users, family members, unpaid carers, or peer supporters. All included studies were assessed for risk of bias. Data were synthesised using the Expert Recommendations for Implementing Change (ERIC) compilation of implementation strategies and the taxonomy of implementation outcomes.ResultsA total of 14 studies were identified which met the inclusion criteria. A variety of implementation strategies were identified, the most commonly reported being ‘Train and educate stakeholders’. All studies reported using a combination of several implementation strategies.ConclusionsUsing a combination of implementation strategies appears to be a helpful method of supporting the implementation of telemental health. Further research is needed to test the impact of specific implementation strategies on implementation outcomes.
“Similar performances but markedly different triaging thresholds in three CAD4TB versions risk systematic errors in TB screening programs”
Authors: Fehr Jana , Wong Emily B. 
Published: May 2022

AbstractTuberculosis (TB) screening programs may apply computer-aided diagnostic (CAD) tools on chest radiographs to select people for microbiological sputum examination using a pre-selected triaging threshold. CAD software-updates are frequently introduced and it is unknown whether their use requires adjustment of triaging thresholds. In a community-based screening program in South Africa, we compared the scores between the three recent CAD4TB versions (v5, v6, and v7) and assessed their performance to identify microbiologically-confirmed TB. The performance of all versions was similar (v5: AUC 0.78, v6: AUC 0.79, v7: AUC 0.80; p-values>0.05), but along a 0-100 point scale, each had markedly different score distributions and optimal triaging thresholds (v5: 40, v6: 47, v7: 20). This has the potential to cause confusion within TB screening programs as these tools are increasingly adopted and new versions released. Independent guidance for adapting CAD triaging thresholds for frequently released software updates is needed.
Effects of gender-affirming hormone therapy on gray matter density, microstructure and monoamine oxidase A levels in transgender subjects
Authors: Handschuh PA , Reed MB , Murgaš M , Vraka C , Kaufmann U , Nics L , Klöbl M , Ozenil M , Konadu ME , Patronas EM , Spurny-Dworak B , Hahn A , Hacker M , Spies M , Baldinger-Melich P , Kranz GS , Lanzenberger R 
Published: May 2022

AbstractMAO-A catalyzes the oxidative degradation of monoamines and is thus implicated in sex-specific neuroplastic processes that influence gray matter (GM) density (GMD) and microstructure (GMM). Given the exact monitoring of plasma hormone levels and sex steroid intake, transgender individuals undergoing gender-affirming hormone therapy (GHT) represent a valuable cohort to potentially investigate sex steroid-induced changes of GM and concomitant MAO-A density. Here, we investigated the effects of long-term GHT over a median time period of 4.5 months on GMD and GMM as well as MAO-A distribution volume. To this end, 20 cisgender women, 11 cisgender men, 20 transgender women and 10 transgender men underwent two MRI scans in a longitudinal design. PET scans using [11C]harmine were performed before each MRI session in a subset of 35 individuals. GM changes determined by diffusion weighted imaging (DWI) metrics for GMM and voxel based morphometry (VBM) for GMD were estimated using repeated measures ANOVA. Regions showing significant changes of both GMM and GMD were used for the subsequent analysis of MAO-A density. These involved the fusiform gyrus, rolandic operculum, inferior occipital cortex, middle and anterior cingulum, bilateral insula, cerebellum and the lingual gyrus (post-hoc tests: pFWE+Bonferroni< 0.025). In terms of MAO-A distribution volume, no significant effects were found. Additionally, the sexual desire inventory (SDI) was applied to assess GHT-induced changes in sexual desire, showing an increase of SDI scores among transmen. Changes in the GMD of the bilateral insula showed a moderate correlation to SDI scores (rho = −0.62, pBonferroni= 0.047). The present results are indicative of a reliable influence of gender-affirming hormone therapy on 1) GMD and GMM following an interregional pattern and 2) sexual desire specifically among transmen.HighlightsGender-affirming hormone therapy led to significant changes in gray matter density and microstructure in various brain regionsGray matter changes found after gender-affirming hormone therapy were not reflected by monoamone oxidase A density changes in the brain.Masculinizing gender-affirming hormone therapy resulted in increased sexual desire in transgender men.
Plasma membrane topography governs the three-dimensional dynamic localization of IgM B cell receptor clusters
Authors: Saltukoglu Deniz , Özdemir Bugra , Holtmannspötter Michael , Reski Ralf , Piehler Jacob , Kurre Rainer , Reth Michael 
Published: May 2022

AbstractB lymphocytes recognize bacterial or viral antigens via different classes of the B cell antigen receptor (BCR). Protrusive structures termed microvilli cover lymphocyte surfaces and are thought to perform sensory functions in screening antigen-bearing surfaces. Here, we have studied the cell surface features of Ramos B cells and the spatiotemporal organization of the IgM-BCR using lattice light sheet microscopy in combination with tailored custom-built 4D image analysis. Ramos B cell surfaces were found to form dynamic networks of elevated ridges bridging individual microvilli. A proportion of membrane-localized IgM-BCR was found in clusters, which were associated with the ridges and the microvilli. The dynamic ridge network organization and the IgM-BCR cluster mobility were linked and both were controlled by Arp2/3 complex activity. Our results suggest that topographical features of the cell surface govern the distribution and dynamic localization of IgM-BCR clusters to facilitate antigen screening.
TET1 attenuates human pluripotency-related heterogeneities and enhances differentiation capabilities
Authors: Motono Makoto , Hiraki-Kamon Keiko , Kamon Masayoshi , Kiyosawa Hidenori , Kondo Yoichi , Kato Hidemasa 
Published: May 2022

AbstractHuman induced pluripotent stem cells (hiPSCs) offer transformative potential for developmental research and therapeutic discovery; however, their variable characteristics are a significant barrier to their broader application. We reprogrammed hiPSCs by adding TET1, a DNA-demethylating dioxygenase, to produce TET1-iPSCs (T-iPSCs) with enhanced epithelialization and differentiation capabilities. A default differentiation survey—designed and implemented in our hiPSC-production pipeline—revealed considerable variation in differentiation capacity across qualitatively pluripotent iPSC clones. By comparing high- differentiation T-iPSCs and conventional iPSCs (C-iPSCs) at the single-cell level, we identified a subpopulation of C-iPSCs in the G0/G1 phase (CDKN2A-positive) exhibiting lowTET1expression and an elevated extraembryonic mesenchymal gene signature. The extraembryonic mesenchymal gene signature is common to iPSCs and quantitatively correlates to default differentiation results. Deviation of C-iPSCs from the cell-cycling embryonic epithelial gene profile was accompanied by DNA hypermethylation concomitant withTET1insufficiency and the accompanying derepression of poised and Polycomb-repressed enhancers, leading to the derepression of senescence-associated and extraembryonic genes. TET1-facilitated reprogramming can ameliorate these deviations. This study provides a standardized hiPSC- production pipeline and discovers an aspect of TET1 for establishing human pluripotency by remedying the inherent heterogeneities resulting from C-iPSC reprogramming.
Core genome sequencing and genotyping ofLeptospira interrogansin clinical samples by target capture sequencing
Authors: Grillova Linda , Cokelaer Thomas , Mariet Jean-François , da Fonseca Juliana Pipoli , Picardeau Mathieu 
Published: May 2022

AbstractThe life-threatening pathogenLeptospira interrogansis the most common agent of leptospirosis, an emerging zoonotic disease. However, little is known about the strains that are circulating worldwide due to the fastidious nature of the bacteria and its difficulty to be culture isolated. In addition, the paucity of bacteria in blood and other clinical samples has proven to be a considerable challenge for directly genotyping the agent of leptospirosis directly from patient material.Here, to elucidate the genomic diversity ofLeptospiracirculating strains, hybridization capture followed by Illumina sequencing of the core genome was performed directly from 20 biological samples that were PCR positive for pathogenicLeptospira. A set of samples subjected to capture with RNA probes covering theL. interroganscore genome resulted in 72 to 13,000-fold increase in pathogen reads when compared to standard sequencing without capture. A SNP analysis of the genomes sequenced from the biological samples using 273Leptospirareference genome was then performed in order to determine the genotype of the infecting strain. For samples with sufficent coverage (19/20 samples with coverage >8X), we could unambigously identifyL. interroganssv Icterohaemorrhagiae (14 samples),L. kirschnerisv Grippotyphosa (4 samples) andL. interroganssv Pyrogenes (1 sample) as the infecting strain.In conclusion, we obtained for most of our biological samples high quality genomic data at suitable coverage for confident core genome genotyping of the agent of leptospirosis. The ability to generate culture-free genomic data opens new opportunities to better understand the epidemiology and evolution of this fastidious pathogen.
MEK inhibitor resistance in lung cancer cells associated with addiction to sustained ERK suppression
Authors: Farnsworth Dylan A. , Inoue Yusuke , Johnson Fraser D. , de Rappard-Yuswack Georgia , Lu Daniel , Shi Rocky , Somwar Romel , Ladanyi Marc , Unni Arun M. , Lockwood William W. 
Published: May 2022

AbstractMEK inhibitors have yielded limited efficacy in KRAS-mutant lung adenocarcinoma (LUAD) patients due to drug resistance. We established trametinib-resistant KRAS-mutant LUAD cells and describe a state of “drug addiction” in a subset of resistant cases where cells are dependent on trametinib for survival. Dependence on ERK2 suppression underlies this phenomenon whereby trametinib removal hyperactivates ERK and results in ER stress and apoptosis. Amplification of KRASG12C occurs in drug-addicted cells and blocking mutant specific activity with AMG 510 rescues the lethality after trametinib withdrawal. Furthermore, increased KRASG12C expression is lethal to other KRAS mutant LUAD cells, consequential to ERK hyperactivation. Our study represents the first instance of this phenotype associated with KRAS amplification and demonstrates that acquired genetic changes that develop in the background of MAPK suppression can have unique consequence. We suggest that the presence of mutant KRAS amplification in patients may identify those that may benefit from a “drug holiday” to circumvent drug resistance. These findings demonstrate the toxic potential of hyperactive ERK signaling and highlight potential therapeutic opportunities in patients bearing KRAS mutations.
You will know by its tail: a method for quantification of heterogeneity of bacterial populations using single cell MIC profiling
Authors: Pacocha Natalia , Zapotoczna Marta , Makuch Karol , Bogusławski Jakub , Garstecki Piotr 
Published: May 2022

AbstractSevere non-healing infections are often caused by multiple pathogens or by genetic variants of the same pathogen exhibiting different levels of antibiotic resistance. For example, polymicrobial diabetic foot infections double the risk of amputation compared to monomicrobial infections. Although these infections lead to increased morbidity and mortality, standard antimicrobial susceptibility methods are designed for homogenous samples and are impaired in quantifying heteroresistance. Here, we propose a droplet-based label-free method for quantifying the antibiotic response of the entire population at the single-cell level. We usedPseudomonas aeruginosaandStaphylococcus aureussamples to confirm that the shape of the profile informs about the coexistence of diverse bacterial subpopulations, their sizes, and antibiotic heteroresistance. These profiles could therefore indicate the outcome of antibiotic treatment in terms of the size of remaining subpopulations. Moreover, we studied phenotypic variants of aS. aureusstrain to confirm that the profile can be used to identify tolerant subpopulations, such as small colony variants, associated with increased risks for the development of persisting infections. Therefore, the profile is a versatile instrument for quantifying the size of each bacterial subpopulation within a specimen as well as their individual and joined heteroresistance.
SPTLC1 variants associated with childhood onset amyotrophic lateral sclerosis produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins
Authors: Lone Museer A. , Aaltonen Mari J. , Zidell Aliza , Pedro Helio F. , Morales Saute Jonas Alex , Mathew Shalett , Mohassel Payam , Bonnemann Carsten , Shoubridge Eric A. , Hornemann Thorsten 
Published: May 2022

SummaryAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Mutations in the SPTLC1 subunit of serine-palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased sphingolipid synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause the peripheral sensory neuropathy HSAN1 due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.
Selenocyanate Derived Se-Incorporation into the Nitrogenase Fe Protein Cluster
Authors: Buscagan Trixia M. , Kaiser Jens T. , Rees Douglas C. 
Published: May 2022

AbstractThe nitrogenase Fe protein mediates ATP-dependent electron transfer to the nitrogenase MoFe protein during nitrogen fixation, in addition to catalyzing MoFe protein independent substrate (CO2) reduction and facilitating MoFe protein metallocluster biosynthesis. The precise role(s) of the Fe protein Fe4S4 cluster in some of these processes remains ill-defined. Herein, we report crystallographic data demonstrating ATP-dependent chalcogenide exchange at the Fe4S4 cluster of the nitrogenase Fe protein when potassium selenocyanate is used as the selenium source. The observed chalcogenide exchange illustrates that this Fe4S4 cluster is capable of core substitution reactions under certain conditions, adding to the Fe protein’s repertoire of unique properties.