Cell Commun Signal. 2021 Mar 10;19(1):31. doi: 10.1186/s12964-021-00712-3.

ABSTRACT

The intestinal epithelium acts as a physical barrier that separates the intestinal microbiota from the host and is critical for preserving intestinal homeostasis. The barrier is formed by tightly linked intestinal epithelial cells (IECs) (i.e. enterocytes, goblet cells, neuroendocrine cells, tuft cells, Paneth cells, and M cells), which constantly self-renew and shed. IECs also communicate with microbiota, coordinate innate and adaptive effector cell functions. In this review, we summarize the signaling pathways contributing to intestinal cell fates and homeostasis functions. We focus especially on intestinal stem cell proliferation, cell junction formation, remodelling, hypoxia, the impact of intestinal microbiota, the immune system, inflammation, and metabolism. Recognizing the critical role of KRAS mutants in colorectal cancer, we highlight the connections of KRAS signaling pathways in coordinating these functions. Furthermore, we review the impact of KRAS colorectal cancer mutants on pathway rewiring associated with disruption and dysfunction of the normal intestinal homeostasis. Given that KRAS is still considered undruggable and the development of treatments that directly target KRAS are unlikely, we discuss the suitability of targeting pathways downstream of KRAS as well as alterations of cell extrinsic/microenvironmental factors as possible targets for modulating signaling pathways in colorectal cancer. Video Abstract.

PMID:33691728 | DOI:10.1186/s12964-021-00712-3

BMC Biotechnol. 2021 Mar 10;21(1):20. doi: 10.1186/s12896-021-00683-w.

ABSTRACT

Over the past decade, therapeutic messenger RNAs (mRNAs) have emerged as a highly promising new class of drugs for protein replacement therapies. Due to the recent developments, the incorporation of modified nucleotides in synthetic mRNAs can lead to maximizing protein expression and reducing adverse immunogenicity. Despite these stunning improvements, mRNA therapy is limited by the need for the development of safe and efficient carriers to protect the mRNA integrity for in vivo applications. Recently, leading candidates for in vivo drug delivery vehicles are cell-derived exosomes, which have fewer immunogenic responses. In the current study, the key hurdles facing mRNA-based therapeutics, with an emphasis on recent strategies to overcoming its immunogenicity and instability, were highlighted. Then the immunogenicity and toxicity of exosomes derived from various cell sources were mentioned in detail. Finally, an overview of the recent strategies in using exosomes for mRNA delivery in the treatment of multiple diseases was stated.

PMID:33691652 | DOI:10.1186/s12896-021-00683-w

Bioorg Med Chem Lett. 2021 Mar 7:127912. doi: 10.1016/j.bmcl.2021.127912. Online ahead of print.

ABSTRACT

A series of novel artemisinin ester derivatives were designed and synthesized for targeting mitochondria. Cytotoxicity against SMMC-7721, HepG2, OVCAR3, A549 and J82 cancer cell lines was evaluated. Compound 2c (IC50 = 3.0 μM) was the most potent anti-proliferative molecule against the OVCAR3 cells with low cytotoxicity in normal HUVEC cells. The mechanism of action of compound 2c was further investigated by analyzing cell apoptosis, mitochondrial membrane potential (Δψm) and intracellular ROS generation. The results indicated that compound 2c targeted mitochondria and induced cell apoptosis. ROS and heme attributed to the cytotoxicity and cell apoptosis of compound 2c. These promising findings indicated the compound 2c could serve as a great candidate against ovarian cancer for further investigation.

PMID:33691167 | DOI:10.1016/j.bmcl.2021.127912

Immunity. 2021 Mar 9;54(3):391-392. doi: 10.1016/j.immuni.2021.02.009.

NO ABSTRACT

PMID:33691124 | DOI:10.1016/j.immuni.2021.02.009

Pac Symp Biocomput. 2021;26:261-272.

ABSTRACT

Molecular mechanisms characterizing cancer development and progression are complex and process through thousands of interacting elements in the cell. Understanding the underlying structure of interactions requires the integration of cellular networks with extensive combinations of dysregulation patterns. Recent pan-cancer studies focused on identifying common dysregulation patterns in a confined set of pathways or targeting a manually curated set of genes. However, the complex nature of the disease presents a challenge for finding pathways that would constitute a basis for tumor progression and requires evaluation of subnetworks with functional interactions. Uncovering these relationships is critical for translational medicine and the identification of future therapeutics. We present a frequent subgraph mining algorithm to find functional dysregulation patterns across the cancer spectrum. We mined frequent subgraphs coupled with biased random walks utilizing genomic alterations, gene expression profiles, and protein-protein interaction networks. In this unsupervised approach, we have recovered expert-curated pathways previously reported for explaining the underlying biology of cancer progression in multiple cancer types. Furthermore, we have clustered the genes identified in the frequent subgraphs into highly connected networks using a greedy approach and evaluated biological significance through pathway enrichment analysis. Gene clusters further elaborated on the inherent heterogeneity of cancer samples by both suggesting specific mechanisms for cancer type and common dysregulation patterns across different cancer types. Survival analysis of sample level clusters also revealed significant differences among cancer types (p < 0.001). These results could extend the current understanding of disease etiology by identifying biologically relevant interactions.Supplementary Information: Supplementary methods, figures, tables and code are available at https://github.com/bebeklab/FSM_Pancancer.

PMID:33691023

FEBS J. 2021 Mar 10. doi: 10.1111/febs.15810. Online ahead of print.

ABSTRACT

Bacteria are constantly subjected to stressful conditions, such as antibiotic exposure, nutrient limitation and oxidative stress. For pathogenic bacteria, adapting to the host environment, escaping defence mechanisms, as well as coping with antibiotic stress is crucial for their survival and the establishment of a successful infection. Stress adaptation relies heavily on the rate at which the organism can remodel its gene expression program to counteract the stress. RNA-binding proteins mediating co- and post-transcriptional regulation have recently emerged as important players in regulating gene expression during adaptive responses. Most of the research on these layers of gene expression regulation has been done in Gram-negative model organisms where, thanks to a wide variety of global studies, large post-transcriptional regulatory networks have been uncovered. Unfortunately, our understanding of post-transcriptional regulation in Gram-positive bacteria is lagging behind. One possible explanation for this is that many proteins employed by Gram-negative bacteria are not well conserved in Gram-positives. And even if they are conserved, they do not always play similar roles as in Gram-negative bacteria. This raises the important question whether Gram-positive bacteria regulate gene expression in a significantly different way. The goal of this review is to discuss this in more detail by reviewing the role of well-known RNA-binding proteins in Gram-positive bacteria and by highlighting their different behaviours with respect to some of their Gram-negative counterparts. Finally, the second part of this review introduces several unusual RNA-binding proteins of Gram-positive species that we believe could also play an important role in adaptive responses.

PMID:33690958 | DOI:10.1111/febs.15810

PLoS One. 2021 Mar 9;16(3):e0248127. doi: 10.1371/journal.pone.0248127. eCollection 2021.

ABSTRACT

BACKGROUND: The atomizers of electronic cigarettes (ECs) contain metals that transfer to the aerosol upon heating and may present health hazards. This study analyzed 4th-generation EC pod atomizer design features and characterized their elemental/metal composition.

METHODS: Eleven EC pods from six brands/manufacturers were purchased at local shops and online. Pods were dissected and imaged using a Canon EOS Rebel SL2 camera. Elemental analysis and mapping of atomizer components was done using a scanning electron microscope coupled with an energy dispersive x-ray spectrometer.

RESULTS: EC pods varied in size and design. The internal atomizer components were similar across brands except for variations occurring mainly in the wicks and filaments of some products. The filaments were either Elinvar (nickel, iron, and chromium) (36.4%), nichrome (36.4%), iron-chromium (18.2%), or nickel (9%). Thick wires present in 55% of the atomizers were mainly nickel and were joined to filaments by brazing. Wire-connector joints were Elinvar. Metal air tubes were made of Elinvar (50%), nickel, zinc, copper, and tin (37.5%), and nickel and copper (12.5%). Most of the wick components were silica, except for two pods (PHIX and Mico), which were mainly ceramic. Connectors contained gold-plated nickel, iron-chromium multiple alloys of nickel, zinc, gold, iron, and copper. Wick chambers were made of Elinvar. Outer casings were either nickel, copper-tin, or nickel-copper alloys. Magnets were nickel with minor iron, copper, and sulfur. Some frequently occurring elements were high in relative abundance in atomizer components.

CONCLUSIONS: The atomizers of pods are similar to previous generations, with the introduction of ceramic wicks and magnets in the newer generations. The elements in EC atomizers may transfer into aerosols and adversely affect health and accumulate in the environment.

PMID:33690644 | DOI:10.1371/journal.pone.0248127

PLoS Biol. 2021 Mar 10;19(3):e3000709. doi: 10.1371/journal.pbio.3000709. Online ahead of print.

ABSTRACT

Daily rhythms are disrupted in patients with mood disorders. The lateral habenula (LHb) and dorsal raphe nucleus (DRN) contribute to circadian timekeeping and regulate mood. Thus, pathophysiology in these nuclei may be responsible for aberrations in daily rhythms during mood disorders. Using the 15-day chronic social defeat stress (CSDS) paradigm and in vitro slice electrophysiology, we measured the effects of stress on diurnal rhythms in firing of LHb cells projecting to the DRN (cellsLHb→DRN) and unlabeled DRN cells. We also performed optogenetic experiments to investigate if increased firing in cellsLHb→DRN during exposure to a weak 7-day social defeat stress (SDS) paradigm induces stress-susceptibility. Last, we investigated whether exposure to CSDS affected the ability of mice to photoentrain to a new light-dark (LD) cycle. The cellsLHb→DRN and unlabeled DRN cells of stress-susceptible mice express greater blunted diurnal firing compared to stress-näive (control) and stress-resilient mice. Daytime optogenetic activation of cellsLHb→DRN during SDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stress-susceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that exposure to strong stressors induces blunted daily rhythms in firing in cellsLHb→DRN, DRN cells and decreases the initial rate of photoentrainment in susceptible-mice. In contrast, resilient-mice may undergo homeostatic adaptations that maintain daily rhythms in firing in cellsLHb→DRN and also show rapid photoentrainment to a new LD cycle.

PMID:33690628 | DOI:10.1371/journal.pbio.3000709

J Virol Methods. 2021 Mar 6:114116. doi: 10.1016/j.jviromet.2021.114116. Online ahead of print.

ABSTRACT

A variety of methods have been developed for quantification of infectious Ebola virus in clinical or laboratory samples, but existing methods often require extensive operator involvement, manual assay scoring, or the use of custom reagents. In this study, we utilize a recently developed Ebola-specific reporter cell line that expresses ZsGreen in response to Ebola virus infection, in conjunction with semi-automated processing and quantification techniques, to develop an unbiased, high-throughput microtitration assay for quantification of infectious Ebola virus in vitro. This assay was found to have equivalent sensitivity to a standardized plaque assay for quantifying viral titers. However, the new assay could be implemented with fewer reagents and processing steps, reduced subjectivity, and higher throughput. This assay may be useful for a variety of applications, particularly studies that require the detection or quantification of infectious Ebola virus in large numbers of samples.

PMID:33689788 | DOI:10.1016/j.jviromet.2021.114116

Curr Biol. 2021 Mar 8;31(5):R218-R220. doi: 10.1016/j.cub.2021.01.090.

ABSTRACT

Dima and Inzé discuss how Europe is lagging behind in embracing the potential of genome editing in crops and highlight how scientists can contribute to advising on effective science-based policies for more sustainable agriculture through genome editing.

PMID:33689712 | DOI:10.1016/j.cub.2021.01.090

Cancer Cell. 2021 Mar 8;39(3):380-393.e8. doi: 10.1016/j.ccell.2021.02.003.

ABSTRACT

Hotspot mutation of IKZF3 (IKZF3-L162R) has been identified as a putative driver of chronic lymphocytic leukemia (CLL), but its function remains unknown. Here, we demonstrate its driving role in CLL through a B cell-restricted conditional knockin mouse model. Mutant Ikzf3 alters DNA binding specificity and target selection, leading to hyperactivation of B cell receptor (BCR) signaling, overexpression of nuclear factor κB (NF-κB) target genes, and development of CLL-like disease in elderly mice with a penetrance of ~40%. Human CLL carrying either IKZF3 mutation or high IKZF3 expression was associated with overexpression of BCR/NF-κB pathway members and reduced sensitivity to BCR signaling inhibition by ibrutinib. Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or overexpression of this CLL driver. This emphasizes the need for combinatorial approaches to overcome IKZF3-mediated BCR inhibitor resistance.

PMID:33689703 | DOI:10.1016/j.ccell.2021.02.003

J Proteome Res. 2021 Mar 9. doi: 10.1021/acs.jproteome.0c00957. Online ahead of print.

ABSTRACT

Software tools that allow the visualization and analysis of protein interaction networks are essential for studies in systems biology. One of the most popular network visualization tools in biology is Cytoscape, which offers a great selection of plug-ins for the interpretation of network data. Chemical cross-linking coupled to mass spectrometry (XL-MS) is an increasingly important source for protein interaction data; however, to date, no Cytoscape tools are available to analyze XL-MS results. In light of the suitability of the Cytoscape platform and to expand its toolbox, here we introduce XlinkCyNET, an open-source Cytoscape Java plug-in for exploring large-scale XL-MS-based protein interaction networks. XlinkCyNET offers the rapid and easy visualization of intra- and interprotein cross-links in a rectangular-bar style as well as on the 3D structure, allowing the interrogation of protein interaction networks at the residue level. XlinkCyNET is freely available from the Cytoscape App Store (http://apps.cytoscape.org/apps/xlinkcynet) and at the Liu lab webpage (https://www.theliulab.com/software/xlinkcynet).

PMID:33689356 | DOI:10.1021/acs.jproteome.0c00957

Phys Chem Chem Phys. 2021 Mar 10. doi: 10.1039/d0cp05948j. Online ahead of print.

ABSTRACT

COVID-19 has recently caused a global health crisis and an effective interventional therapy is urgently needed. Remdesivir is one effective inhibitor for SARS-CoV-2 viral RNA replication. It supersedes other NTP analogues because it not only terminates the polymerization activity of RNA-dependent RNA polymerase (RdRp), but also inhibits the proofreading activity of intrinsic exoribonuclease (ExoN). Even though the static structure of Remdesivir binding to RdRp has been solved and biochemical experiments have suggested it to be a "delayed chain terminator", the underlying molecular mechanisms is not fully understood. Here, we performed all-atom molecular dynamics (MD) simulations with an accumulated simulation time of 24 microseconds to elucidate the inhibitory mechanism of Remdesivir on nucleotide addition and proofreading. We found that when Remdesivir locates at an upstream site in RdRp, the 1'-cyano group experiences electrostatic interactions with a salt bridge (Asp865-Lys593), which subsequently halts translocation. Our findings can supplement the current understanding of the delayed chain termination exerted by Remdesivir and provide an alternative molecular explanation about Remdesivir's inhibitory mechanism. Such inhibition also reduces the likelihood of Remdesivir to be cleaved by ExoN acting on 3'-terminal nucleotides. Furthermore, our study also suggests that Remdesivir's 1'-cyano group can disrupt the cleavage site of ExoN via steric interactions, leading to a further reduction in the cleavage efficiency. Our work provides plausible and novel mechanisms at the molecular level of how Remdesivir inhibits viral RNA replication, and our findings may guide rational design for new treatments of COVID-19 targeting viral replication.

PMID:33688867 | DOI:10.1039/d0cp05948j

Elife. 2021 Mar 10;10:e67269. doi: 10.7554/eLife.67269.

ABSTRACT

An approach called deep mutational scanning is improving our understanding of amyloid beta aggregation.

PMID:33688830 | DOI:10.7554/eLife.67269

Proc Natl Acad Sci U S A. 2021 Mar 16;118(11):e2020024118. doi: 10.1073/pnas.2020024118.

ABSTRACT

Phosphite is the most energetically favorable chemotrophic electron donor known, with a half-cell potential (E o') of -650 mV for the PO4 3-/PO3 3- couple. Since the discovery of microbial dissimilatory phosphite oxidation (DPO) in 2000, the environmental distribution, evolution, and diversity of DPO microorganisms (DPOMs) have remained enigmatic, as only two species have been identified. Here, metagenomic sequencing of phosphite-enriched microbial communities enabled the genome reconstruction and metabolic characterization of 21 additional DPOMs. These DPOMs spanned six classes of bacteria, including the Negativicutes, Desulfotomaculia, Synergistia, Syntrophia, Desulfobacteria, and Desulfomonilia_A Comparing the DPO genes from the genomes of enriched organisms with over 17,000 publicly available metagenomes revealed the global existence of this metabolism in diverse anoxic environments, including wastewaters, sediments, and subsurface aquifers. Despite their newfound environmental and taxonomic diversity, metagenomic analyses suggested that the typical DPOM is a chemolithoautotroph that occupies low-oxygen environments and specializes in phosphite oxidation coupled to CO2 reduction. Phylogenetic analyses indicated that the DPO genes form a highly conserved cluster that likely has ancient origins predating the split of monoderm and diderm bacteria. By coupling microbial cultivation strategies with metagenomics, these studies highlighted the unsampled metabolic versatility latent in microbial communities. We have uncovered the unexpected prevalence, diversity, biochemical specialization, and ancient origins of a unique metabolism central to the redox cycling of phosphorus, a primary nutrient on Earth.

PMID:33688048 | DOI:10.1073/pnas.2020024118

mBio. 2021 Mar 9;12(2):e03457-20. doi: 10.1128/mBio.03457-20.

ABSTRACT

Cryptococcus neoformans is a ubiquitous, opportunistic fungal pathogen that kills almost 200,000 people worldwide each year. It is acquired when mammalian hosts inhale the infectious propagules; these are deposited in the lung and, in the context of immunocompromise, may disseminate to the brain and cause lethal meningoencephalitis. Once inside the host, C. neoformans undergoes a variety of adaptive processes, including secretion of virulence factors, expansion of a polysaccharide capsule that impedes phagocytosis, and the production of giant (Titan) cells. The transcription factor Pdr802 is one regulator of these responses to the host environment. Expression of the corresponding gene is highly induced under host-like conditions in vitro and is critical for C. neoformans dissemination and virulence in a mouse model of infection. Direct targets of Pdr802 include the quorum sensing proteins Pqp1, Opt1, and Liv3; the transcription factors Stb4, Zfc3, and Bzp4, which regulate cryptococcal brain infectivity and capsule thickness; the calcineurin targets Had1 and Crz1, important for cell wall remodeling and C. neoformans virulence; and additional genes related to resistance to host temperature and oxidative stress, and to urease activity. Notably, cryptococci engineered to lack Pdr802 showed a dramatic increase in Titan cells, which are not phagocytosed and have diminished ability to directly cross biological barriers. This explains the limited dissemination of pdr802 mutant cells to the central nervous system and the consequently reduced virulence of this strain. The role of Pdr802 as a negative regulator of Titan cell formation is thus critical for cryptococcal pathogenicity.IMPORTANCE The pathogenic yeast Cryptococcus neoformans presents a worldwide threat to human health, especially in the context of immunocompromise, and current antifungal therapy is hindered by cost, limited availability, and inadequate efficacy. After the infectious particle is inhaled, C. neoformans initiates a complex transcriptional program that integrates cellular responses and enables adaptation to the host lung environment. Here, we describe the role of the transcription factor Pdr802 in the response to host conditions and its impact on C. neoformans virulence. We identified direct targets of Pdr802 and also discovered that it regulates cellular features that influence movement of this pathogen from the lung to the brain, where it causes fatal disease. These findings significantly advance our understanding of a serious disease.

PMID:33688010 | DOI:10.1128/mBio.03457-20

Gut. 2021 Mar 9:gutjnl-2020-322599. doi: 10.1136/gutjnl-2020-322599. Online ahead of print.

ABSTRACT

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a global disease characterised by chronic obstruction of lung airflow interfering with normal breathing. Although the microbiota of respiratory tract is established to be associated with COPD, the causality of gut microbiota in COPD development is not yet established. We aimed to address the connection between gut microbiota composition and lung COPD development, and characterise bacteria and their derived active components for COPD amelioration.

DESIGN: A murine cigarette smoking (CS)-based model of COPD and strategies evaluating causal effects of microbiota were performed. Gut microbiota structure was analysed, followed by isolation of target bacterium. Single cell RNA sequencing, together with sera metabolomics analyses were performed to identify host responsive molecules. Bacteria derived active component was isolated, followed by functional assays.

RESULTS: Gut microbiota composition significantly affects CS-induced COPD development, and faecal microbiota transplantation restores COPD pathogenesis. A commensal bacterium Parabacteroides goldsteinii was isolated and shown to ameliorate COPD. Reduction of intestinal inflammation and enhancement of cellular mitochondrial and ribosomal activities in colon, systematic restoration of aberrant host amino acids metabolism in sera, and inhibition of lung inflammations act as the important COPD ameliorative mechanisms. Besides, the lipopolysaccharide derived from P. goldsteinii is anti-inflammatory, and significantly ameliorates COPD by acting as an antagonist of toll-like receptor 4 signalling pathway.

CONCLUSION: The gut microbiota-lung COPD axis was connected. A potentially benefial bacterial strain and its functional component may be developed and used as alternative agents for COPD prevention or treatment.

PMID:33687943 | DOI:10.1136/gutjnl-2020-322599

BMJ. 2021 Mar 9;372:n579. doi: 10.1136/bmj.n579.

ABSTRACT

OBJECTIVE: To establish whether there is any change in mortality from infection with a new variant of SARS-CoV-2, designated a variant of concern (VOC-202012/1) in December 2020, compared with circulating SARS-CoV-2 variants.

DESIGN: Matched cohort study.

SETTING: Community based (pillar 2) covid-19 testing centres in the UK using the TaqPath assay (a proxy measure of VOC-202012/1 infection).

PARTICIPANTS: 54 906 matched pairs of participants who tested positive for SARS-CoV-2 in pillar 2 between 1 October 2020 and 29 January 2021, followed-up until 12 February 2021. Participants were matched on age, sex, ethnicity, index of multiple deprivation, lower tier local authority region, and sample date of positive specimens, and differed only by detectability of the spike protein gene using the TaqPath assay.

MAIN OUTCOME MEASURE: Death within 28 days of the first positive SARS-CoV-2 test result.

RESULTS: The mortality hazard ratio associated with infection with VOC-202012/1 compared with infection with previously circulating variants was 1.64 (95% confidence interval 1.32 to 2.04) in patients who tested positive for covid-19 in the community. In this comparatively low risk group, this represents an increase in deaths from 2.5 to 4.1 per 1000 detected cases.

CONCLUSIONS: The probability that the risk of mortality is increased by infection with VOC-202012/01 is high. If this finding is generalisable to other populations, infection with VOC-202012/1 has the potential to cause substantial additional mortality compared with previously circulating variants. Healthcare capacity planning and national and international control policies are all impacted by this finding, with increased mortality lending weight to the argument that further coordinated and stringent measures are justified to reduce deaths from SARS-CoV-2.

PMID:33687922 | DOI:10.1136/bmj.n579

J Thromb Haemost. 2021 Mar 9. doi: 10.1111/jth.15289. Online ahead of print.

ABSTRACT

INTRODUCTION: Vitamin K Antagonists (VKA) and non-vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off-target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup.

MATERIAL AND METHODS: Female Apoe-/- mice (age 12 weeks) were fed western type diet (WTD) as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18 F]-NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed.

RESULTS: Short-term treatment with warfarin promoted formation of atherosclerotic lesions with a pro-inflammatory phenotype, and more rapid plaque progression compared to control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared to control. Long-term warfarin treatment significantly increased both presence and activity of plaque calcification compared to control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran.

CONCLUSION: Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

PMID:33687782 | DOI:10.1111/jth.15289

Environ Microbiol. 2021 Mar 9. doi: 10.1111/1462-2920.15457. Online ahead of print.

ABSTRACT

A deeper understanding of the complex relationship between plants and their microbiota is allowing researchers to appreciate a plethora of possibilities to improve crops using chemical-free alternatives based on beneficial microorganisms. An increase in crop yield from the promotion of plant growth or even simultaneous protection of the plants from the attack of phytopathogens can be achieved in the presence of different plant-associated microorganisms known as plant-growth-promoting rhizobacteria (PGPR) and biocontrol agents (BCAs), respectively. Thus, the study of the great diversity of plant-microbe and microbe-microbe interactions is an attention-grabbing topic covering studies of interactions since the plant seed and through all developmental stages, from root to shoot. The intricate communication systems that plant holobionts co-evolved has resulted in many different strategies and interplays between these organisms shaping the bacterial communities and the plant fitness simultaneously. Herein, we emphasize two understudied delivery systems existing in plant-associated bacteria: the type VI secretion system (T6SS) and the membrane vesicles with a huge potential to boost a highly demanded and necessary green agriculture. This article is protected by copyright. All rights reserved.

PMID:33687778 | DOI:10.1111/1462-2920.15457