bluuebunny/crossref_metadata_2025_split huggingface dataset:
Canonical Wnt and TGF-β/BMP signaling enhance melanocyte regeneration and suppress invasiveness, migration, and proliferation of melanoma cells
Authors: Katkat Esra , Demirci Yeliz , Heger Guillaume , Karagulle Doga , Papatheodorou Irene , Brazma Alvis , Ozhan Gunes 
Published: March 2022

ABSTRACTTissue regeneration and cancer share remarkable features including activation of cell proliferation and migration. Yet, tumors considerably differ from the regenerating tissue with respect to abnormal proliferation, invasive growth, and metastasis. Thus, it is likely that cancer resembles early stages of regeneration with increased proliferation, but separates from the later stages with reduced proliferation and enhanced differentiation. Here, by exploiting the zebrafish melanocytes that can efficiently regenerate and be induced to undergo malignant melanoma, we unravel the transcriptome profiles of the regenerating melanocytes during early and late regeneration, and the melanocytic nevi and malignant melanoma. Our global comparison of the gene expression profiles of melanocyte regeneration and nevi/melanoma uncovers the differential regulation of a substantial number of genes related to Wnt signaling and TGF-β/BMP signaling pathways between regeneration and cancer. Functional activation of canonical Wnt or TGF-β/BMP pathways during melanocyte regeneration promoted melanocyte regeneration and potently suppressed the invasiveness, migration, and proliferation of human melanoma cellsin vitroandin vivo. Therefore, differential regulation of signaling mechanisms between regeneration and cancer can be exploited to stop tumor growth and develop new anticancer therapies.
Short-chain fatty acid concentrations in the incidence and risk-stratification of colorectal cancer: a systematic review and meta-analysis
Authors: Alvandi Ehsan , Wong Wilson K M , Joglekar Mugdha V , Spring Kevin J , Hardikar Anandwardhan A 
Published: March 2022

AbstractThe beneficial role of gut microbiota and bacterial metabolites, including short-chain fatty acids (SCFAs), is well recognized; although the available literature around their role in colorectal cancer (CRC) has been inconsistent.We performed a systematic review and meta-analysis to examine associations of fecal SCFA concentrations to the incidence and risk of CRC.Data extraction through Medline, Embase, and Web of Science was carried out from database conception to May 21, 2021. Predefined criteria included human clinical observational studies, while excluding cell/animal model studies, conference proceedings, and reviews. Quality assessment of selected 16 case-control and six cross-sectional studies is reported using PRISMA 2020 guidelines. Studies were categorized for CRC risk or incidence, and RevMan 5.4 was used to perform the meta-analyses. Standardized mean differences (SMD) with 95% confidence intervals (CI) were calculated using a random-effects model.Combined analysis of acetic-, propionic-, and butyric-acid revealed significantly lower concentrations of these SCFAs in individuals with high-risk of CRC (SMD = 2.02, 95% CI 0.31 to 3.74, P = 0.02). Further, CRC incidence increased in individuals with lower levels of SCFAs (SMD = 0.45, 95% CI 0.19 to 0.72, P = 0.0009), compared to healthy individuals.Overall, lower fecal concentrations of the three major SCFAs is associated with higher risk and incidence of CRC.
The triadic structure of personality space in the house mouse resembles that of species with known personality badges; suggesting reciprocal hierarchies are an evolutionary motif with mixed strategies being more common
Authors: Forkosh Oren , Sinervo Barry 
Published: March 2022

AbstractDifferences in animal personalities are generally hard to measure - even in an animal as common as the house mouse. Yet, in some rare cases, nature has provided us with clear visual cues as to the nature of a specific individual. These so-called badges are the case for the side botched lizard, often referred to as the ‘rock-paper-scissor’ lizard. Here, we show that mice have behavioral archetypes that are similar to the triadic social dynamics of the lizards. We find analogs in territoriality, aggressiveness, and pro-social behavior linking ultra-dominant, dominant, and subordinate mice to the lizard’s orange, blue, and yellow morphs accordingly. Yet, unlike the lizards, most mice in the study displayed mixed strategies rather than fall into clear behavioral archetypes. In such a case, it makes less sense to have distinct visual cues to distinguish between personalities. The result implies that, although visual distinctions are infrequent in nature, having multiple behavioral archetypes might serve as an evolutionary motif. In addition, we find that mammals, like mice, might have circular hierarchies, similar to the lizards, where no single behavioral strategy outweighs others.
Combination treatment can hinder the evolution of resistance to antimicrobial peptides
Authors: Maron Bar , Friedman Jonathan , Hayouka Zvi 
Published: March 2022

AbstractAntibiotic resistant microbial pathogens are becoming a major threat to human health. Therefore, there is an urgent need to develop new alternatives to conventional antibiotics. One such promising alternative is antimicrobial peptides (AMPs), which are produced by virtually all organisms and typically inhibit bacteria via membrane disruption. However, previous studies demonstrated that bacteria can rapidly develop AMP resistance. Here, we study whether combination therapy, known to be able to inhibit the evolution of resistance to conventional antibiotics, can also hinder the evolution of AMP resistance. To do so, we evolved the opportunistic pathogen S. aureus in the presence of individual AMP, AMP pairs, and a combinatorial antimicrobial peptide library. Treatment with some AMP pair indeed hindered the evolution of resistance compared with individual AMPs. In particular, resistance to pairs was delayed when resistance to the individual AMPs came at a cost of impaired bacterial growth, and did not confer cross-resistance to other tested AMPs. The lowest level of resistance evolved during treatment with the combinatorial antimicrobial peptide library termed random antimicrobial peptide mixture, which contains more than a million different peptides. A better understanding of how AMP combinations affect the evolution of resistance is a crucial step in order to design ‘resistant proof’ AMPs cocktails that will offer a sustainable treatment option for antibiotic resistant pathogens.
In vitro engineering of the lung alveolus
Authors: Leiby Katherine L. , Yuan Yifan , Ng Ronald , Raredon Micha Sam Brickman , Adams Taylor S. , Baevova Pavlina , Hirschi Karen K. , Campbell Stuart G. , Kaminski Naftali , Herzog Erica L. , Niklason Laura E. 
Published: March 2022

ABSTRACTTherapeutic lung regeneration is predicated upon successful reconstitution of lung alveoli, the functional units of gas exchange. Here, we identify requisite multimodal cues that are critical to reconstructing the alveolar epithelium and alveoli in lung scaffolds. Alveolar reconstruction in vitro is divided into several distinct phases. In the first phase, endothelial cells coordinate with fibroblasts and select exogenous factors to promote alveolar scaffold population with surfactant-secreting alveolar epithelial type 2 cells (AEC2s). After formation of organized epithelial alveolar-like structures, subsequent withdrawal of Wnt and FGF agonism synergizes with tidal-level mechanical strain to induce differentiation of AEC2s to squamous type 1 AECs (AEC1s) in cultured alveoli, in situ. These results outline a rational strategy to engineer an alveolus of AEC2s and AEC1s contained within epithelial-mesenchymal-endothelial units, and reveal the critical interplay amongst biochemical, cellular, and mechanical niche cues within the reconstituting alveolus.
Acidity of expiratory aerosols controls the infectivity of airborne influenza virus and SARS-CoV-2
Authors: Luo Beiping , Schaub Aline , Glas Irina , Klein Liviana K. , David Shannon C. , Bluvshtein Nir , Violaki Kalliopi , Motos Ghislain , Pohl Marie , Hugentobler Walter , Nenes Athanasios , Krieger Ulrich K. , Stertz Silke , Peter Thomas , Kohn Tamar 
Published: March 2022

Enveloped viruses are prone to inactivation when exposed to strong acidity levels characteristic of atmospheric aerosol. Yet, the acidity of expiratory aerosol particles and its effect on airborne virus persistence has not been examined. Here, we combine pH-dependent inactivation rates of influenza A virus and SARS-CoV-2 with microphysical properties of respiratory fluids under indoor conditions using a biophysical aerosol model. We find that particles exhaled into indoor air become mildly acidic (pH ≈ 4), rapidly inactivating influenza A virus within minutes, whereas SARS-CoV-2 requires days. If indoor air is enriched with non-hazardous levels of nitric acid, aerosol pH drops by up to 2 units, decreasing 99%-inactivation times for both viruses in small aerosol particles to below 30 seconds.Conversely, unintentional removal of volatile acids from indoor air by filtration may elevate pH and prolong airborne virus persistence. The overlooked role of aerosol pH has profound implications for virus transmission and mitigation strategies.One Sentence SummaryRespiratory viruses are sensitive to aerosol pH, an unidentified factor in the mitigation of airborne virus transmission
Migrants’ primary care utilisation before and during the COVID-19 pandemic in England: An interrupted time series
Authors: Zhang Claire X. , Boukari Yamina , Pathak Neha , Mathur Rohini , Katikireddi Srinivasa Vittal , Patel Parth , Campos-Matos Ines , Lewer Dan , Nguyen Vincent , Hugenholtz Greg , Burns Rachel , Mulick Amy , Henderson Alasdair , Aldridge Robert W. 
Published: March 2022

AbstractBackgroundHow international migrants access and use primary care in England is poorly understood. We aimed to compare primary care consultation rates between international migrants and non-migrants in England before and during the COVID-19 pandemic (2015– 2020).MethodsUsing linked data from the Clinical Practice Research Datalink (CPRD) GOLD and the Office for National Statistics, we identified migrants using country-of-birth, visa-status or other codes indicating international migration. We ran a controlled interrupted time series (ITS) using negative binomial regression to compare rates before and during the pandemic.FindingsIn 262,644 individuals, pre-pandemic consultation rates per person-year were 4.35 (4.34-4.36) for migrants and 4.6 (4.59-4.6) for non-migrants (RR:0.94 [0.92-0.96]). Between 29 March and 26 December 2020, rates reduced to 3.54 (3.52-3.57) for migrants and 4.2 (4.17-4.23) for non-migrants (RR:0.84 [0.8–0.88]). Overall, this represents an 11% widening of the pre-pandemic difference in consultation rates between migrants and non-migrants during the first year of the pandemic (RR:0.89, 95%CI:0.84–0.94). This widening was greater for children, individuals whose first language was not English, and individuals of White British, White non-British and Black/African/Caribbean/Black British ethnicities.InterpretationMigrants were less likely to use primary care before the pandemic and the first year of the pandemic exacerbated this difference. As GP practices retain remote and hybrid models of service delivery, they must improve services and ensure they are accessible and responsive to migrants’ healthcare needs.FundingThis study was funded by the Medical Research Council (MR/V028375/1) and Wellcome Clinical Research Career Development Fellowship (206602).
Modifiable lifestyle activities affect cognition in cognitively healthy middle-aged individuals at risk for late-life Alzheimer’s Disease
Authors: Heneghan Amy , Deng Feng , Wells Katie , Ritchie Karen , Muniz-Terrera Graciela , Ritchie Craig W , Lawlor Brian , Naci Lorina 
Published: March 2022

AbstractIt is now acknowledged that Alzheimer’s Disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid-life. We asked whether modifiable lifestyle activities impact cognition in middle-aged individuals who are cognitively healthy, but at risk for late life AD. Participants (40–59 years) completed cognitive and clinical assessments at baseline (N = 206) and two years follow-up (N = 174). Mid-life activities were measured with the Lifetime of Experiences Questionnaire. We assessed the impact of lifestyle activities, known risk factors for sporadic late-onset AD (Apolipoprotein E □4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score), and their interactions on cognition. More frequent engagement in physically, socially and intellectually stimulating activities was associated with better cognition (verbal, spatial and relational memory), at baseline and follow-up. Critically, more frequent engagement in these activities was associated with stronger cognition (verbal and visuospatial functions, and conjunctive short-term memory binding) in individuals with family history of dementia. Impaired visuospatial function is one of the earliest cognitive deficits in AD and has previously associated with increased AD risk in this cohort. Additionally, conjunctive memory functions have been found impaired in the pre-symptomatic stages of AD. These findings suggest that modifiable lifestyle activities offset cognitive decrements due to AD risk in mid-life and support the targeting of modifiable lifestyle activities for the prevention of Alzheimer’s Disease.
Parsing the role of NSP1 in SARS-CoV-2 infection
Authors: Fisher Tal , Gluck Avi , Narayanan Krishna , Kuroda Makoto , Nachshon Aharon , Hsu Jason C. , Halfmann Peter J. , Yahalom-Ronen Yfat , Finkel Yaara , Schwartz Michal , Weiss Shay , Tseng Chien-Te K. , Israely Tomer , Paran Nir , Kawaoka Yoshihiro , Makino Shinji , Stern-Ginossar Noam 
Published: March 2022

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 19 (COVID-19) pandemic. Despite its urgency, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis and its ability to antagonize innate immune responses. SARS-CoV-2 leads to shutoff of cellular protein synthesis and over-expression of nsp1, a central shutoff factor in coronaviruses, inhibits cellular gene translation. However, the diverse molecular mechanisms nsp1 employs as well as its functional importance in infection are still unresolved. By overexpressing various nsp1 mutants and generating a SARS-CoV-2 mutant in which nsp1 does not bind ribosomes, we untangle the effects of nsp1. We uncover that nsp1, through inhibition of translation and induction of mRNA degradation, is the main driver of host shutoff during SARS-CoV-2 infection. Furthermore, we find the propagation of nsp1 mutant virus is inhibited specifically in cells with intact interferon (IFN) response as well as in-vivo, in infected hamsters, and this attenuation is associated with stronger induction of type I IFN response. This illustrates that nsp1 shutoff activity has an essential role mainly in counteracting the IFN response. Overall, our results reveal the multifaceted approach nsp1 uses to shut off cellular protein synthesis and uncover the central role it plays in SARS-CoV-2 pathogenesis, explicitly through blockage of the IFN response.
Contribution of the Golgi apparatus in morphogenesis of a virus induced cytopathic vacuolar system
Authors: Sengupta Ranjan , Mihelc Elaine M. , Angel Stephanie , Lanman Jason K. , Kuhn Richard J. , Stahelin Robert V. 
Published: March 2022

AbstractThe Golgi apparatus (GA) in mammalian cells is pericentrosomally anchored and exhibits a stacked architecture. During infections by members of the alphavirus genus, the host cell GA is thought to give rise to distinct mobile pleomorphic vacuoles known as CPV-II (cytopathic vesicle-II) via unknown morphological steps. To dissect this, we adopted a phased electron tomography approach to image multiple overlapping volumes of a cell infected with Venezuelan equine encephalitis virus (VEEV) and complemented it with localization of peroxidase tagged Golgi marker. Analysis of the tomograms revealed a pattern of progressive cisternal bending into double-lamellar vesicles as a central process underpinning the biogenesis and the morphological complexity of this vacuolar system. Here we propose a model for the conversion of GA to CPV-II that reveals a unique pathway of intracellular virus envelopment. Our result has implications for alphavirus virus induced displacement of Golgi cisternae to the plasma membrane to aid viral egress operating late in the infection cycle.
Group II Intron-Like Reverse Transcriptases Function in Double-Strand Break Repair by Microhomology-Mediated End Joining
Authors: Park Seung Kuk , Mohr Georg , Yao Jun , Russell Rick , Lambowitz Alan M. 
Published: March 2022

SummaryBacteria encode free-standing reverse transcriptases (RTs) of unknown function that are closely related to group II intron-encoded RTs. Here, we found that a Pseudomonas aeruginosa group II intron-like RT (G2L4 RT) with YIDD instead of YADD at its active site functions in DNA repair in its native host and when transferred into Escherichia coli. G2L4 RT has biochemical activities strikingly similar to those of human DNA repair polymerase θ and uses them for translesion DNA synthesis and double-strand break repair (DSBR) via microhomology-mediated end-joining (MMEJ) in vitro and in vivo. We also found that a group II intron RT can function similarly to G2L4 RT in DNA repair, with reciprocal substitutions at the active site showing an I residue favors MMEJ and an A residue favors primer extension in both enzymes. The DNA repair functions of these enzymes utilize conserved structural features of non-LTR-retroelement RTs, including human LINE-1 and other eukaryotic non-LTR-retrotransposon RTs, suggesting such enzymes may have an inherent ability to function in DSBR in a wide range of organisms.
Validation of a small molecule inhibitor of PDE6D-RAS interaction with potent anti-leukemic effects
Authors: Nunes Sara Canovas , De Vita Serena , Anighoro Andrew , Autelitano François , Beaumont Edward , Klingbeil Pamela , McGuinness Meaghan , Duvert Beatrice , Harris Chad , Yang Lu , Pokharel Sheela Pangeni , Chen Chun-Wei , Ermann Monika , Williams David A. , Xu Haiming 
Published: March 2022

AbstractRAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights on the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.
Imaging tools generated by CRISPR/Cas9 tagging reveal cytokinetic diversity in mammalian cells
Authors: Husser Mathieu C. , Ozugergin Imge , Resta Tiziana , Martin Vincent J. J. , Piekny Alisa J. 
Published: March 2022

AbstractCytokinesis is required to physically separate the daughter cells at the end of mitosis. This process occurs via the ingression of an actomyosin ring that assembles in anaphase and pulls in the overlying plasma membrane as it constricts. Mechanistic studies have uncovered different pathways that regulate the assembly and position of the ring in mammalian cells, but the majority of these studies were done using HeLa cells with overexpressed transgenes, and the relative requirement for these mechanisms among the majority of cell types is not known. Here, we used CRISPR/Cas9 gene editing to endogenously tag cytokinesis proteins, anillin, Ect2 and RhoA, as well as other cellular components, with fluorescent proteins. These tools enabled the visualization of cytokinesis by live imaging to quantitatively study these proteins at endogenous levels. As a proof-of-concept, tagging anillin in multiple mammalian cell lines revealed cytokinetic diversity, which will be useful for studies of how mechanisms controlling cytokinesis vary among cell types. We also successfully tagged multiple cellular components in the same cell line, demonstrating the versatility of these tagging tools.
Arctic phytoplankton spring bloom diversity across the marginal ice zone in Baffin Bay
Authors: Ribeiro Catherine Gérikas , dos Santos Adriana Lopes , Trefault Nicole , Marie Dominique , Lovejoy Connie , Vaulot Daniel 
Published: March 2022

AbstractPhytoplankton under-ice blooms have been recently recognized as an important Arctic phenomenon for global primary production and biogeochemical cycling. Drastic sea-ice decline in both extension and thickness enables the development of early blooms, sometimes hundreds of kilometers beneath the pack ice. Baffin Bay is a semi-enclosed sea where Arctic and North Atlantic water masses interact. It is totally covered by sea-ice by March and ice-free by August/September. In the present work, we investigated the phytoplankton community structure across the marginal ice zone between the ice-free, Atlantic-influenced, east and the ice-covered, Arctic-influenced, west Baffin Bay using 18S rRNA high-throughput amplicon sequencing, flow cytometry cell counting and numerous environmental and biological data collected and compiled in the scope of the Green Edge project. Sampling was performed during June-July 2016 in a total of 16 stations with around 6 depths each. Stations were clustered into “Under Ice” (UI), “Marginal Ice Zone” (MIZ) and “Open Water” (OW) on the basis of its sea ice cover upon sampling. Phytoplankton community structure was analyzed by 18S rRNA metabarcoding with the microdiversity approach. The UI sector was characterized by a shallow nitracline, high pico-phytoplankton abundance and a shared dominance between Micromonas and Phaeocystis in the 0.2-3 µm size fraction, as well as an increased contribution of Cryptophyceae and non-diatom Ochrophyta in the 3-20 µm size fraction. Several amplicon sequence variants (ASVs) were flagged as indicator for the UI+MIZ sector group, including known ice-associated taxa such as the diatoms Melosira arctica and Pseudo-nitzschia seriata, but also specific ASVs assigned to the green alga Micromonas polaris and the cryptophyte Falcomonas daucoides, the silicoflagellate Dictyocha speculum, one member of the uncultivated MOCH-2 group, and a Pterosperma sp. (green algae) rarely seen in other metabarcoding datasets, including from the Arctic. The OW sector harbored a community adapted to a nutrient-depleted/high light environment, with a significant contribution of the haptophytePhaeocystis pouchetii and big centric diatoms, including several Thalassiosira species.