bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pkd1andWnt5agenetically interact to control lymphatic vascular morphogenesis in mice
Authors: Chau Tevin CY. , Baek Sungmin , Coxam Baptiste , Skoczylas Renae , Rondon-Galeano Maria , Bower Neil I. , Wainwright Elanor N. , Stacker Steven SA. , Cooper Helen M. , Lagendijk Anne K. , Harvey Natasha L. , François Mathias , Hogan Benjamin M. 
Published: April 2021

AbstractLymphatic vascular development is regulated by well-characterised signalling and transcriptional pathways. These pathways regulate lymphatic endothelial cell (LEC) migration, motility, polarity and and morphogenesis. Canonical and non-canonical WNT signalling pathways are known to control LEC polarity and development of lymphatic vessels and valves.PKD1, encoding Polycystin-1, is the most commonly mutated gene in polycystic kidney disease but has also been shown to be essential in lymphatic vascular morphogenesis. The mechanism by whichPkd1acts during lymphangiogenesis remains unclear. Here we find that loss of non-canonical WNT signalling componentsWnt5aandRykphenocopy lymphatic defects seen inPkd1knockout mice. To investigate genetic interaction, we generatedPkd1/Wnt5adouble knockout mice. Loss ofWnt5asuppressed phenotypes seen in the lymphatic vasculature ofPkd1−/−mice and Pkd1 deletion suppressed phenotypes observed inWnt5a−/−mice. Thus, we report mutually suppressive roles forPkd1andWnt5a,with developing lymphatic networks restored to a more wild-type state in double mutant mice. This genetic interaction betweenPkd1and the non-canonical WNT signalling pathway ultimately controls LEC polarity and the morphogenesis of developing vessel networks. Our work suggests thatPkd1acts at least in part by regulating non-canonical WNT signalling during the formation of lymphatic vascular networks.
Structural basis for the tryptophan sensitivity of TnaC-mediated ribosome stalling
Authors: van der Stel Anne-Xander , Gordon Emily R. , Sengupta Arnab , Martínez Allyson K. , Klepacki Dorota , Perry Thomas N. , del Valle Alba Herrero , Vazquez-Laslop Nora , Sachs Matthew S. , Cruz-Vera Luis R. , Innis C. Axel 
Published: April 2021

ABSTRACTFree L-tryptophan (L-Trp) induces the expression of theEscherichia colitryptophanase operon, leading to the production of indole from L-Trp. Tryptophanase operon expression is controlled via a mechanism involving the tryptophan-dependent stalling of ribosomes engaged in translation oftnaC, a leader sequence upstream oftnaAthat encodes a 24-residue peptide functioning as a sensor for L-Trp. Although extensive biochemical characterization has revealed the elements of the TnaC peptide and the ribosome that are responsible for translational arrest, the molecular mechanism underlying the recognition and response to L-Trp by the TnaC-ribosome complex remains unknown. Here, we use a combined biochemical and structural approach to characterize a variant of TnaC (R23F) in which stalling by L-Trp is enhanced because of reduced cleavage of TnaC(R23F)-peptidyl-tRNA. In contrast to previous data originated from lower resolution structural studies, we show that the TnaC–ribosome complex captures a single L-Trp molecule to undergo tryptophan-dependent termination arrest and that nascent TnaC prevents the catalytic GGQ loop of release factor 2 from adopting an active conformation at the peptidyl transferase center. In addition, we show that the conformation of the L-Trp binding site is not altered by the R23F mutation. This leads us to propose a model in which rates of TnaC-peptidyl-tRNA cleavage by release factor and binding of the L-Trp ligand to the translating ribosome determine the tryptophan sensitivity of the wild-type and mutant TnaC variants. Thus, our study reveals a strategy whereby a nascent peptide assists the bacterial ribosome in sensing a small metabolite.
Genome-wide association study on 13,167 individuals identifies regulators of hematopoietic stem and progenitor cell levels in human blood
Authors: Portilla Aitzkoa Lopez de Lapuente , Ekdahl Ludvig , Cafaro Caterina , Ali Zain , Miharada Natsumi , Thorleifsson Gudmar , Žemaitis Kristijonas , Arrizabalaga Antton Lamarca , Thodberg Malte , Pertesi Maroulio , Dhapola Parashar , Bao Erik , Niroula Abhishek , Bali Divya , Norddahl Gudmundur , Damboriena Nerea Ugidos , Sankaran Vijay G. , Karlsson Göran , Thorsteinsdottir Unnur , Larsson Jonas , Stefansson Kari , Nilsson Björn 
Published: April 2021

ABSTRACTUnderstanding how hematopoietic stem and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and stem cell transplantation. To date, HSPC regulation has been extensively studiedin vitroand in animal models, but less is known about the mechanismsin vivoin humans. Here, in a genome-wide association study on 13,167 individuals, we identify 9 significant and 2 suggestive DNA sequence variants that influence HSPC (CD34+) levels in human blood. The identified loci associate with blood disorders, harbor known and novel HSPC genes, and affect gene expression in HSPCs. Interestingly, our strongest association maps to thePPM1Hgene, encoding an evolutionarily conserved serine/threonine phosphatase never previously implicated in stem cell biology.PPM1His expressed in HSPCs, and the allele that confers higher blood CD34+cell levels downregulatesPPM1H. By functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates a MYB transcription factor binding site inPPM1Hintron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, rs772557-A selectively increases HSPC subpopulations in which the MYB site is active, andPPM1HshRNA- knockdown increased CD34+and CD34+90+cell proportions in umbilical cord blood cultures. Our findings represent the first large-scale association study on a stem cell trait, illuminating HSPC regulationin vivoin humans, and identifyingPPM1Has a novel inhibition target that can potentially be utilized clinically to facilitate stem cell harvesting for transplantation.
Mild impairment of mitochondrial function increases longevity and pathogen resistance through ATFS-1-driven activation of p38-regulated innate immunity
Authors: Campos Juliane C. , Wu Ziyun , Rudich Paige D. , Soo Sonja K. , Mistry Meeta , Ferreira Julio C.B. , Blackwell T. Keith , Van Raamsdonk Jeremy M. 
Published: April 2021

AbstractWhile mitochondrial function is essential for life in all multicellular organisms, a mild impairment of mitochondrial function can extend longevity. By understanding the molecular mechanisms involved, these pathways might be targeted to promote healthy aging. In studying two long-lived mitochondrial mutants inC. elegans,we found that disrupting subunits of the mitochondrial electron transport chain resulted in upregulation of genes involved in innate immunity, which we found to be dependent on not only the canonical p38-mediated innate immune signaling pathway but also on the mitochondrial unfolded protein response. Both of these pathways are absolutely required for the increased resistance to bacterial pathogens and extended longevity of the long-lived mitochondrial mutants, as is the FOXO transcription factor DAF-16. This work demonstrates that both the p38-mediated innate immune signaling pathway and the mitochondrial unfolded protein response can act on the same innate immunity genes to promote resistance to bacterial pathogens, and that input from the mitochondria can extend longevity by signaling through these two pathways. Combined, this indicates that multiple evolutionarily conserved genetic pathways controlling innate immunity also function to modulate lifespan.Significance StatementIn this work, we explore the relationship between mitochondrial function, aging and innate immunity. We find that mild impairment of mitochondrial function results in upregulation of genes involved in innate immunity, increased resistance to bacterial pathogens and lifespan extension, all of which are dependent on two evolutionarily conserved signaling pathways. This work demonstrates how changes in functional status of the mitochondria can trigger activation of innate immunity, and that the underlying mechanisms are important for the longevity of the organism. This work advances our understanding of connections between metabolism and immunity. As the pathways studied here are conserved up to mammals, these insights may help us to understand the role of mitochondrial health, innate immunity and lifespan in humans.
Differential mutational profile of SARS-CoV-2 proteins across deceased and asymptomatic patients
Authors: Laskar Rezwanuzzaman , Ali Safdar 
Published: April 2021

AbstractThe SARS-CoV-2 infection spread at an alarming rate with many places showed multiple peaks in incidence. Present study involves a total of 332 SARS-CoV-2 sequences from 114 Asymptomatic and 218 Deceased patients from twenty-one different countries. The mining of mutations was done using the GISAID CoVSurver (www.gisaid.org/epiflu-applications/covsurver-mutations-app) with the reference sequence ‘hCoV-19/Wuhan/WIV04/2019’ present in NCBI with Accession number NC-045512.2. The impact of the mutations on SARS-CoV-2 proteins mutation was predicted using PredictSNP1(loschmidt.chemi.muni.cz/predictsnp1) which is a meta-server integrating six predictor tools: SIFT, PhD-SNP, PolyPhen-1, PolyPhen-2, MAPP and SNAP. The iStable integrated server (predictor.nchu.edu.tw/iStable) was used to predict shifts in the protein stability due to mutations. A total of 372 variants were observed in the 332 SARS-CoV-2 sequences with several variants incident in multiple patients accounting for a total of 1596 incidences. Asymptomatic and Deceased specific mutants constituted 32% and 62% of the repertoire respectively indicating their exclusivity. However, the most prevalent mutations were those present in both. Though some parts of the genome are more variable than others but there was clear difference between incidence and prevalence. NSP3 with 68 variants had total occurrence of only 105 whereas Spike protein had 346 occurrences with just 66 variants. For Deleterious variants, NSP3 had the highest incidence of 25 followed by NSP2 (16), ORF3a (14) and N (14). Spike protein had just 7 Deleterious variants out of 66. Deceased patients have more Deleterious than Neutral variants as compared to the symptomatic ones. Further, it appears that the Deleterious variants which decrease protein stability are more significant in pathogenicity of SARS-CoV-2.
Large-scale identification of protein histidine methylation in human cells
Authors: Kapell Sebastian , Jakobsson Magnus E. 
Published: April 2021

ABSTRACTMethylation can occur on histidine, lysine and arginine residues in proteins and often serves a regulatory function. Histidine methylation has recently attracted notable attention through the discovery of the human histidine methyltransferase enzymes SETD3 and METTL9. There are currently no methods to enrich histidine methylated peptides for mass spectrometry analysis and large-scale analyses of the modification are hitherto absent. In the present study we query ultra-comprehensive proteomic datasets to generate a resource of histidine methylation sites in human cells. We use this resource to explore the frequency, localization, targeted domains, protein types and sequence requirements of histidine methylation and benchmark all analyses to methylation events on lysine and arginine. Our results demonstrate that histidine methylation is widespread in human cells and tissues and that the modification is over-represented in regions of mono-spaced histidine repeats. We also report colocalization of the modification with functionally important phosphorylation sites and disease associated mutations to identify regions of likely regulatory and functional importance. Taken together, we here report a system level analysis of human histidine methylation and our results represent a comprehensive resource enabling targeted studies of individual histidine methylation events.
Balance training improves feedback control of perturbed balance in older adults
Authors: Alizadehsaravi Leila , Bruijn Sjoerd M. , van Dieën Jaap H. 
Published: April 2021

AbstractRecovering balance after perturbations becomes challenging with aging, but an effective balance training could reduce such challenges. In this study, we examined the effect of balance training on feedback control after unpredictable perturbations by investigating balance performance, recovery strategy, and muscle synergies. We assessed the effect of balance training on unipedal perturbed balance in twenty older adults (>65 years) after short-term (one session) and long-term (3-weeks) training. Participants were exposed to random medial and lateral perturbations consisting of 8-degree rotations of a robot-controlled balance platform. We measured full-body 3D kinematics and activation of 9 muscles (8 stance leg muscles, one trunk muscle) during 2.5 s after the onset of perturbation. The perturbation was divided into 3 phases: phase1 from the onset to maximum rotation of the platform, phase 2 from the maximum rotation angle to the 0-degree angle and phase 3 after platform movement. Balance performance improved after long-term training as evidenced by decreased amplitudes of center of mass acceleration and rate of change of body angular momentum. The rate of change of angular momentum did not directly contribute to return of the center of mass within the base of support, but it reoriented the body to an aligned and vertical position. The improved performance coincided with altered activation of synergies depending on the direction and phase of the perturbation. We concluded that balance training improves control of perturbed balance, and reorganizes feedback responses, by changing temporal patterns of muscle activation. These effects were more pronounced after long-term than short-term training.
Differences in Regional Grey Matter Volume Predict the Extent to which Openness influences Judgments of Beauty and Pleasantness of Interior Architectural Spaces
Authors: Skov Martin , Vartanian Oshin , Navarrete Gorka , Modroño Cristian , Chatterjee Anjan , Leder Helmut , Gonzalez-Mora José L. , Nadal Marcos 
Published: April 2021

AbstractHedonic evaluation of sensory objects varies from person to person. While this variability has been linked to differences in experience and personality traits, little is known about why stimuli lead to different evaluations in different people. We used linear mixed effect models to determine the extent to which the openness, contour, and ceiling height of interior architectural spaces influenced the beauty and pleasantness ratings of 18 participants. Then, by analyzing structural brain images acquired for the same group of participants we asked if any regional grey matter volume (rGMV) co‐varied with these differences in the extent to which openness, contour and ceiling height influence beauty and pleasantness ratings. Voxel‐based morphometry analysis revealed that the influence of openness on pleasantness ratings correlated with rGMV in the anterior prefrontal cortex (BA 10), and the influence of openness on beauty ratings correlated with rGMV in the temporal pole (BA 38) and posterior cingulate cortex (BA 31). There were no significant correlations involving contour or ceiling height. Our results suggest that regional variance in grey matter volume may play a role in the computation of hedonic valuation, and account for differences in the way people weigh certain attributes of interior architectural spaces.
A Tool for Reliable Detection of Aflatoxin Biosynthetic Gene Clusters in Aflatoxigenic and AtoxigenicAspergillus flavusIsolates
Authors: Mitema Alfred , Feto Naser Aliye , Okoth Sheila , Rafudeen Mohamed Suhail 
Published: April 2021

AbstractMolecular techniques and phenotypic characterisation have been used to differentiate aflatoxigenic and atoxigenicAspergillus flavusstrains. However, there is a lack of a consistent and reliable tool for discrimination between these strains ofA. flavus. Here we report, an optimised real-time qPCR-based tool for reliable differentiation between aflatoxigenic and atoxigenic strains ofA. flavus. Accordingly, expression profiles and deletion patterns of genes responsible for aflatoxin production in five representative aflatoxigenic and atoxigenicA. flavusstrains (KSM012, KSM014, HB021, HB026 and HB027) were examined using the optimised real-time qPCR tool. We observed that under induced conditions,aflP, aflS, aflRandaflOtranscripts were the most upregulated genes across the tested isolates whileaflSandaflOwere always expressed in both induced and uninduced isolates. However,aflRandaflPdid not give clear distinctions between non-toxin and toxin producing isolates. The deletion patterns were prominent foraflDandaflRwhereasalfO, aflSandaflPhad no deletions among the isolates. Significant variation in transcript abundance foraflD, aflRandaflSwere observed for aflatoxigenic isolate KSM014 under induced and uninduced states. False detection ofaflDgene transcript in atoxigenic strain KSM012 was evident in both induced and uninduced conditions. With the exception of KSM012,aflPgene did not exhibit significant variation in expression in the isolates between induced and uninduced conditions. One-way ANOVA and Post-test analysis for linear trends revealed that aflatoxin biosynthetic cluster genes show significant (P < 0.05) differences between atoxigenic and aflatoxigenic isolates. Our optimized qPCR-based tool reliably discriminated between aflatoxigenic and atoxigenicA. flavusisolates and could complement existing detection methods.
New metabolic alterations and predictive marker pipecolic acid in sera for esophageal squamous cell carcinoma
Authors: Liu Lei , Wu Jia , Shi Minxin , Wang Fengying , Lu Haimin , Liu Jibing , Chen Weiqin , Yu Guanzhen , Liu Dan , Yang Jing , Luo Qin , Ni Yan , Jin Xing , Jin Xiaoxia , Chen Wen-Lian 
Published: April 2021

AbstractEsophageal squamous cell carcinoma (ESCC) is a major histological subtype of esophageal cancer with dismal prognosis. Although several serum metabolomic investigations have been reported, ESCC tumor-associated metabolic alterations along with predictive biomarkers in sera were not defined. Here we enrolled 34 treatment-naive ESCC patients and collected their pre-and post-esophagectomy sera together with sera from 34 healthy volunteers for metabolomic survey. Our comprehensive analysis discerned ESCC tumor-associated metabolic alterations as represented by a panel of 12 serum metabolites. Notably, postoperative abrosia and parenteral nutrition significantly perturbed the serum metabolome. Furthermore, we performed examination using sera from carcinogen-induced mice at dysplasia and ESCC stages, and identified three ESCC tumor-associated metabolites conserved between mice and humans. Notably, among these metabolites, pipecolic acid was progressively increased in mouse sera from dysplasia to cancerization, and it could accurately discriminate between mice at dysplasia stage and healthy control mice. Furthermore, this metabolite was essential for ECSS cells to oppose oxidative stress-induced DNA damage and cell proliferation arrest. Together, this study uncovered 12 ESCC tumor-associated serum metabolites with potential for monitoring therapeutic efficacy and disease relapse, presented evidence for refining parenteral nutrition composition, and highlighted serum pipecolic acid as an attractive biomarker for prediction of ESCC tumorigenesis.
CRISPR-mediated knock-in of transgenes into the malaria vectorAnopheles funestus
Authors: Quinn Charlotte , Anthousi Amalia , Wondji Charles , Nolan Tony 
Published: April 2021

ABSTRACTThe ability to introduce mutations, or transgenes, of choice to precise genomic locations has revolutionised our ability to understand how genes and organisms work.In many mosquito species that are vectors of various human disease, the advent of CRISPR genome editing tools has shed light on basic aspects of their biology that are relevant to their efficiency as disease vectors. This allows a better understanding of how current control tools work and opens up the possibility of novel genetic control approaches, such as gene drives, that deliberately introduce genetic traits into populations. Yet for theAnopheles funestusmosquito, a significant vector of malaria in sub-Saharan Africa and indeed the dominant vector species in many countries, transgenesis has yet to be achieved.We describe herein an optimised transformation system based on the germline delivery of CRISPR components that allows efficient cleavage of a previously validated genomic site and preferential repair of these cut sites via homology-directed repair (HDR), which allows introduction of exogenous template sequence, rather than end-joining repair. The rates of transformation achieved are sufficiently high that it should be able to introduce alleles of choice to a target locus, and recover these, without the need to include additional dominant marker genes. Moreover, the high rates of HDR observed suggest that gene drives, which employ an HDR-type mechanism to ensure their proliferation in the genome, may be well suited to work inAn. funestus.
Differential heating of metal nanostructures by radio frequencies: a theoretical study
Authors: Rommelfanger Nicholas J. , Ou Zihao , Keck Carl H.C. , Hong Guosong 
Published: April 2021

AbstractNanoparticles with strong absorption of incident radio frequency (RF) or microwave irradiation are desirable for remote hyperthermia treatments. While controversy has surrounded the absorption properties of spherical metallic nanoparticles, other geometries such as prolate and oblate spheroids have not received sufficient attention for application in hyperthermia therapies. Here, we use the electrostatic approximation to calculate the relative absorption ratio of metallic nanoparticles in various biological tissues. We consider a broad parameter space, sweeping across frequencies from 1 MHz to 10 GHz, while also tuning the nanoparticle dimensions from spheres to high-aspect-ratio spheroids approximating nanowires and nanodiscs. We find that while spherical metallic nanoparticles do not offer differential heating in tissue, large absorption cross sections can be obtained from long prolate spheroids, while thin oblate spheroids offer minor potential for absorption. Our results suggest that metallic nanowires should be considered for RF- and microwave-based wireless hyperthermia treatments in many tissues going forward.
Design principles of collateral sensitivity-based dosing strategies
Authors: Aulin Linda B. S. , Liakopoulos Apostolos , van der Graaf Piet H. , Rozen Daniel E. , van Hasselt J. G. Coen 
Published: April 2021

AbstractCollateral sensitivity (CS)-based antibiotic treatments, where increased resistance to one antibiotic leads to increased sensitivity to a second antibiotic, may have the potential to limit the emergence of antimicrobial resistance. However, it remains unclear how to best design CS-based treatment schedules. To address this problem, we use mathematical modelling to study the effects of pathogen- and drug-specific characteristics for different treatment designs on bacterial population dynamics and resistance evolution. We confirm that simultaneous and one-day cycling treatments could supress resistance in the presence of CS. We show that the efficacy of CS-based cycling therapies depends critically on the order of drug administration. Finally, we find that reciprocal CS is not essential to suppress resistance, a result that significantly broadens treatment options given the ubiquity of one-way CS in pathogens. Overall, our analyses identify key design principles of CS-based treatment strategies and provide guidance to develop treatment schedules to suppress resistance.