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Dynamics of the adhesion complex of the human pathogens Mycoplasma pneumoniae and Mycoplasma genitalium
No full textMycoplasma pneumoniae and Mycoplasma genitalium are bacterial wall-less human pathogens and the causative agents of respiratory and reproductive tract infections. Infectivity, gliding motility and adhesion of these mycoplasmas to host cells are mediated by orthologous adhesin proteins forming a transmembrane adhesion complex that binds to sialylated oligosaccharides human cell ligands. Here we report the cryo-EM structure of M. pneumoniae P1 adhesin bound to the Fab fragment of monoclonal antibody P1/MCA4, which stops gliding and induces detachment of motile cells. The epitope of P1/MCA4 involves residues only from the small C-domain of P1. This epitope is accessible to antibodies only in the “closed conformation” of the adhesion complex and is not accessible in the “open” conformation, when the adhesion complex is ready for attachment to sialylated oligosaccharides. Polyclonal antibodies generated against the large N-domain of P1 or against the whole ectodomain of P40/P90 have little or no effects on adhesion or motility. Moreover, mutations in the highly conserved Engelman motifs found in the transmembrane helix of M. genitalium P110 adhesin also alter adhesion and motility. These results show that antibodies directed to the C-domain of P1 hinder the large conformational rearrangements in this domain required to alternate between the “open” and “closed” conformations of the adhesion complex. Since transition between both conformations is essential to complete the attachment/detachment cycle of the adhesion complex, interfering with the gliding of mycoplasma cells and providing a new potential target to confront M. pneumoniae and M. genitalium infections.E.M. was supported by grants RYC2018-025295-I and PID2020-120098GA-I00, I. F. and J. P. were supported by grants PID2021-125632OB-C21 and -C22 from the Spanish Ministry of Science and Innovation. K.N. was supported by grants JP23am121003 of Research Support Project for Life Science and Drug Discovery (BINDS) from AMED and by JEOL YOKOGUSHI Research Alliance Laboratories of Osaka University. T.K. was supported by Grants-in-Aid for Scientific Research (15H01337 and 22K07063) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and grant 24fk0108697j0101 from the Japan Agency for Medical Research and Development.Peer reviewe
Supplementary Materials: Metabolic and antioxidant variations in “Regina” raspberries: A comparative analysis of early and late harvests
No full textTable S1: Fragmentation patterns of the most representative compounds in raspberries according to the Phenol-Explorer database; Table S2: Significant features identified through a volcano plot analysis. The table lists the significantly altered metabolites between the two conditions (RiJ and RiS). Cut-off: fold change > 1 and adjusted p-value < 0.05.Peer reviewe
Regulation of gibberellin signalling at the shoot apical meristem by the class I KNOX transcription factor brevipedicellus
No full textThe shoot apical meristem (SAM) is the source of all
above-ground plant organs, including fruits and seeds. The
balance between cell proliferation and differentiation must
be precisely regulated in the SAM to maintain a stable
population of stem cells while continuously supplying
new cells for organ formation. This balance relies on the
accurate interpretation of endogenous and environmental
signals that are transmitted to SAM cells through different
hormone signalling pathways, such as that of gibberellins
(GAs). Under favourable environmental conditions, high
levels of GAs promote flowering and plant growth through
the degradation of DELLA proteins. However, an excess of
GAs can disrupt the cellular homeostasis of the SAM and
thus impair its ability to produce new organs.
Previous works propose that Class I KNOX transcription
factors, such as SHOOT MERISTEMLESS and
BREVIPEDICELLUS (BP) in Arabidopsis, are responsible
for maintaining a low GA concentration in the central
region of the SAM, which is thought to be beneficial for
meristem activity (Tsuda and Hake, 2015). We show that
the SAM of bp mutants is more susceptible to increasing
GA levels and that GA content is indeed higher in bp SAM
cells. A ChIP-seq assay revealed direct links between BP
and GA metabolism, GA transport and DELLA content.
In conclusion, our work suggests that BP orchestrates GA
signalling in SAM cells by acting at different points of the
pathway
VCAN is essential for ERK5-driven tumorigenesis in soft tissue sarcoma
Get PDFThe ERK5 signaling pathway has recently emerged as a critical regulator of soft tissue sarcoma (STS) biology, contributing to tumor initiation, progression, and maintenance. In this study, we identify VCAN, a chondroitin sulfate proteoglycan, as a novel transcriptional target of ERK5 and a central mediator of ERK5-related oncogenesis. Through a combination of genetic (silencing, overexpression) and pharmacological approaches, applied in both a chemically induced murine sarcoma model and several human STS cell lines, we demonstrate that ERK5 positively regulates VCAN expression. Functionally, VCAN silencing (by shRNAs) recapitulates the phenotypes of ERK5 silencing, including impaired migration, adhesion, proliferation, and tumorigenesis. Conversely, VCAN overexpression rescues these effects, confirming its essential role in ERK5-mediated oncogenesis. Furthermore, transcriptomic profiling reveals that VCAN accounts for a substantial portion of ERK5-regulated gene expression program. Analyses of human STS patient samples reveal significantly elevated mRNA levels of both VCAN and ERK5 compared to normal tissues. Notably, a strong correlation between VCAN and ERK5 expression, both at mRNA and protein levels, emerged in biopsies from leiomyosarcomas and undifferentiated pleomorphic sarcomas. Together, these findings uncover VCAN as a key effector in ERK5-driven tumorigenesis and highlight the ERK5/VCAN signaling axis as a promising therapeutic target in soft tissue sarcomas.Agencia Estatal de Investigación, PID2021-122222OB-I00, PID2019-104416RB-I00, PID2020-115605RB-I00
Junta de comunidades de Castilla La Mancha, SBPLY/23/180225/000007.
Instituto de Salud Carlos III, https://ror.org/00ca2c886, PI19/00840
Universidad de Castilla La Mancha, 2022-GRIN-34150N
Maintenance of cell wall remodeling and vesicle production are connected in Mycobacterium tuberculosis
Get PDF38 p.-9 fig.Pathogenic and nonpathogenic mycobacteria secrete extracellular vesicles (EVs) under various conditions. EVs produced by Mycobacterium tuberculosis (Mtb) have raised significant interest for their potential in cell communication, nutrient acquisition, and immune evasion. However, the relevance of vesicle secretion during tuberculosis infection remains unknown due to the limited understanding of mycobacterial vesicle biogenesis. We have previously shown that a transposon mutant in the LCP-related gene virR (virRmut) manifested a strong attenuated phenotype during experimental macrophage and murine infections, concomitant to enhanced vesicle release. In this study, we aimed to understand the role of VirR in the vesicle production process in Mtb. We employ genetic, transcriptional, proteomics, ultrastructural, and biochemical methods to investigate the underlying processes explaining the enhanced vesiculogenesis phenomenon observed in the virRmut. Our results establish that VirR is critical to sustain proper cell permeability via regulation of cell envelope remodeling possibly through the interaction with similar cell envelope proteins, which control the link between peptidoglycan and arabinogalactan. These findings advance our understanding of mycobacterial extracellular vesicle biogenesis and suggest that these set of proteins could be attractive targets for therapeutic intervention.RP-R acknowledges support by MINECO/FEDER EU contracts SAF2016–77433-R,PID2019-110240RB-
I00,PID2022-136611OB-I00;and NIH-R01AI162821.CICbioGUNE thanks MINECO for the Severo Ochoa Excellence Accreditation (SEV-2016–0644). LP-L and JKH acknowledges support by the Wellcome Trust (212197/Z/19/Z) which funded part of this research. For the purpose of open access, the authors have applied and will apply a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. JS acknowledges support from the Spanish Ministry of Science and Innovation (MICINN) through grant PID2019-106859GA-I00 and Ramón y Cajal research grant RYC-2017-23560,as well as to the Government of Aragón, Spain,through grant B49-23R (NeuroBioSys). FC lab research is supported by the Swedish Research Council (VR2018-02823 and VR2018-05882), the Laboratory for Molecular Infection Medicine Sweden (MIMS),Umeå University, the Knut and Alice Wallenberg Foundation (KAW) grant KAW2012.0184 and the Kempe Foundation.Peer reviewe
Methodology for stiffness prediction in structural timber using cross-validation RMSE analysis
No full textNon-destructive testing (NDT) methods are becoming increasingly popular for estimating the mechanical properties of structural timber without altering the samples. These methods yield parameters that can be integrated into multivariate models, improving predictive accuracy compared to univariate models. Unfortunately, overfitting is often neglected, resulting in models that fit the experimental dataset perfectly but perform poorly on new data. The aim of the present paper is to analyse model prediction for timber stiffness through cross-validated root-mean-square error (RMSE), oriented to support the results obtained using several NDT methodologies avoiding overfitting. The research involved 491 samples of Pinus pinaster Aiton structural sawn timber. The results pointed out that dynamic moduli of elasticity had the lowest prediction error for stiffness, regardless of the device employed. Furthermore, no statistically significant differences were identified according to the sensor arrangements on the devices based on time-of-flight. Artificial Neural Networks and Multiple Linear Regression were effective multivariate algorithms for stiffness prediction, with no statistically significant differences in their prediction errors. The device which combined the lowest prediction error and number of variables was the Portable Lumber Grader which uses dynamic modulus of elasticity and knottiness. In contrast, the device with the lowest predictive capacity was machine strength grading.This research was undertaken thanks to funding received through the project AGL-2004-1598/FOR under the National Plan for R & D 2003–2005 of the Ministry for Education and Science and to the collaboration agreement CC02-0031 between the INIA and the Xunta de Galicia (Spain).Peer reviewe
La Biblia Hebraica de Benito Arias Montano: Un Tesoro en la Biblioteca Tomás Navarro Tomás
No full textPieza del mes de la Biblioteca Tomás Navarro Tomás elaborada por la Prof. Elvira Martín-Contreras del Dpto. de Estudios Judíos e Islámicos. Historia Cultural del Mediterráneo (ILC-CSIC)El Fondo Antiguo de la Biblioteca Tomás Navarro Tomás (BTNT) alberga un ejemplar extraordinario cuyas singularidades, inadvertidas hasta ahora, lo convierten en una pieza única. Se trata de la Biblia hebraica / Eorundem latina interpretatio Xantis Pagnini Lucensis, recenter Benedicti Ariae Montani Hispal. & quorumdam aliorum collato studio,... Accesserunt & huic editioni Libri Graecè Scripti, qui vocantur Apocryphi...Peer reviewe
Pathogenicity assessment of genetic variants identified in patients with severe hypertriglyceridemia: Novel cases of familial chylomicronemia syndrome from the Dyslipidemia Registry of the Spanish Atherosclerosis Society
Get PDFGenetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases.[Purpose] Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases.[Methods] 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients.[Results] Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in LMF1 remained as VUS. Additionally, 1 variant in LPL and 2 in GPIHBP1 were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations.[Conclusion] The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.María José Ariza received honoraria for presentations from Akcea and Sobi and a research grant from Sobi. José Rioja received honoraria for a presentation from Ferrer. Pedro Valdivielso received honoraria for presentations and advisory boards from AMGEN, Sanofi, Servier, Novartis, MSD, Alexion, Sobi, Akcea, and PTB. Pedro Valdivielso also received research grants from Ferrer and Sobi and Technology Transfer contracts with Lipigon Pharmaceuticals and Capenergy Medical. Inmaculada Coca-Prieto,...Peer reviewe
Rhizosphere effects of Helianthus annuus and Hordeum vulgare on allelochemical sorption and degradation in soil
No full textSoil plays a crucial role in determining the activity of allelochemicals in natural and agricultural ecosystems. To identify potential differences in allelochemical availability and persistence between root-influenced soil (rhizosphere) and bulk soil, we designed experiments to compare the sorption and degradation patterns of three putative allelochemicals (S-abscisic acid, S-pulegone, and khellin) in soil near the roots of laboratory-grown Helianthus annuus and Hordeum vulgare with those obtained in unplanted soil controls. Soil compositional and bacterial population changes were monitored and linked to the observed allelochemical sorption and degradation patterns. Root-influenced soil underwent chemical and biological changes that affected its capacity to degrade the three allelochemicals, whereas the soiĺs inherent sorption capacity for the allelochemicals remained unaltered. Notably, rhizospheric soils showed a 36–70% increase in dissolved inorganic carbon, an 8–14% increase in dissolved organic carbon, a 0.20–0.51 unit decrease in pH, and distinct bacterial community structures compared to non-rhizospheric soil controls. The dissipation of the allelochemicals in root-influenced soil followed sigmoidal biodegradation patterns that depended on the plant species, the specific allelochemical, and the soil's proximity to the roots. We suggest that plant-specific changes in rhizospheric bacterial communities, likely influenced by root exudates, drove the observed differences in allelochemical dissipation between rhizospheric and non-rhizospheric soil. Our results indicate that evaluating the persistence of allelochemicals in soil near plant roots can help improve predictions of their environmental fate and activity in natural and agricultural ecosystems.This research was funded by the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033), through grants PID2020-112563RB-I00 and PID2023-146470OB-I00, co-financed with EU (ERDF) funds. M.V. Muñoz-Muñoz also thanks MCIN for a pre-doctoral contract (grant PRE2021-100664) co-financed with EU (ESF) funds. .Peer reviewe
Multicenter validation of secondary hemophagocytic lymphohistiocytosis diagnostic criteria
Get PDF[Background] Five fulfilled hemophagocytic lymphohistiocytosis (HLH)-2004 criteria, and the HScore are widely used and recommended by international expert consensus to diagnose secondary HLH. Both diagnostic scores have never been validated in heterogeneous patient cohorts of secondary HLH patients. We aimed to systematically optimize and validate diagnostic criteria of secondary HLH using a multicenter approach.[Methods] We developed optimized criteria in our cohort of critically ill patients as a first step. We next validated these new criteria together with the original and modified HLH-2004 criteria as well as the HScore using original data of 13 published cohorts, which were identified by a systematic literature search.[Results] The best performing HLH diagnostic criteria sets over all 13 validation cohorts were the original HLH-2004 criteria with a decreased cut-off (cut-off 4, mean sensitivity 86.5%, mean specificity 86.1%), followed by the revised HLH-2004 criteria (natural killer cell activity removed; cut-off 4, mean sensitivity 83.8%, mean specificity 87.8%) and the HScore (cut-off 169, mean sensitivity 82.4%, mean specificity 87.6%). Our newly developed HLH diagnostic criteria showed inferior performance. Ferritin ≥500 µg/L had 94.0% mean sensitivity over all cohorts.[Conclusions] In this first multicenter validation study, four fulfilled HLH-2004 criteria and an HScore of 169 were suitable to diagnose secondary HLH, which will lead to rapid diagnosis and improved patient outcomes. Ferritin proved as a reliable HLH screening marker. Our results should be taken into account in clinical recommendations and in designing new studies.Cornelia Lachmann is a participant in the Berlin Institute of Health (BIH) Charité Digital Clinician Scientist Program funded by the Charité—Universitätsmedizin Berlin and the BIH at Charité. Gunnar Lachmann was a participant in the BIH Charité Clinician Scientist Program funded by the Charité—Universitätsmedizin Berlin and the BIH at Charité.Peer reviewe