Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that ...nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
Abstract
Motivation
Protein function is intrinsically linked to native dynamics, but the systematic characterization of functionally relevant dynamics remains elusive besides specific examples. Here ...we exhaustively characterize three types of dynamical couplings between protein residues: co-directionality (moving along collinear directions), coordination (small fluctuations of the interatomic distance) and deformation (the extent by which perturbations applied at one residue modify the local structure of the other one), which we analytically compute through the torsional network model.
Results
We find that ligand binding sites are characterized by large within-site coordination and co-directionality, much larger than expected for generic sets of residues with equivalent sequence distances. In addition, catalytic sites are characterized by high coordination couplings with other residues in the protein, supporting the view that the overall protein structure facilitates the catalytic dynamics. The binding sites of allosteric effectors are characterized by comparably smaller coordination and higher within-site deformation than other ligands, which supports their dynamic nature. Allosteric inhibitors are coupled to the active site more frequently through deformation than through coordination, while the contrary holds for activators. We characterize the dynamical couplings of the sodium-dependent Leucine transporter protein (LeuT). The couplings between and within sites progress consistently along the transport cycle, providing a mechanistic description of the coupling between the uptake and release of ions and substrate, and they highlight qualitative differences between the wild-type and a mutant for which chloride is necessary for transport.
Availability and implementation
The program tnm is freely available at https://github.com/ugobas/tnm
Supplementary information
Supplementary data are available at Bioinformatics online.
Imaging of subclinical atherosclerosis improves cardiovascular risk prediction on top of traditional risk factors. However, cardiovascular imaging is not universally available. This work aims to ...identify circulating proteins that could predict subclinical atherosclerosis.
Hypothesis-free proteomics was used to analyze plasma from 444 subjects from PESA cohort study (222 with extensive atherosclerosis on imaging, and 222 matched controls) at two timepoints (three years apart) for discovery, and from 350 subjects from AWHS cohort study (175 subjects with extensive atherosclerosis on imaging and 175 matched controls) for external validation. A selected three-protein panel was further validated by immunoturbidimetry in the AWHS population and in 2999 subjects from ILERVAS cohort study.
PIGR, IGHA2, APOA, HPT and HEP2 were associated with subclinical atherosclerosis independently from traditional risk factors at both timepoints in the discovery and validation cohorts. Multivariate analysis rendered a potential three-protein biomarker panel, including IGHA2, APOA and HPT. Immunoturbidimetry confirmed the independent associations of these three proteins with subclinical atherosclerosis in AWHS and ILERVAS. A machine-learning model with these three proteins was able to predict subclinical atherosclerosis in ILERVAS (AUC 95%CI:0.73 0.70–0.74, p < 1 × 10−99), and also in the subpopulation of individuals with low cardiovascular risk according to FHS 10-year score (0.71 0.69–0.73, p < 1 × 10−69).
Plasma levels of IGHA2, APOA and HPT are associated with subclinical atherosclerosis independently of traditional risk factors and offers potential to predict this disease. The panel could improve primary prevention strategies in areas where imaging is not available.
This study was supported by competitive grants from the Spanish Ministry of Science, Innovation and Universities (BIO2015-67580-P, PGC2018-097019-B-I00, PID2019-106814RB-I00 and SAF2016-80843-R), through the Carlos III Institute of Health-Fondo de Investigacion Sanitaria grant PRB3 (IPT17/0019 - ISCIII-SGEFI / ERDF, ProteoRed), CIBERCV and CIBERDEM, the Fundacio MaratoTV3 (grant 122/C/2015) and “la Caixa” Banking Foundation (project HR17-00247). The PESA study is co-funded equally by the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain, and Banco Santander, Madrid, Spain. The ILERVAS study was funded by the Diputacio de Lleida. The study also receives funding from the Instituto de Salud Carlos III (PI15/02019; PI18/00610; RD16/0009) and the FEDER funds. The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacion y Universidades (MCNU) and the Pro CNIC Foundation.
This work presents the highest resolution micrographs reported so far of two beam‐sensitive microporous materials: Ti‐doped AlPO4‐5 (TAPO‐5) and the metal–organic framework Zn–MOF‐74. They were ...registered by means of Cs‐corrected STEM. The high‐resolution images of the TAPO‐5 along the 0 0 1 orientation allows a clear observation of the aluminophosphate‐five (AFI) type framework, and illustrates the atomic distribution of the “T” atoms of the structure. However, no definitive conclusions about Ti substitution mechanism could be afforded because of the high symmetry of the AFI framework. In the case of Zn–MOF‐74, the images were also obtained at 300 kV proving that under certain conditions of beam current this technique can provide invaluable information of an ever‐increasing variety of molecular sieves.
High resolution: Aberration‐corrected scanning transmission electron microscopy allows extracting atomic resolution data from the aluminophosphate AlPO4‐5 doped with Ti. Ultrahigh‐resolution images of Zn–MOF‐74 can be obtained by the same approach, opening up new possibilities for the analysis of highly beam‐sensitive materials.
Background/Objectives: To analyze the best noninvasive tests prognosis marker in patients with diabetic foot ulcer (DFU) who underwent endovascular revascularization based on clinical outcomes, such ...as healing rate, time to heal, and free amputation survival after at least a six-month follow-up. Methods: A multicentric prospective observational study was performed with 28 participants with ischemic or neuroischemic DFU who came to the participant centers and underwent endovascular revascularization between January 2022 and March 2023. Toe systolic pressure (TP), ankle systolic pressure (AP), the ankle brachial pressure index (ABPI), the toe brachial pressure index (TBPI), transcutaneous pressure of oxygen (TcPO2), and skin perfusion pressure (SPP) were evaluated using PeriFlux 6000 System, Perimed, Sweden, before (Visit 0) and four weeks after revascularization (Visit 1). The primary clinical outcome was an evaluation of the clinical evolution of noninvasive tests comparing Visit 0 and Visit 1, estimating the sensitivity for predicting wound healing of noninvasive tests at six months following initial recruitment. Results: After six months, 71.43% (n = 20) of DFU healed, four patients (14.3%) received major amputations, and one (3.5%) died. The two tests that best predicted wound healing after revascularization according to the ROC curve were TcPO2 and TP with sensitivities of 0.89 and 0.70 for the cut-off points of 24 mmHg and 46 mmHg, respectively. Conclusions: TcPO2 and TP were the two tests that best predicted wound healing in patients who underwent endovascular revascularization. Clinicians should consider the importance of the evaluation of microcirculation in the healing prognosis of patients with diabetic foot ulcers.
Abstract
This work presents the highest resolution micrographs reported so far of two beam‐sensitive microporous materials: Ti‐doped AlPO
4
‐5 (TAPO‐5) and the metal–organic framework Zn–MOF‐74. They ...were registered by means of C
s
‐corrected STEM. The high‐resolution images of the TAPO‐5 along the 0 0 1 orientation allows a clear observation of the aluminophosphate‐five (AFI) type framework, and illustrates the atomic distribution of the “T” atoms of the structure. However, no definitive conclusions about Ti substitution mechanism could be afforded because of the high symmetry of the AFI framework. In the case of Zn–MOF‐74, the images were also obtained at 300 kV proving that under certain conditions of beam current this technique can provide invaluable information of an ever‐increasing variety of molecular sieves.
ObjectiveTo assess the effect of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients in Spain.SettingsThe initial flood of COVID-19 patients overwhelmed an unprepared ...healthcare system. Different measures were taken to deal with this overburden. The effect of these measures on neurosurgical patients, as well as the effect of COVID-19 itself, has not been thoroughly studied.ParticipantsThis was a multicentre, nationwide, observational retrospective study of patients who underwent any neurosurgical operation from March to July 2020.InterventionsAn exploratory factorial analysis was performed to select the most relevant variables of the sample.Primary and secondary outcome measuresUnivariate and multivariate analyses were performed to identify independent predictors of mortality and postoperative SARS-CoV-2 infection.ResultsSixteen hospitals registered 1677 operated patients. The overall mortality was 6.4%, and 2.9% (44 patients) suffered a perioperative SARS-CoV-2 infection. Of those infections, 24 were diagnosed postoperatively. Age (OR 1.05), perioperative SARS-CoV-2 infection (OR 4.7), community COVID-19 incidence (cases/105 people/week) (OR 1.006), postoperative neurological worsening (OR 5.9), postoperative need for airway support (OR 5.38), ASA grade ≥3 (OR 2.5) and preoperative GCS 3–8 (OR 2.82) were independently associated with mortality. For SARS-CoV-2 postoperative infection, screening swab test <72 hours preoperatively (OR 0.76), community COVID-19 incidence (cases/105 people/week) (OR 1.011), preoperative cognitive impairment (OR 2.784), postoperative sepsis (OR 3.807) and an absence of postoperative complications (OR 0.188) were independently associated.ConclusionsPerioperative SARS-CoV-2 infection in neurosurgical patients was associated with an increase in mortality by almost fivefold. Community COVID-19 incidence (cases/105 people/week) was a statistically independent predictor of mortality.Trial registration numberCEIM 20/217.
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