Thalattosuchians are a group of Mesozoic crocodylomorphs known from aquatic deposits of the Early Jurassic-Early Cretaceous that comprises two main lineages of almost exclusively marine forms, ...Teleosauridae and Metriorhynchoidea. Teleosaurids were found in shallow marine, brackish and freshwater deposits, and have been characterized as semiaquatic near-shore forms, whereas metriorhynchids are a lineage of fully pelagic forms, supported by a large set of morphological characters of the skull and postcranial anatomy. Recent contributions on Thalattosuchia have been focused on the study of the endocranial anatomy. This newly available information provides novel evidence to suggest adaptations on the neuroanatomy, senses organs, vasculature, and behavioral evolution of these crocodylomorphs. However, is still not clear if the major morphological differences between teleosaurids and metriorhynchids were also mirrored by changes in the braincase and endocranial anatomy. Based on X-ray CT scanning and digital endocast reconstructions we describe the braincase and endocranial anatomy of two well-preserved specimens of Thalattosuchia, the semiaquatic teleosaurid
and the pelagic metriorhynchid
. We propose that some morphological traits, such as: an enlarged foramen for the internal carotid artery, a carotid foramen ventral to the occipital condyle, a single CN XII foramen, absence of brain flexures, well-developed cephalic vascular system, lack of subtympanic foramina and the reduction of the paratympanic sinus system, are distinctive features of Thalattosuchia. It has been previously suggested that the enlarged foramen for the internal carotid artery, the absence of brain flexures, and the hypertrophied cephalic vascular system were synapomorphies of Metriorhynchidae; however, new information revealed that all of these features were already established at the base of Thalattosuchia and might have been exapted later on their evolutionary history. Also, we recognized some differences within Thalattosuchia that previously have not been received attention or even were overlooked (e.g., circular/bilobate trigeminal foramen, single/double CN XII foramen, separation of the cranioquadrate canal from the external otic aperture, absence/presence of lateral pharyngeal foramen). The functional significances of these traits are still unclear. Extending the sampling to other Thalattosuchia will help to test the timing of acquisition and distribution of these morphological modifications among the whole lineage. Also comparison with extant marine tetrapods (including physiological information) will be crucial to understand if some (and/or which) of the morphological peculiarities of thalattosuchian braincases are products of directional natural selection resulting in a fully adaptation to a nektonic life style.
Acute vascular endothelial dysfunction is a central event in the pathogenesis of sepsis, increasing vascular permeability, promoting activation of the coagulation cascade, tissue edema and ...compromising perfusion of vital organs. Aging and chronic diseases (hypertension, dyslipidaemia, diabetes mellitus, chronic kidney disease, cardiovascular disease, cerebrovascular disease, chronic pulmonary disease, liver disease, or cancer) are recognized risk factors for sepsis. In this article we review the features of endothelial dysfunction shared by sepsis, aging and the chronic conditions preceding this disease. Clinical studies and review articles on endothelial dysfunction in sepsis, aging and chronic diseases available in PubMed were considered. The main features of endothelial dysfunction shared by sepsis, aging and chronic diseases were: (1) increased oxidative stress and systemic inflammation, (2) glycocalyx degradation and shedding, (3) disassembly of intercellular junctions, endothelial cell death, blood-tissue barrier disruption, (4) enhanced leukocyte adhesion and extravasation, (5) induction of a pro-coagulant and anti-fibrinolytic state. In addition, chronic diseases impair the mechanisms of endothelial reparation. In conclusion, sepsis, aging and chronic diseases induce similar features of endothelial dysfunction. The potential contribution of pre-existent endothelial dysfunction to sepsis pathogenesis deserves to be further investigated.
•A cost-effective and simple to use colorimetric sensing protocol is proposed.•No need for special light sources, neither costly microscopes or plate readers.•Porous silicon microcavities are used to ...detect 10 fg ml−1 anti-histones in serum.•The RGB analysis of the color formed in diffuse light enables to quantify molecules.•Use of photonic substrates amplify 100 x detection sensitivity compared to ELISA.
Cost-effective health care technologies for detection of disease biomarkers at ultralow concentrations can significantly improve the quality of life in resource-constrained countries. However, current techniques require expensive instruments, complex conjugation protocols and tedious laboratory procedures that may not be affordable for the major part of the world population. Here, we propose to sidestep the problem by establishing a simple, relatively inexpensive sensing method employing a photonic substrate, a material affinity peptide, and a smart phone CCD detector to achieve detection of clinically relevant proteins in serum at concentrations much lower than standard enzyme-linked immunosorbent assay (ELISA). Easy to process porous silicon (PSi) microcavities were employed as substrates that provide a three-dimensionality, large surface area, and convenient light enhancement properties for molecular detection. Anti-histone H2 B antibodies and biomarkers of severe illnesses are detected in whole serum at concentrations as low as 10 fg mL−1 by using the proposed PSi- ELISA protocol. Due to its easy use, cost effectiveness and high sensitivity, the proposed method has potential large-scale applications in ultrasensitive sensing of different other clinically relevant molecules for early stage diagnostics.
Oxidative stress may be a key player in COVID-19 pathogenesis due to its significant role in response to infections. A defective redox balance has been related to viral pathogenesis developing a ...massive induction of cell death provoked by oxidative stress. The aim of this study is to perform a complete oxidative stress profile evaluation regarding antioxidant enzymes, total antioxidant capacity and oxidative cell damage in order to characterize its role in diagnosis and severity of this disease.
Blood samples were obtained from 108 COVID-19 patients and 28 controls and metabolites representative of oxidative stress were assessed. The association between lipid peroxidation and 28-day intubation/death risk was evaluated by multivariable regression analysis. Probability of intubation/death to day-28 was analyzed by using Kaplan-Meier curves and tested with the log-rank test.
Antioxidant enzymes (Superoxide dismutase (SOD) and Catalase) and oxidative cell damage (Carbonyl and Lipid peroxidation (LPO)) levels were significantly higher in COVID-19 patients while total antioxidant capacity (ABTS and FRAP) levels were lower in these patients. The comparison of oxidative stress molecules’ levels across COVID-19 severity revealed that only LPO was statistically different between mild and intubated/death COVID-19 patients. COX multivariate regression analysis identified LPO levels over the OOP (LPO>1948.17 μM) as an independent risk factor for 28-day intubation/death in COVID-19 patients OR: 2.57; 95% CI: 1.10–5.99; p = 0.029. Furthermore, Kaplan-Meier curve analysis revealed that COVID-19 patients showing LPO levels above 1948.17 μM were intubated or died 8.4 days earlier on average (mean survival time 15.4 vs 23.8 days) when assessing 28-day intubation/death risk (p < 0.001).
These findings deepen our knowledge of oxidative stress status in SARS-CoV-2 infection, supporting its important role in COVID-19. In fact, higher lipid peroxidation levels are independently associated to a higher risk of intubation or death at 28 days in COVID-19 patients.
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•Antioxidant enzymes and oxidative cell damage levels were significantly higher while total antioxidant capacity was lower in COVID-19 patients.•Only lipid peroxidation was statistically different across COVID-19 severity.•Lipid peroxidation levels over 1948.17 μM are an independent risk factor for 28-day intubation/death in COVID-19 patients.•COVID-19 patients showing lipid peroxidation levels above 1948.17 μM were intubated or died 8.4 days earlier on average.
TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, ...7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.
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•Homozygous LoF TBK1 produces systemic autoinflammation, not overt viral disease.•Expressed but inactive TBK1 inhibits IFN-I induction more than no TBK1.•Autoinflammation is driven by TNF-induced cell death caused by dysregulated RIPK1.•Treatment with anti-TNF resolves clinical disease.
TBK1 signals activation of antiviral defenses and controls TNF-mediated inflammation. Deletion of TBK1 in mice is embryonically lethal. Humans lacking TBK1 expression survive and have adequate antiviral function. Instead, these individuals suffer from inflammatory pathology driven by sensitivity to TNF-induced cell death that can be effectively treated with anti-TNF therapeutics.
OBJECTIVES:To quantify immunological dysfunction in surgical patients with presence/absence of sepsis using a droplet digital polymerase chain reaction (ddPCR) transcriptomic analysis. The study also ...aims to evaluate this approach for improving identification of sepsis in these patients.
BACKGROUND:Immune dysregulation is a central event in sepsis. Quantification of the expression of immunological genes participating in the pathogenesis of sepsis could represent a new avenue to improve its diagnosis.
METHODS:Expression of 6 neutrophil protease genes (MMP8, OLFM4, LCN2/NGAL, LTF, PRTN3, MPO) and also of 5 genes involved in the immunological synapse (HLA-DRA, CD40LG, CD3E, CD28, ICOS) was quantified in blood from 101 surgical patients with sepsis, 53 uninfected surgical patients, and 16 blood donors by using ddPCR. Areas under receiver operating characteristic curves (AUROC) and multivariate regression analysis were employed to test individual genes and gene ratios to identify sepsis, in comparison with procalcitonin.
RESULTS:Sepsis-induced overexpression of neutrophil protease genes and depressed expression of immunological synapse genes. MMP8/HLA-DRA, LCN2/HLA-DRA outperformed procalcitonin in differentiating between patients with sepsis and surgical controls in the AUROC analysisLCN2/HLA-DRA0.90 (0.85–0.96), MMP8/HLA-DRA0.89 (0.84–0.95), procalcitonin0.80 (0.73–0.88) (AUROC, confidence interval 95%), and also in the multivariate analysisLCN2/HLA-DRA8.57 (2.25–32.62); MMP8/HLA-DRA8.03 (2.10–30.76), procalcitonin4.20 (1.15–15.43) odds ratio (confidence interval 95%). Gene expression levels of HLA-DRA were an independent marker of hospital mortality.
CONCLUSIONS:Quantifying the transcriptomic ratios MMP8/HLA-DRA, LCN2/HLA-DRA by ddPCR is a promising approach to improve sepsis diagnosis in surgical patients.
Type I interferons (IFN-Is) are a group of potent inflammatory and antiviral cytokines. They induce IFN stimulated genes (ISGs), which act as proinflammatory mediators, antiviral effectors, and ...negative regulators of the IFN-I signaling cascade itself. One such regulator is interferon stimulated gene 15 (ISG15). Humans with complete ISG15 deficiency express persistently elevated levels of ISGs, and consequently, exhibit broad spectrum resistance to viral infection. Here, we demonstrate that IFN-I primed fibroblasts derived from ISG15-deficient individuals are more resistant to infection with single-cycle HIV-1 compared to healthy control fibroblasts. Complementation with both wild-type (WT) ISG15 and ISG15ΔGG (incapable of ISGylation while retaining negative regulation activity) was sufficient to reverse this phenotype, restoring susceptibility to infection to levels comparable to WT cells. Furthermore, CRISPR-edited ISG15ko primary CD4+ T cells were less susceptible to HIV-1 infection compared to cells treated with non-targeting controls. Transcriptome analysis of these CRISPR-edited ISG15ko primary CD4+ T cells recapitulated the ISG signatures of ISG15 deficient patients. Taken together, we document that the increased broad-spectrum viral resistance in ISG15-deficiency also extends to HIV-1 and is driven by a combination of T-cell-specific ISGs, with both known and unknown functions, predicted to target HIV-1 replication at multiple steps.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent works have demonstrated a significant reduction in cholesterol levels and increased oxidative stress in patients with coronavirus disease 2019 (COVID-19). The cause of this alteration is not ...well known. This study aimed to comprehensively evaluate their possible association during the evolution of COVID-19. This is an observational prospective study. The primary endpoint was to analyze the association between lipid peroxidation, lipid, and inflammatory profiles in COVID-19 patients. A multivariate regression analysis was employed. The secondary endpoint included the long-term follow-up of lipid profiles. COVID-19 patients presented significantly lower values in their lipid profile (total, low, and high-density lipoprotein cholesterol) with greater oxidative stress and inflammatory response compared to the healthy controls. Lipid peroxidation was the unique oxidative parameter with a significant association with the total cholesterol (OR: 0.982; 95% CI: 0.969-0.996;
= 0.012), IL1-RA (OR: 0.999; 95% CI: 0.998-0.999;
= 0.021) IL-6 (OR: 1.062; 95% CI: 1.017-1.110;
= 0.007), IL-7 (OR: 0.653; 95% CI: 0.433-0.986;
= 0.042) and IL-17 (OR: 1.098; 95% CI: 1.010-1.193;
= 0.028). Lipid abnormalities recovered after the initial insult during long-term follow-up (IQR 514 days); however, those with high LPO levels at hospital admission had, during long-term follow-up, an atherogenic lipid profile. Our study suggests that oxidative stress in COVID-19 is associated with derangements of the lipid profile and inflammation. Survivors experienced a recovery in their lipid profiles during long-term follow-up, but those with stronger oxidative responses had an atherogenic lipid profile.
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