After more than one year since the COVID-19 outbreak, patients with severe disease still constitute the bottleneck of the pandemic management. Aberrant inflammatory responses, ranging from cytokine ...storm to immune-suppression, were described in COVID-19 and no treatment was demonstrated to change the prognosis significantly. Therefore, there is an urgent need for understanding the underlying pathogenic mechanisms to guide therapeutic interventions. This study was designed to assess myeloid cell activation and phenotype leading to recovery in patients surviving severe COVID-19. We evaluated longitudinally patients with COVID-19 related respiratory insufficiency, stratified according to the need of intensive care unit admission (ICU, n = 11, and No-ICU, n = 9), and age and sex matched healthy controls (HCs, n = 11), by flow cytometry and a wide array of serum inflammatory/immune-regulatory mediators. All patients featured systemic immune-regulatory myeloid cell phenotype as assessed by both unsupervised and supervised analysis of circulating monocyte and dendritic cell subsets. Specifically, we observed a reduction of CD14lowCD16+ monocytes, and reduced expression of CD80, CD86, and Slan. Moreover, mDCs, pDCs, and basophils were significantly reduced, in comparison to healthy subjects. Contemporaneously, both monocytes and DCs showed increased expression of CD163, CD204, CD206, and PD-L1 immune-regulatory markers. The expansion of M2-like monocytes was significantly higher at admission in patients featuring detectable SARS-CoV-2 plasma viral load and it was positively correlated with the levels of specific antibodies. In No-ICU patients, we observed a peak of the alterations at admission and a progressive regression to a phenotype similar to HCs at discharge. Interestingly, in ICU patients, the expression of immuno-suppressive markers progressively increased until discharge. Notably, an increase of M2-like HLA-DRhighPD-L1+ cells in CD14++CD16− monocytes and in dendritic cell subsets was observed at ICU discharge. Furthermore, IFN-γ and IL-12p40 showed a decline over time in ICU patients, while high values of IL1RA and IL-10 were maintained. In conclusion, these results support that timely acquisition of a myeloid cell immune-regulatory phenotype might contribute to recovery in severe systemic SARS-CoV-2 infection and suggest that therapeutic agents favoring an innate immune system regulatory shift may represent the best strategy to be implemented at this stage.
T-cell development ensures the formation of diverse repertoires of T-cell receptors (TCRs) that recognize a variety of antigens. Glycosylation is a major posttranslational modification present in ...virtually all cells, including T-lymphocytes, that regulates activity/functions. Although these structures are known to be involved in TCR-selection in DP thymocytes, it is unclear how glycans regulate other thymic development processes and how they influence susceptibility to disease. Here, we discovered stage-specific glycome compositions during T-cell development in human and murine thymocytes, as well as dynamic alterations. After restricting the N-glycosylation profile of thymocytes to high-mannose structures, using specific glycoengineered mice (Rag1
Mgat1
), we showed remarkable defects in key developmental checkpoints, including ß-selection, regulatory T-cell generation and γδT-cell development, associated with increased susceptibility to colon and kidney inflammation and infection. We further demonstrated that a single N-glycan antenna (modeled in Rag1
Mgat2
mice) is the sine-qua-non condition to ensure normal development. In conclusion, we revealed that mannosylated thymocytes lead to a dysregulation in T-cell development that is associated with inflammation susceptibility.
Among the aspects with major impacts on the energy and environmental performance of a building, the thermal insulation of the opaque elements of its envelope stands out. This work assesses the ...influence of the application of thermal insulation to the opaque elements of the building’s envelope on the thermal comfort conditions indoors; moreover, the influence of the thermal insulation on the energy, environmental, and economic costs over the building’s complete life cycle is evaluated. For this purpose, the three most commonly used thermal insulating materials (expanded polystyrene—EPS, extruded polystyrene—XPS, and mineral wool—MW), thicknesses between 0 (without insulation) and 40 cm, five climates (hot, warm, moderate, cold, and very cold), and six types of use (apartment, housing, clinic, school, bank branch, and supermarket) were considered. EPS reveals itself to be the most promising thermal insulation material, both in economic and environmental terms, so it was selected for this study. The EPS’ optimal thickness depends on the building’s type of use, the climate, and the perspective from which the assessment is carried out (energy, environmental, or economic). The results show that the economically optimal thicknesses of thermal insulation are significantly lower than the corresponding ones in environmental terms. Furthermore, the application of thermal insulation to the opaque building’s envelope is more beneficial in energy and environmental terms than from an economic perspective.
Exploring membrane respiratory chains Marreiros, Bruno C.; Calisto, Filipa; Castro, Paulo J. ...
Biochimica et biophysica acta,
August 2016, 2016-Aug, 2016-08-00, Letnik:
1857, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Acquisition of energy is central to life. In addition to the synthesis of ATP, organisms need energy for the establishment and maintenance of a transmembrane difference in electrochemical potential, ...in order to import and export metabolites or to their motility. The membrane potential is established by a variety of membrane bound respiratory complexes. In this work we explored the diversity of membrane respiratory chains and the presence of the different enzyme complexes in the several phyla of life. We performed taxonomic profiles of the several membrane bound respiratory proteins and complexes evaluating the presence of their respective coding genes in all species deposited in KEGG database. We evaluated 26 quinone reductases, 5 quinol:electron carriers oxidoreductases and 18 terminal electron acceptor reductases. We further included in the analyses enzymes performing redox or decarboxylation driven ion translocation, ATP synthase and transhydrogenase and we also investigated the electron carriers that perform functional connection between the membrane complexes, quinones or soluble proteins. Our results bring a novel, broad and integrated perspective of membrane bound respiratory complexes and thus of the several energetic metabolisms of living systems. This article is part of a Special Issue entitled ‘EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2–6, 2016’, edited by Prof. Paolo Bernardi.
•Taxonomic profiles of membrane bound respiratory complexes in the 3 life domains are presented.•Proteobacteria show the highest respiratory versatility.•Oxygen is the preferred terminal electron acceptor.•Redox-driven ion pumps are fundamental for life.
Monocytes are key modulators in acute viral infections, determining both inflammation and development of specific B- and T-cell responses. Recently, these cells were shown to be associated to ...different SARS-CoV-2 infection outcome. However, their role in acute HIV-1 infection remains unclear. We had the opportunity to evaluate the mononuclear cell compartment in an early hyper-acute HIV-1 patient in comparison with an untreated chronic HIV-1 and a cohort of SARS-CoV-2 infected patients, by high dimensional flow cytometry using an unsupervised approach. A distinct polarization of the monocyte phenotype was observed in the two viral infections, with maintenance of pro-inflammatory M1-like profile in HIV-1, in contrast to the M2-like immunosuppressive shift in SARS-CoV-2. Noticeably, both acute infections had reduced CD14low/−CD16+ non-classical monocytes, with depletion of the population expressing Slan (6-sulfo LacNac), which is thought to contribute to immune surveillance through pro-inflammatory properties. This depletion indicates a potential role of these cells in acute viral infection, which has not previously been explored. The inflammatory state accompanied by the depletion of Slan+ monocytes may provide new insights on the critical events that determine the rate of viral set-point in acute HIV-1 infection and subsequent impact on transmission and reservoir establishment.
Cancer is among the leading causes of death worldwide. One of the most challenging obstacles in cancer treatment is multidrug resistance (MDR). Overexpression of P-glycoprotein (P-gp) is associated ...with MDR. The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs to overcome the MDR problem. Royleanones are natural bioactive compounds frequently found in
spp. The cytotoxic diterpene 6,7-dehydroroyleanone (
) is the main component of the
(Pers.) Benth. essential oil, while 7α-acetoxy-6β-hydroxyroyleanone (
) can be isolated from acetonic extracts of
Gürke. The reactivity of the natural royleanones
and
was explored to obtain a small library of new P-gp inhibitors. Four new derivatives (6,7-dehydro-12-
-
-butyl-carbonate-royleanone (
), 6,7-dehydro-12-
-methylroyleanone (
), 6,7-dehydro-12-
-benzoylroyleanone (
), and 7α-acetoxy-6β-hydroxy-12-
-benzoylroyleanone (
) were obtained as pure with overall modest to excellent yields (21-97%). P-gp inhibition potential of the derivatives
-
was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R with the P-gp overexpression, through MTT assay. Previously prepared diterpene 7α-acetoxy-6β-benzoyloxy-12-
-(4-chloro)benzoylroyleanone (
), has also been tested. The P-gp inhibiting effects of compounds
-
were also assessed through a Rhodamine 123 accumulation assay. Derivatives
and
have significant P-gp inhibitory potential. Regarding stability and P-gp inhibition potential, results suggest that the formation of benzoyl esters is a more convenient approach for future derivatives with enhanced effect on the cell viability decrease. Compound
presented higher anti-P-gp potential than the natural diterpenes
,
and
, with comparable inhibitory potential to Dexverapamil. Moreover, derivative
showed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin.
Accelerate lung repair in SARS‐CoV‐2 pneumonia is essential for pandemic handling. Innate lymphoid cells (ILCs) are likely players, given their role in mucosal protection and tissue homeostasis. We ...studied ILC subpopulations at two time points in a cohort of patients admitted in the hospital due to SARS‐CoV‐2 infection. COVID‐19 patients with moderate/severe respiratory failure featured profound depletion of circulating ILCs at hospital admission, in agreement with overall lymphocyte depletion. However, ILCs recovered in direct correlation with lung function improvement as measured by oxygenation index and in negative association with inflammatory and lung/endothelial damage markers like RAGE. While both ILC1 and ILC2 expanded, ILC2 showed the most striking phenotype changes, with CCR10 upregulation in strong correlation with these parameters. Overall, CCR10+ ILC2 emerge as relevant contributors to SARS‐CoV‐2 pneumonia recovery.
Moderate to severe COVID‐19 is associated with an overall decrease in all innate lymphoid cells’ subsets in parallel with the well‐known lymphopenia. We report, in association with the oxygenation improvement, a significant expansion of ILC1, irrespectively of CD161 expression, and of CCR10 expressing ILC2, suggesting their involvement in lung regeneration.
An analytical solution is derived for the micro-channel flow of viscoelastic fluids by combined electro-osmosis and pressure gradient forcing. The viscoelastic fluid is described by the ...Phan-Thien–Tanner model with due account for the near-wall layer depleted of macromolecules. This skimming layer is wider than the electric double layer (EDL) and leads to an enhanced flow rate relative to that of the corresponding uniform concentration flow case. The derived solution allows a detailed investigation of the flow characteristics due to the combined effects of fluid rheology, forcing strengths ratio, skimming layer thickness and relative rheology of the two fluids. In particular, when the EDL is much thinner than the skimming layer and simultaneously the viscosity of the Newtonian fluid inside this layer is much lower than that of the fluid outside, the flow is dominated by the characteristics of the Newtonian fluid. Outside these conditions, proper account of the various fluid layers and their properties must be considered for an accurate prediction of the flow characteristics. The analytical solution remains valid for the flow driven by a pressure gradient and its streaming potential, which is determined in the appendix.
There were eight fog events in five years at Maceio international airport on the northern coast of Brazil, and all were analyzed. Fog duration was short and its intensity was weak or moderate. The ...principal objectives of the study were: (1) analysis of the physical processes of fog formation (synoptic and thermodynamic conditions and processes), (2) PAFOG model testing, and (3) estimation of the effect of vegetation on fog forecast. Cyclonic curvature and divergence of the air current over the ocean at low levels and anticyclonic curvature at high levels were associated with the fog. Weak lifting at low levels was identified by the NCEP/DOE II, ECMWF, and WRF models for all eight events. Sinking at high levels was dominant in the ECMWF and WRF models. Absence of thermal inversion and conditional instability at low levels was identified by the NCEP/DOE II and ECMWF models. According to the WRF model a typical temperature profile during fog comprises three layers: (1) a very thin layer (up to 166 m, 985 hPa) of temperature inversion with very high humidity; (2) a conditional layer of instability from 985–860 hPa; and (3) a dry and stable layer above 860 hPa. Moderate fog with visibility between 200 and 300 m was associated with ocean cooling whereas weak fog was associated with ocean warming. A warm oscillation on the sea surface near the Brazilian northeast was observed for all fog events. It was found there was colder air over the warmer water near the coast. Weak confluence in troughs at low levels contributes to weak lifting at low levels. This current creates conditions resulting in humidity increase. A warmer sea surface contributes to more evaporation and, as a consequence, increases the amount of water vapor in the surrounding air at low levels near the coast. The PAFOG model was used to forecast the fog for three events (i.e., for all cases possible), and was satisfactory for two cases. Satisfactory results for fog duration and intensity were obtained with 9 h of antecedence. No significant effect of fast-growing sugarcane on the low visibility forecast was detected.
Purpose
Myocardial injury is common in hypertensive patients with 2019 coronavirus disease (COVID-19). Immune dysregulation could be associated to cardiac injury in these patients, but the underlying ...mechanism has not been fully elucidated.
Methods
All patients were selected prospectively from a multicenter registry of adults hospitalized with confirmed COVID-19. Cases had hypertension and myocardial injury, defined by troponin levels above the 99th percentile upper reference limit, and controls were hypertensive patients with no myocardial injury. Biomarkers and immune cell subsets were quantified and compared between the two groups. A multiple logistic regression model was used to analyze the associations of clinical and immune variables with myocardial injury.
Results
The sample comprised 193 patients divided into two groups: 47 cases and 146 controls. Relative to controls, cases had lower total lymphocyte count, percentage of T lymphocytes, CD8
+
CD38
+
mean fluorescence intensity (MFI), and percentage of CD8
+
human leukocyte antigen DR isotope (HLA-DR)
+
CD38
–
cells and higher percentage of natural killer lymphocytes, natural killer group 2A (NKG2A)
+
MFI, percentage of CD8
+
CD38
+
cells, CD8
+
HLA-DR
+
MFI, CD8
+
NKG2A
+
MFI, and percentage of CD8
+
HLA-DR
–
CD38
+
cells. On multivariate regression, the CD8
+
HLA-DR
+
MFI, CD8
+
CD38
+
MFI, and total lymphocyte count were associated significantly with myocardial injury.
Conclusion
Our findings suggest that lymphopenia, CD8
+
CD38
+
MFI, and CD8
+
HLA-DR
+
MFI are immune biomarkers of myocardial injury in hypertensive patients with COVID-19. The immune signature described here may aid in understanding the mechanisms underlying myocardial injury in these patients. The study data might open a new window for improvement in the treatment of hypertensive patients with COVID-19 and myocardial injury.
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