COVID-19 and Lung Mast Cells: The Kallikrein–Kinin Activation Pathway

Mast cells (MCs) have relevant participation in inflammatory and vascular hyperpermeability events, responsible for the action of the kallikrein–kinin system (KKS), that affect patients inflicted by the severe form of COVID-19. Given a higher number of activated MCs present in COVID-19 patients and their association with vascular hyperpermeability events, we investigated the factors that lead to the activation and degranulation of these cells and their harmful effects on the alveolar septum environment provided by the action of its mediators. Therefore, the pyroptotic processes throughout caspase-1 (CASP-1) and alarmin interleukin-33 (IL-33) secretion were investigated, along with the immunoexpression of angiotensin-converting enzyme 2 (ACE2), bradykinin receptor B1 (B1R) and bradykinin receptor B2 (B2R) on post-mortem lung samples from 24 patients affected by COVID-19. The results were compared to 10 patients affected by H1N1pdm09 and 11 control patients. As a result of the inflammatory processes induced by SARS-CoV-2, the activation by immunoglobulin E (IgE) and degranulation of tryptase, as well as Toluidine Blue metachromatic (TB)-stained MCs of the interstitial and perivascular regions of the same groups were also counted. An increased immunoexpression of the tissue biomarkers CASP-1, IL-33, ACE2, B1R and B2R was observed in the alveolar septum of the COVID-19 patients, associated with a higher density of IgE⁺ MCs, tryptase⁺ MCs and TB-stained MCs, in addition to the presence of intra-alveolar edema. These findings suggest the direct correlation of MCs with vascular hyperpermeability, edema and diffuse alveolar damage (DAD) events that affect patients with a severe form of this disease. The role of KKS activation in events involving the exacerbated increase in vascular permeability and its direct link with the conditions that precede intra-alveolar edema, and the consequent DAD, is evidenced. Therapy with drugs that inhibit the activation/degranulation of MCs can prevent the worsening of the prognosis and provide a better outcome for the patient.     

己二酸的清洁催化氧化合成研究进展

综述了近年来以环己烯、环己酮、环己醇或环己烷等作原料,以过氧化氢或氧气等为氧源,采用不同的催化体系清洁合成己二酸的新进展.指出:在这些方法中,改性的分子筛及负载型催化剂-双氧水体系将是今后己二酸清洁合成的重点研究方向.     

Multiple allocation hub-and-spoke network design under hub congestion

The multiple allocation hub-and-spoke network design under hub congestion problem is addressed in this paper. A non-linear mixed integer programming formulation is proposed, modeling the congestion as a convex cost function. A generalized Benders decomposition algorithm has been deployed and has successfully solved standard data set instances up to 81 nodes. The proposed algorithm has also outperformed a commercial leading edge non-linear integer programming package. The main contribution of this work is to establish a compromise between the transportation cost savings induced by the economies of scale exploitation and the costs associated with the congestion effects.     

EPR studies of (Bi, Pb)-2223 phase substituted by Ruthenium ions

This work studied X-ray powder diffraction (XRD), electrical resistivity and electron paramagnetic resonance (EPR) measurements for Bi_1.8Pb_0.4Sr₂Ca_2.1Cu_3−xRu_xO_10+δ (0.0 ≤ x ≤ 0.4) superconducting samples. XRD analysis and electrical resistivity data showed that the low-content of Ru, x ≤ 0.05, enhanced both the phase formation and the superconducting transition temperature of (Bi, Pb)-2223 phase. A phase change from (Bi, Pb)-2223 phase to (Bi, Pb)-2212 phase was reported for x ≥ 0.15. Two EPR lines were observed for 0.0 ≤ x ≤ 0.075, indicating the presence of both (Bi, Pb)-2223 and (Bi, Pb)-2212 phases. While, one EPR line was observed for x ≥ 0.15, corresponding to the (Bi, Pb)-2212 phase formation. The number of spins (N) participating in the resonance and its spin paramagnetic susceptibility (χ), for the two phases, were calculated as a function of both Ru-content and temperature. In addition, we reported the variation of activation energy (E_a), Curie constant (C), Curie temperature (θ) and effective magnetic moment (μ) with Ru-content.     

High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy

A majority of the human tumor-associated Ags characterized to date are derived from nonmutated "self"-proteins. Little is currently understood about the nature of the self-reactive lymphocytes that recognize these Ags. We recently characterized two nonmutated tumor-associated Ags for the B16 murine melanoma: tyrosinase-related protein-2 (TRP-2) and the endogenous retroviral envelope protein, p15E. We previously reported that both TRP-2 and p15E reactive CTL could be detected in the spleens of naive animals after a single in vitro stimulation using 10(-5)-10(-6) M of the appropriate Kb-binding 9-amino acid epitope. In this report we show that the CTL found in naive animals are low avidity lymphocytes, that respond only to high concentrations of peptide in vitro. We demonstrate that titration of in vitro-stimulating peptide to limiting concentrations distinguishes qualitative differences in the lymphocyte reactivity to these two Ags between vaccinated and unvaccinated animals. We further demonstrate that in vitro expansion of CTL in either high or low concentrations of stimulating peptide generated CTL cultures with different avidities for the relevant epitopes. CTL expanded in low concentrations demonstrated higher avidity for peptide-pulsed targets and better tumor recognition, when compared to CTL generated in the presence of high concentrations of Ag. More importantly, high avidity CTL demonstrated superior in vivo antitumor activity. These results demonstrate that qualitative differences in the CTL that recognize these two self-Ags are critically important to their in vitro and in vivo anti-tumor efficacy.     

Prediction of anticoagulation during hemodialysis by population kinetics and an artificial neural network

All systems currently used for routine hemodialysis require heparin administration to prevent blood clotting in the extracorporeal circuit. We tested the hypothesis that population-based statistical techniques can be used to predict heparin concentrations during routine hemodialysis. Two predictive models were developed, one based on nonlinear mixed effects modeling (NONMEM) and the other on a multilayer perceptron neural network. Serial clotting time data were obtained from forty-nine patients and used to develop the models. The models were used to predict the clotting times of 70 patients in a prospective test. We determined that the neural network provided greater precision, had fewer outliers in its predictions, and did not have the model misspecification in bolus administration that the NONMEM predictions demonstrated. A final NONMEM model was developed using all data from 119 patients to identify important covariates for predicting the heparin pharmacodynamic parameters, volume of distribution, and clearance. Both the volume of distribution and clearance increased following the initiation of dialysis and as the patient's baseline clotting time increased. The volume of distribution also increased as the patient's weight increased but was decreased by smoking and diabetes. Population-based statistical techniques may provide a useful alternative to existing methods for prescribing heparin.     

A home-based exercise program for nondisabled older adults

OBJECTIVES: This paper describes a videotaped, home-based, strength training program, titled Strong-for-Life and reports on its effectiveness in improving muscle strength, psychological well-being, and health status in a sample of older persons. DESIGN AND SETTING: We enrolled 102 nondisabled, community-dwelling older people aged 66 to 87, identified from the Medicare beneficiary list, into a randomized, controlled trial. MEASUREMENTS: Effectiveness was based on change in isokinetic upper and lower extremity muscle strength, psychologic well-being, and health status. RESULTS: Results revealed several statistically significant short-term benefits after 12 to 15 weeks of exercise, especially for men. Younger older adults demonstrated a 10% improvement in knee extensor strength relative to control subjects. Older male exercisers achieved significant differences relative to controls in perceived anger, tension, and overall social functioning. Male exercisers, in general, achieved significant improvement in perceived vigor. Women did not report psychological benefits following participation in the program. CONCLUSION: Study results reveal that the Strong for Life program, designed to be widely disseminated to the nondisabled older population, has many short-term positive benefits.