Inhibition of platelet aggregation by carbon monoxide-releasing molecules (CO-RMs): comparison with NO donors

Carbon monoxide (CO) and CO-releasing molecules (CO-RMs) inhibit platelet aggregation in vitro. Herein, we compare the anti-platelet action of CORM-3, which releases CO rapidly (t½ 1 min), and CORM-A1, which slowly releases CO (t½ = 21 min). The anti-platelet effects of NO donors with various kinetics of NO release were studied for comparison. The effects of CO-RMs and NO donors were analyzed in washed human platelets (WP), platelets rich plasma (PRP), or whole blood (WB) using aggregometry technique. CORM-3 and CORM-A1 inhibited platelet aggregation in human PRP, WP, or WB, in a concentration-dependent manner. In all three preparations, CORM-A1 was more potent than CORM-3. Inhibition of platelets aggregation by CORM-A1 was not significantly affected by a guanylate cyclase inhibitor (ODQ) and a phosphodiesterase-5 inhibitor, sildenafil. In contrast, inhibition of platelet aggregation by NO donors was more potent with a fast NO releaser (DEA-NO, t½ = 2 min) than slow NO releasers such as PAPA-NO (t½ = 15 min) or other slow NO donors. Predictably, the anti-platelet effect of DEA-NO and other NO donors was reversed by ODQ while potentiated by sildenafil. In contrast to NO donors which inhibit platelets proportionally to the kinetics of NO released via activation of soluble guanylate cyclase (sGC), the slow CO-releaser CORM-A1 is a superior anti-platelet agent as compared to CORM-3 which releases CO instantly. The anti-platelet action of CO-RMs does not involve sGC activation. Importantly, CORM-A1 or its derivatives representing the class of slow CO releasers display promising pharmacological profile as anti-platelet agents

Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors

Whole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Increasing the performance of Finite-Set Model Predictive Control by oversampling

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Characteristics of depositional environments of Czechowskie Lake basin and its vicinity

W artykule przedstawiono przegląd badań nad morfogenezą misy jeziornej Jeziora Czechowskiego na Pojezierzu Starogardzkim. W dostępnych odsłonięciach, wkopach i wierceniach o nienaruszonej strukturze przeprowadzono analizę sedymentologiczną osadów glacjofluwialnych, glacjolimnicznych, limnicznych i stokowych. Wyniki tej analizy uzupełniono rezultatami kartowania geologicznego i geomorfologicznego. W efekcie przeprowadzonych prac stwierdzono, że misa jeziora założona jest w głębokiej rynnie subglacjalnej, która do początku allerødu zakonserwowana była bryłami martwego lodu. Ich wytopienie doprowadziło do powstania zróżnicowanej morfologii dna rynny. W najgłębszych miejscach, dzięki ograniczonej miksji, były warunki do zachowania rocznej laminacji osadów dennych. Sedymentacja osadów glacjofluwialnych w otoczeniu rynny była bardzo zróżnicowana i w wielu miejscach wskazuje na warunki przepływu nadkrytycznego. W przypowierzchniowej warstwie osadów sandrowych stwierdzono ślady zapisu procesów mrozowych (gleby mrozowe) oraz wytrącenia węglanowe wskazujące na występowanie warunków peryglacjalnych po zaprzestaniu przepływu proglacjalnego. Osady limniczne są również zróżnicowane w zależności od cech morfometrycznych basenu sedymentacyjnego, a przede wszystkim od głębokości ich depozycji. Osady stokowe pochodzą w większości z ostatnich dwustu lat, a ich depozycja nastąpiła wskutek działalności gospodarczej człowieka.The paper aims to review the investigations on the genesis of the Czechowskie Lake basin (Starogard Lakeland, north-central Poland). The sedimentological analysis of the glaciofluvial, glaciolimnic, limnic and colluvial deposits have been conducted in the outcrops, pits and boreholes with undisturbed cores. They were supplemented by the results of the geological and geomorphological mapping. Summing up the investigations it can be stated that the lake basin developed within a deep subglacial channel which was preserved by the dead ice blocks till the onset of the Allerød. Their melting led to the emergence of a morphologically diversified lake basin. The conditions in its deepest parts, due to hampered mixing and wave action, favoured the preservation of the annually laminated sediments. The glaciofluvial deposition in the vicinity of the lake was diverse and in many places it indicates the supercritical condition of the water flow. Within the near-surface layer of outwash deposits were recognized the traces of the periglacial processes and calcareous precipitates which indicate short glaciolimnic periods or breaks in sedimentation. The limnic sediments are also diversified and dependent on the morphometric features of the sedimentary basin, mostly the depth of the deposition. Colluvial deposits have originated mostly in the last 200 years as a consequence of the transient deforestation of the surrounding area