Synthesis, structure, solution behaviour and biological evaluation of oxidovanadium(IV/V) complexes: Substrate specific DMSO assisted methylation of a thiosemicarbazone

The synthesis and characterization of an oxidovanadium(IV) [VIVO(L)(acac)] (1) and of two dioxidovanadium(V) [VVO2(L')] (2) and [VVO2(L)] (2a) complexes of the Schiff base formed from the reaction of 4-(p-fluorophenyl) thiosemicarbazone with pyridine-2-aldehyde (HL) is described.The oxidovanadium(IV) species [VIVO(L)(acac)] (1) was synthesized by the reaction of VIVO(acac)2 with the thiosemicarbazone HL in refluxing ethanol. The recrystallization of [VIVO(L)(acac)] (1) in DMF, CH3CN or EtOH gave the same product i.e. the dioxidovanadium(V) complex [VVO2(L)] (2a); however, upon recrystallization of 1 in DMSO a distinct compound [VVO2(L')] (2) was formed, wherein the original ligand L- is transformed to a rearranged one, L’-. In the presence of DMSO the ligand in complex 1 is found to undergo methylation at the carbon centre attached to imine nitrogen (aldimine) and transformed to the corresponding V VO2- species through in situ reaction. The synthesized HL and the metal 2 complexes were characterized by elemental analysis, IR, UV–Vis, NMR and EPR spectroscopy. The molecular structure of [VVO2(L')] (2) was determined by single crystal X–ray crystallography.The methylation of various other ligands and complexes prepared from different vanadium precursors under similar reaction conditions was also attempted and it was confirmed that the imine methylation observed is both ligand and metal precursor specific. Complexes 1 and 2 show in vitro insulin-like activity against insulin responsive L6 myoblast cells, with complex 1 being more potent. In addition, the in vitro cytotoxicity studies of HL, and of complexes 1 and 2 against the MCF–7 and Vero cell lines were also done. The ligand is not cytotoxic and complex 2 is significantly more cytotoxic than 1. DAPI staining experiments indicate that increase in time of incubation as well as increase of concentration of the complexes lead to increase in cell death

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary artery pressure leading to right ventricular (RV) failure. While current PAH therapies improve patient outlook, they show limited benefit in attenuating RV dysfunction. Recent investigations demonstrated that the thromboxane (TX) A2 receptor (TP) antagonist NTP42 attenuates experimental PAH across key hemodynamic parameters in the lungs and heart. This study aimed to validate the efficacy of NTP42:KVA4, a novel oral formulation of NTP42 in clinical development, in preclinical models of PAH while also, critically, investigating its direct effects on RV dysfunction. Methods: The effects of NTP42:KVA4 were evaluated in the monocrotaline (MCT) and pulmonary artery banding (PAB) models of PAH and RV dysfunction, respectively, and when compared with leading standard-of-care (SOC) PAH drugs. In addition, the expression of the TP, the target for NTP42, was investigated in cardiac tissue from several other related disease models, and from subjects with PAH and dilated cardiomyopathy (DCM). Results: In the MCT-PAH model, NTP42:KVA4 alleviated disease-induced changes in cardiopulmonary hemodynamics, pulmonary vascular remodeling, inflammation, and fibrosis, to a similar or greater extent than the PAH SOCs tested. In the PAB model, NTP42:KVA4 improved RV geometries and contractility, normalized RV stiffness, and significantly increased RV ejection fraction. In both models, NTP42:KVA4 promoted beneficial RV adaptation, decreasing cellular hypertrophy, and increasing vascularization. Notably, elevated expression of the TP target was observed both in RV tissue from these and related disease models, and in clinical RV specimens of PAH and DCM. Conclusion: This study shows that, through antagonism of TP signaling, NTP42:KVA4 attenuates experimental PAH pathophysiology, not only alleviating pulmonary pathologies but also reducing RV remodeling, promoting beneficial hypertrophy, and improving cardiac function. The findings suggest a direct cardioprotective effect for NTP42:KVA4, and its potential to be a disease-modifying therapy in PAH and other cardiac conditions

Exploring subsurface fluid flow and active dewatering along the oceanic plate boundary between Africa and Eurasia (Gloria Fault)

R/V Meteor cruise M162 was conducted as a systematic continuation of ongoing work dedicated to understand if and howfluid flow through crust and sedimentscontinues along transform-type plate boundaries and fracture zones away from mid-ocean ridges and continental margins. Central target was the Gloria Fault in the central Northeast Atlantic. Previous findings along the eastern continuation of the Gloria Fault revealed fault-controlled fluid advection and mud volcanism along strike-slip faults in the Horseshoe Abyssal Plain and the Gulf of Cadiz, where fluid geochemistry revealed the admixture of fluids from deeply buried oceanic crust and oldest sediments on top of it. TheGloria Fault itselfis an old, reactivated, and seismically active oceanic fracture zone. During M162 a systematic survey along the main trace of the Gloria Fault between the Azores Plateau and the Madeira-Tore Rise was carried out, including sub-bottom profiler surveys, heat flow transects, gravity corer sampling, as well as video-guided CTD and multicorer deployments. In accordance to recently recorded seismic activity along the fault, there isevidence for tectonic motion both in sub-bottom profiler records and sediment cores. Heat flow measurements revealed values significantly elevated above the background in many places, predominantly along the main fault trace and other active faults.Ina number of placesfluid geochemistry revealed enhanced diagenetic processes in the sediments, implying the potential relation to upward-directed fluid flow. In summary, cruise M162revealed the first complementary data set on heat flow and fluid geochemistry along an oceanic fault zone, which will further our understanding on themes like the alteration of oceanic lithosphere and crust-ocean element exchange

A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURO bservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry

Aims: Given the advances in atrial fibrillation (AF) management and the availability of new European Society of Cardiology (ESC) guidelines, there is a need for the systematic collection of contemporary data regarding the management and treatment of AF in ESC member countries. Methods and results: We conducted a registry of consecutive in- and outpatients with AF presenting to cardiologists in nine participating ESC countries. All patients with an ECG-documented diagnosis of AF confirmed in the year prior to enrolment were eligible. We enroled a total of 3119 patients from February 2012 to March 2013, with full data on clinical subtype available for 3049 patients (40.4% female; mean age 68.8 years). Common comorbidities were hypertension, coronary disease, and heart failure. Lone AF was present in only 3.9% (122 patients). Asymptomatic AF was common, particularly among those with permanent AF. Amiodarone was the most common antiarrhythmic agent used (~20%), while beta-blockers and digoxin were the most used rate control drugs. Oral anticoagulants (OACs) were used in 80% overall, most often vitamin K antagonists (71.6%), with novel OACs being used in 8.4%. Other antithrombotics (mostly antiplatelet therapy, especially aspirin) were still used in one-third of the patients, and no antithrombotic treatment in only 4.8%. Oral anticoagulants were used in 56.4% of CHA 2DS2-VASc = 0, with 26.3% having no antithrombotic therapy. A high HAS-BLED score was not used to exclude OAC use, but there was a trend towards more aspirin use in the presence of a high HAS-BLED score. Conclusion: The EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry has provided systematic collection of contemporary data regarding the management and treatment of AF by cardiologists in ESC member countries. Oral anticoagulant use has increased, but novel OAC use was still low. Compliance with the treatment guidelines for patients with the lowest and higher stroke risk scores remains suboptimal. © The Author 2013

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

Towards a Quantitative Analysis of Security Protocols

This paper contributes to further closing the gap between formal analysis and concrete implementations of security protocols by introducing a quantitative extension of the usual Dolev-Yao intruder model. This extended model provides a basis for considering protocol attacks that are possible when the intruder has a reasonable amount of computational power, in particular when he is able, with a certain probability, to guess encryption keys or other particular kind of data such as the body of a hashed message. We also show that these extensions do not augment the computational complexity of the protocol insecurity problem in the case of a finite number of interleaved protocol sessions

Incorporating free-flowing rivers into global biodiversity targets : prioritization and targeted interventions to maintain ecological integrity

DATA AVAILABILITY STATEMENT : The data that support the findings of this study are available from the corresponding author upon reasonable request.SUPPLEMENTARY MATERIAL : TABLE S1. An overview of existing data used with resolution, date, source, and the subsequent data derived. TABLE S2. Free-flowing rivers in South Africa with IDs. The bold italics indicate flagship free-flowing rivers.Free-flowing rivers (FFRs) are important surrogates for freshwater biodiversity as there are increasingly fewer rivers that reflect intact habitat and species diversity from source to sea. The status and changes in the ecological condition or protection of FFRs is not explicitly reported on in global biodiversity targets. Indices are proposed for reporting such changes to the Sustainable Development Goals (SDGs) 6 and 15, Aichi Target 11, and the post-2020 global biodiversity framework. FFRs were identified at a countrywide scale in South Africa for protection, planning, monitoring, and assessing changes in their ecological condition and protection status. They were selected and prioritized using criteria co-produced with national, provincial, and local river managers and policy makers. Given the high competition for water resources and the unlikely possibility for strictly protecting all FFRs, a subset of FFRs, termed ‘flagship FFRs’, was identified. Methods for reporting changes in the protection levels of prioritized FFRs at a countrywide scale were developed, which included indices of FFRs related to global targets: the loss of the extent of FFRs in a natural and largely natural ecological condition for SDG 6; changes in the connectivity of FFRs included in the post-2020 global biodiversity framework targets; and changes in protection levels of FFRs for Aichi Target 11 and SDG 15.1.2. Flagship FFRs attracted targeted management initiatives and thus maintained their connectivity and ecological condition. This was not true when all FFRs were considered; in the broader set of FFRs, longitudinal fragmentation increased and ecological condition declined from 2011 to 2018. Considering the increasing pressures rivers are likely to experience from human and climate change impacts, particularly in semi-arid to temperate environments, urgent prioritization and monitoring of FFRs is called for so that a targeted set of protection and management strategies can be applied.CSIR- Parliamentary Grant Funding and South African National Biodiversity Institute (SANBI).http://wileyonlinelibrary.com/journal/aqc2023-12-01hj2023Geography, Geoinformatics and MeteorologySDG-06:Clean water and sanitationSDG-15:Life on lan

Review of available data for a South African Inventory of Inland Aquatic Ecosystems (SAIIAE)

The National Biodiversity Assessment of 2011 found freshwater ecosystems to be highly threatened and poorly protected. However, a number of studies have shown that the National Wetland Map (NWM) Version 4 represents less than 54% of wetlands mapped at a fine scale. A more comprehensive South African Inventory of Inland Aquatic Ecosystems (SAIIAE) would greatly improve the assessment of wetland ecosystem types and their condition and conservation status, and is crucial for monitoring trends to inform decision making and planning. In preparation for the third National Biodiversity Assessment of 2018, a review was undertaken to identify possible data sources that could contribute to the SAIIAE. The objectives of the study were to (i) assess which type of information is available for developing a SAIIAE; and (ii) list and understand the availability of fine-scale wetland data for updating the NWM. A variety of data related to species occurrence and distribution, extent and type of inland wetlands and rivers, as well as datasets which describe regional settings of inland aquatic ecosystems, were found across a number of institutions. Fine-scale spatial data amounted to more than double the extent of inland wetlands mapped by remote sensing at a country-wide scale. Nearly 5 million ha of fine-scale data were collected from a diverse number of institutions, with the majority (73%) of these data mapped by Government (3 681 503 ha or 3% of South Africa). It is estimated that < 8% of the sub-quaternary catchments of South Africa had complete wetland data sets, primarily in the Gauteng, Mpumalanga and Western Cape Provinces. Accuracy assessment reports and confidence ratings were however not consistently available for the wetland datasets. Inland wetlands in the majority of South Africa (84%) therefore remain poorly represented. We recommend future steps to improve the SAIIAE, including improving the representation of inland wetland ecosystem types and focusing on accuracy assessment