Potential Reversibility Research Articles

China's public health initiatives for climate change adaptation.

China's health gains over the past decades face potential reversals if climate change adaptation is not prioritized. China's temperature rise surpasses the global average due to urban heat islands and ecological changes, and demands urgent actions to safeguard public health. Effective adaptation need to consider China's urbanization trends, underlying non-communicable diseases, an aging population, and future pandemic threats. Climate change adaptation initiatives and strategies include urban green space, healthy indoor environments, spatial planning for cities, advance location-specific early warning systems for extreme weather events, and a holistic approach for linking carbon neutrality to health co-benefits. Innovation and technology uptake is a crucial opportunity. China's successful climate adaptation can foster international collaboration regionally and beyond.

Assessing the combined effects of local climate and mounting configuration on the electrical and thermal performance of photovoltaic systems. Application to the greater Sydney area

Extremely high urban temperatures adversely affect photovoltaic (PV) system performance. Accurate PV cell temperature assessment relies on local weather conditions, exacerbated by urban overheating, often overlooked by inadequate temperature models and non-local data. This study investigates the electrical and thermal PV performance, considering mounting configurations and local conditions. Data from ten weather stations in Greater Sydney (NSW) during 2016–2017, including a hot summer, are used. The Sandia model is used to predict cell temperatures and power output for four mounting configurations, from open rack to building-integrated (BIPV). A PV thermal model is implemented to analyse daytime convection, crucial for understanding PV impact on local climate. Results show peak cell temperatures of 60 °C (open rack) to over 90 °C (BIPV), causing up to 50% power loss and 11% reduction in monthly performance ratio. Local climate variations impact PV energy output up to 6%, with mounting configuration effects up to 11%. Daytime convective flux averages 150–180 W/m2, peaking at 700 W/m2. Convective release varies up to 22% based on local climate, generally higher for open rack than close roof mounts, with potential reversals under low wind speed conditions. These findings can improve the knowledge of PV performances in urban areas facing extreme temperatures.

Carbon source priority and availability limit bidirectional electron transfer in freshwater mixed culture electrochemically active bacterial biofilms

This study investigated, if a mixed electroactive bacterial (EAB) culture cultivated heterotrophically at a positive applied potential could be adapted from oxidative to reductive or bidirectional extracellular electron transfer (EET). To this end, a periodic potential reversal regime between − 0.5 and 0.2 V vs. Ag/AgCl was applied. This yielded biofilm detachment and mediated electroautotrophic EET in combination with carbonate, i.e., dissolved CO2, as the sole carbon source, whereby the emerged mixed culture (S1) contained previously unknown EAB. Using acetate (S2) as well as a mixture of acetate and carbonate (S3) as the main carbon sources yielded primarily alternating electrogenic organoheterotropic metabolism with the higher maximum oxidation current densities recorded for mixed carbon media, exceeding on average 1 mA cm−2. More frequent periodic polarization reversal resulted in the increase of maximum oxidative current densities by about 50% for S2-BES and 80% for S3-BES, in comparison to half-batch polarization. The EAB mixed cultures developed accordingly, with S1 represented by mostly aerobes (84.8%) and being very different in composition to S2 and S3, dominated by anaerobes (96.9 and 96.5%, respectively). S2 and S3 biofilms remained attached to the electrodes. There was only minor evidence of fully reversible bidirectional EET. In conclusion the three triplicates fed with organic and/or inorganic carbon sources demonstrated two forms of diauxie: Firstly, S1-BES showed a preference for the electrode as the electron donor via mediated EET. Secondly, S2-BES and S3-BES showed a preference for acetate as electron donor and c-source, as long as this was available, switching to CO2 reduction, when acetate was depleted.Graphical

Application of hydroxyethylidene diphosphonic acid as a depressant for efficient pyrite separation from serpentine: a performance and mechanistic study

Hydroxyethylidene diphosphonic acid (HEDP) is an industrial environmental reagent, often used as a chemical raw material in industrial water treatment, household cleaning products and personal care products. In this work, the effort to use HEDP to the flotation of pyrite containing fine-grained serpentine was conducted, and the selective separation of serpentine and pyrite was accomplished. During the flotation process, the introduction of 30 mg/L HEDP resulted in a rapid increase and recovery of 89% pyrite recovery at pH 9 under deteriorated conditions. The results of the micro-flotation method showed how well HEDP was selectively inhibited in the pyrite-serpentine flotation separation process. On the basis of a number of measures, including ICP-OES tests, Zeta potential testing, Scanning electron microscopy (SEM) characterization, and X-ray photoelectron spectroscopy (XPS) analysis, it was discovered that a substantial amount of HEDP was selectively adsorbed on the serpentine surface by chemically chelating with the Mg active site. In contrast, the adsorption of HEDP on the surface of pyrite was almost negligible. HEDP prefers to adsorb on the positively charged serpentine surface in the form of H5C2P2O73- negative charge, while accelerating the release of Mg from the serpentine surface into the solution by forming Mg3[H5C2P2O7]2 hydrophilic chelate. Both of these effects remarkably contribute to the reversal of the serpentine surface potential to a negative potential. Due to electrostatic repulsion, the hetero-coagulation of negatively charged serpentine and negatively charged pyrite was broken, and the selective collecting capability of the PBX collector on the surface of pyrite was regained, allowing for the selective separation of pyrite and serpentine minerals. The application of HEDP in the actual ore (Peru copper ore BM1-type sample) sorting further demonstrated its good selective inhibition effect, and HEDP was able to enhance the grade and recovery of Cu and S in the concentrate while ensuring the reduction of Mg grade and recovery.

Routine Endoscopy Prior to Surgical Ostomy Closure: An Obsolete Concept

BackgroundClosure of temporary diverting ostomies is commonly preceded by an endoscopic study of the colonic mucosa and anastomosis, despite lacking evidence of its relevance and impact on subsequent operative management.AimWe sought to determine the incidence of pathological findings and therefore evaluate the clinical benefit of routine pre-operative endoscopy in asymptomatic patients, hypothesizing sole evaluation of the anastomotic integrity to be sufficient in these cases.MethodsWe retrospectively identified all adult patients with ostomy installations who were followed up for potential reversal surgery between 2002 and 2020 at the University Hospital of Zurich, Switzerland. Main outcome measures were the incidence of endoscopically identified pathological findings in the asymptomatic case cohort and their impact on the subsequent course of treatment.ResultsPre-procedural endoscopic data of 187 cases evaluated for ostomy closure were evaluated. Relevant mucosal findings in the asymptomatic cohort were documented in 26.3% and findings at the anastomotic site detected in 8.7%. A change in subsequent surgical management was noted in 10 patients of the entire cohort (5.3%) and in 9 (5.1%) of all asymptomatic cases. Upon multivariate analyses, the age range of 51 to 60 years old was found to be significantly linked to the presence of endoscopic findings entailing a change in patient management.ConclusionOur findings strongly suggest ostomy closure surgery without previous assessment of the bowel mucosa by means of endoscopy to be acceptable in asymptomatic patients. However, we found it to be indicated in all patients meeting the screening criteria for colorectal carcinoma.

Modelling the Effect of Matrix Metalloproteinases in Dermal Wound Healing

With over 2 million people in the UK suffering from chronic wounds, understanding the biochemistry and pharmacology that underpins these wounds and wound healing is of high importance. Chronic wounds are characterised by high levels of matrix metalloproteinases (MMPs), which are necessary for the modification of healthy tissue in the healing process. Overexposure of MMPs, however, adversely affects healing of the wound by causing further destruction of the surrounding extracellular matrix. In this work, we propose a mathematical model that focuses on the interaction of MMPs with dermal cells using a system of partial differential equations. Using biologically realistic parameter values, this model gives rise to travelling waves corresponding to a front of healthy cells invading a wound. From the arising travelling wave analysis, we observe that deregulated apoptosis results in the emergence of chronic wounds, characterised by elevated MMP concentrations. We also observe hysteresis effects when both the apoptotic rate and MMP production rate are varied, providing further insight into the management (and potential reversal) of chronic wounds.

Deposition behaviors of carboxyl-modified polystyrene nanoplastics with goethite in aquatic environment: Effects of solution chemistry and organic macromolecules

The ubiquitous nanoplastics (NPs) in the environment are emerging contaminants due to their risks to human health and ecosystems. The interaction between NPs and minerals determines the environmental and ecological risks of NPs. In this study, the deposition behaviors of carboxyl modified polystyrene nanoplastics (COOH-PSNPs) with goethite (α-FeOOH) were systematically investigated under various solution chemistry and organic macromolecules (OMs) conditions (i.e., pH, ionic type, humic acid (HA), sodium alginate (SA), and bovine serum albumin (BSA)). The study found that electrostatic interactions dominated the interaction between COOH-PSNPs and goethite. The deposition rates of COOH-PSNPs decreased with an increase in solution pH, due to the enhanced electrostatic repulsion by higher pH. Introducing cations or anions could compress the electrostatic double layers and compete for interaction sites on COOH-PSNPs and goethite, thereby reducing the deposition rates of COOH-PSNPs. The stabilization effects, which were positive with ions valence, followed the orders of NaCl ≈ KCl < CaCl2, NaNO3 ≈ NaCl < Na2SO4 < Na3PO4. Specific adsorption of SO42− or H2PO4− caused a potential reversal of goethite from positive to negative, leading to the electrostatic forces between COOH-PSNPs and goethite changed from attraction to repulsion, and thus significantly decreasing deposition of COOH-PSNPs. Organic macromolecules could markedly inhibit the deposition of COOH-PSNPs with goethite because of enhanced electrostatic repulsion, steric hindrance, and competition of surface binding sites. The ability for inhibiting the deposition of COOH-PSNPs followed the sequence of SA > HA > BSA, which was related to their structure (SA: linear, semi-flexible, HA: globular, semi-rigid, BSA: globular, with protein tertiary structure) and surface charge density (SA > HA > BSA). The results of this study highlight the complexity of the interactions between NPs and minerals under different environments and provide valuable insights in understanding transport mechanisms and environmental fate of nanoplastics in aquatic environments.

Adsorption and Electropolymerization of p-Aminophenol Reduces Reproducibility of Electrochemical Immunoassays

Electrochemical immunoassays are a class of biosensors that achieve high specificity, low detection limits, and low cost attributed to strong antibody-antigen interactions and inexpensive electrochemical instrumentation. Electrochemical assays typically use an enzyme/substrate pair to enable electrochemical signal production. p-Aminophenyl phosphate is a commonly used enzymatic substrate which is hydrolyzed into p-aminophenol (PAP)by alkaline phosphatase. PAP exhibits low oxidation potential and electrochemical reversibility, making it an appealing candidate for assay design. The electrochemical oxidative signal from PAP is increased by its adsorption to the electrode. This is further confirmed by the prevention of PAP adsorption via self-assembled monolayers on gold electrodes reducing PAP’s oxidative current. On bare screen-printed electrodes (SPE), PAP adsorption results in oxidative current variability depending on the electroactive surface area of the working electrode. This variability could not be remedied by cleaning and reusing the same gold SPE. However, adsorption of PAP displays concentration dependence, as the decrease ofthe PAP concentration to 3.8 μM greatly improved the consistency of the measurements. PAP use is also limited in continuous monitoring applications as multiple PAP oxidations on the same electrode caused polymerization. The results from this study suggest that the use of PAP production in immunoassays with SPEs must be fine-tuned and electrodes must be cleaned or disposed of between measurements.

The Farmer, the Influencer, and the Labors of Rural Self-Media

ABSTRACT The genre of Chinese rural “self-” or “we-media” (zi meiti) has drawn ire for “spectacularizing” the “rural lifescape” for urban consumers of China’s rapidly developing platform economy. This article focuses instead on how the videos of Li Ziqi and Qiaofu Jiumei recenter production as a key visual force in global capitalism. By depicting the dynamic reciprocities between traditionally rural, artisanal or craft-based, and immaterial or affective labor, and—on the other hand—more ostensibly commercial farm work and e-commerce, Chinese microcelebrities show that different labor relations can dialectically coexist and overlap under contemporary state capitalism despite developments in productivity and automation that impute a historical directionality to the nature of work. The article discusses this in relation to the historical context and theoretical design of the People’s Republic of China’s recent Rural Revitalization strategic plan, as well as the country’s growing platform economy. Belying Li’s aestheticized portrayal of craftsmanship and self-sufficiency is the notorious non-appearing of alienated labor, private property, and the continuous expropriation of nature—but also their potential reversibility. Jiumei’s candid depictions of rural e-commerce evidence rural platformization’s value-extraction; and yet, perceptible in her comparatively more impoverished images are hints of the return of more conventional forms of work.

Longitudinal Analysis of Pulmonary Function Impairment One Year Post-COVID-19: A Single-Center Study.

Persistent pulmonary impairment post-COVID-19 has been reported, albeit variably. This single-center observational study aims to longitudinally evaluate pulmonary function in 140 COVID-19 survivors one year after recovery, assessing associations with disease severity and pre-existing lung conditions. Participants aged 18 and older, with confirmed SARS-CoV-2 infection, were evaluated using spirometry and Diffusion Capacity of Lungs for Carbon Monoxide (DLCO) tests. Pulmonary function parameters like Forced Expiratory Volume at 1 s (FEV1), Forced Vital Capacity (FVC), and Total Lung Capacity (TLC) were measured. Participants were stratified by age, gender, body mass index, smoking status, and lung damage severity via computed tomography (CT). The cohort consisted of mostly males (58.6%), with a mean age of 53.8 years and body mass index of 24.9 kg/m2. Post-COVID fibrosis was seen in 22.7%, 27.3%, and 51.9% of mild, moderate, and severe disease patients, respectively (p = 0.003). FVC significantly reduced with disease severity (p < 0.001), while FEV1, FEF25-75, and DLCO showed a non-significant downward trend. FEV1/FVC ratio increased with disease severity (p = 0.033), and TLC and RV significantly declined (p = 0.023 and p = 0.003, respectively). A one-year follow-up indicated a non-significant change in FVC, FEV1, FEV1/FVC ratio, FEF25-75, and RV compared with the 40-day measurement, but it revealed significant improvements in DLCO and TLC (p = 0.010). There were significant mean increases in FVC, FEV1, DLCO, TLC, and RV across all disease severities over one year. They were most pronounced in the patients with a history of severe COVID-19, who had a better recovery over one year, compared with the mild and moderate COVID-19 patients whose lung function almost normalized. One year after the SARS-CoV-2 infection, we observed a significant association between disease severity and post-COVID fibrotic changes. Though some lung function parameters remained stable over the year, significant improvements were noted in DLCO and TLC. Particularly, individuals with severe disease showed substantial recovery in lung function, indicating the potential reversibility of COVID-19-related pulmonary damage.

Investigating Risk Factors and Magnetic Resonance Imaging (MRI)-Based Grading of Subchondral Incomplete Fracture (SIF) of Medial Femoral Condyle.

Subchondral insufficiency fractures (SIF) of the knee joint are prevalent in osteoporosis patients over the age of 55. Early diagnosis of SIF fracture of the medial femoral condyle is crucial for delaying disease progression, early therapy, and potential disease reversal. Magnetic resonance imaging (MRI) is useful in detecting SIF, which is often undetectable on initial radiographs. This study aimed at developing a grading system for subchondral insufficiency fractures (SIF) based on MRI to predict outcomes and evaluate risk factors. In this study, MRI was used to examine SIF risk variables in the medial condyle of the femur to help clinicians diagnose, treat, and delay the condition. A total of 386 patients with SIF from 2019 to 2021 were retrospectively analyzed and divided into 106 patients in the disease group and 280 patients in the control group according to whether they had SIF. The lesion site, meniscus, ligament, and other parameters were evaluated and compared. At the same time, a grading system was introduced to stratify and statistically analyze the size of the lesion area, the degree of bone marrow edema (BME), meniscus tears, and other parameters in the patients. Most SIF were low-grade (LG) fractures, and the predictors of LG and high-grade (HG) fractures included heel tear (P =0.031), degree of medial malleolus degeneration (P < 0.001), advanced age (P < 0.001), and lesion size (P < 0.001). The prognostic factors that showed significant differences between the two groups included age (P =0.027), gender (P =0.005), side (P =0.005), medial tibial plateau injury (P < 0.0001), femoral medullary bone marrow edema (P < 0.0001), medial tibial plateau bone marrow edema (P < 0.0001), meniscus body partial injury (P =0.016), heel tear (P =0.001), anterior cruciate ligament injury (P =0.002), and medial collateral ligament injury (P < 0.0001). This current study proposed an MRI-based grading system for inferior condylar fractures of the femur, in which HG inferior condylar fractures are associated with severe medial malleolus degeneration, advanced age, lesion size (correlation), and meniscus heel tears.

Reliability of the g factor over time in Italian INVALSI data (2010-2022): What can achievement-g tell us about the Flynn effect?

Generational intelligence test score gains over large parts of the 20th century have been observed to be negatively associated with psychometric g. Recent reports about changes in the cross-temporal IQ trajectory suggest that ability differentiation may be responsible for both changes in g as well as increasingly (sub-)domain-specific and inconsistent trajectories. Schooling is considered to be a main candidate cause for the Flynn effect, which suggests that school achievement might be expected to show similar cross-temporal developments. In the present study, we investigated evidence for cross-temporal changes in achievement-based g in a formal large-scale student assessment in Italy (i.e., the INVALSI assessment; N = 1,900,000+). Based on data of four school grades (i.e., grades 2, 5, 8, and 10) over 13 years (2010–2022), we observed little evidence for changes in achievement g in general. However, cross-temporal trajectories were differentiated according to school grade, indicating cross-temporal g decreases for lower grade students whilst changes for higher grade students were positive. These findings may be interpreted as tentative evidence for age-dependent achievement-g differentiation. The presently observed achievement g trajectory appears to be consistent with recently observed evidence for a potential stagnation or reversal of cognitive test score gains.

Protection of Substation Grounding Grid by Gadolinium Magnesium Sacrificial Anode

Abstract Since lower galvanic efficiency and potential reversal might occur in magnesium (Mg) sacrificial anode applied in anti-corrosion project for grounding grid in substation, rare earth gadolinium (Gd) was incorporated into Mg sacrificial anode material for activating and improving the performance of the anode, and the influence of Gd concentration on properties of Mg sacrificial anode was evaluated by electrochemical method. The results revealed that the incorporation of Gd could effectively improve the electrochemical properties of magnesium sacrificial anode. The present of 0.1%(wt) Gd in the anode caused the best electrochemical properties as follows: the OCP decreased to as low as -1.78V (SEC) while the galvanic efficiency increased to as high as 62%, and the minimal anodic corrosion current, 0.0186mA, was realized, also the reverse potential and current density in DC leakage process increased from 500mV to 900mV and 1mA/dm2 to 2.27mA/dm2, respectively.

Regional impairment of left ventricular longitudinal strain in aortic regurgitation: have we found the missing piece?

Abstract Funding Acknowledgements Type of funding sources: None. Background Aortic regurgitation (AR) has been shown to have an impact on myocardial mechanics and recent studies have proved the value of global longitudinal strain (GLS) as an additional parameter in the assessment of disease severity and prognosis. However, a direct and localized influence of the regurgitant jet (RJ) on regional deformation has not yet been demonstrated. Purpose To assess if there is a regional pattern of longitudinal strain (LS) impairment in AR connected to the direction of the RJ, as well as its potential reversibility and prognostic impact. Methods We studied patients (pts) with chronic moderate and severe isolated AR referred for echocardiographic evaluation. For each patient, we established the direction of the RJ according to the myocardial segments impacted by its turbulent portion. Pts were considered to have a jet-related LS reduction (JRSR) when the wall segments impacted by the jet had a relative reduction in LS of at least 30% compared to non-affected segments. Parameters of AR severity and left ventricular size and function were assessed. For those who underwent surgical correction of AR, the postop TTE was also compared with the preop. Results Of the 203 AR pts screened, 80 met inclusion criteria (median age 57 years, 83% male). Mean GLS and ejection fraction (EF) were -16% and 54%, respectively. In 34 of the 80 pts, there was a regional reduction of 10 percentage points in the absolute value of LS in the segments impacted by the jet, compared to non-affected segments (median −8% vs −18%, p&amp;lt;0.001), corresponding to a 56% relative decrease. The predominant jet directions were towards the basal septum (44%), mid posterior/mid lateral segments (24%), and basal inferior segment (12%). Demographics, severity of AR and parameters of systolic and diastolic function did not significantly differ between those who had JRSR or not. Of the 34 pts with JRSR, 20 underwent corrective surgery. In an early postop TTE, the difference in LS between the segments impacted by the jet and the non-affected segments attenuated (4.7% absolute difference vs 10% in the preop TTE, p = 0.001). Pts with JRSR in the preop echo had lower rates of improvement of GLS (11 vs 46% of pts improved at least 2.5%, p = 0.043) and a tendency towards lower rates of recovery of EF after surgery (17% vs 46% recovered at least 5% in EF, p = 0.07). Conclusion This study identifies an association between the parietal impact of the RJ in AR and regional LS impairment. It suggests that external factors such as blood flow dynamics affect myocardial deformation. Additionally, the longstanding impact of the jet might damage the myocardium to the point of limiting recovery of systolic function after corrective surgery. This is, to our knowledge, the first reported case series showing the negative effect of the jet’s impact on LV longitudinal function and, most importantly, on postop outcomes. Longer follow-up is needed to confirm its prognostic role.

Progresses and Perspectives of All‐Iron Aqueous Redox Flow Batteries

AbstractRedox flow batteries (RFBs) are a promising option for long‐duration energy storage (LDES) due to their stability, scalability, and potential reversibility. However, solid‐state and non‐aqueous flow batteries have low safety and low conductivity, while aqueous systems using vanadium and zinc are expensive and have low power and energy densities, limiting their industrial application. An approach to lower capital cost and improve scalability is to utilize cheap Earth‐abundant metals such as iron (Fe). Nevertheless, all‐iron RFBs have many complications, involving voltage loss from ohmic resistance, side reactions such as hydrogen evolution, oxidation, and most significantly electrode plating, and dendrite growth. To address these issues, researchers have begun to examine the effects of various alterations to all‐iron RFBs, such as adding organic ligands to form Fe complexes and using a slurry electrode instead of common materials such as graphite or platinum rods. Overall, progress in improving aqueous all‐iron RFBs is at its infant stage, and new strategies must be introduced, such as the utilization of nanoparticles, which can limit dendrite growth while increasing storage capacity. This review provides an in‐depth overview of current research and offers perspectives on how to design the next generation of all‐iron aqueous RFBs.

Impact of temperature, pH value and multiple ions on the physisorption of chloride ion on C-S-H gel surface

Calcium silicate hydrate (C-S-H) gel, as the main hydration phase of cement, intensely influences the penetration and diffusion of chloride ions (Cl-) by interacting with multiple ions in diverse environments, affecting the durability of reinforced concrete. However, the adsorption mechanism and critical influence factor are indistinct. To reveal the micro/nano mechanism of the adsorption characteristics for Cl-, a comprehensive investigation was conducted, which included ion adsorption experiments, thermodynamic calculations, and molecular dynamic simulations. In contrast to the prevailing opinion that Ca2+ is a potential determining ion in cement paste systems. The results indicate that pH value and concentration of Ca2+ are the partner to determine the Cl- adsorption capacity and potential reversal of C-S-H gels. They are unable to function in isolation from each other. It should be mentioned that OH− is more important than Ca2+ for ions adsorption of C-S-H gels. Compared with Ca2+, the compensation of Na+ on the surface charge and the promotion of Cl- adsorption is limited. SO42- competes for adsorption sites with Cl-, and forms Na-SO4 clusters to inhibit the diffusion and adsorption of Cl-. Furthermore, elevated temperature not only promotes the thermal movement of ions but also decreases the Ca2+ concentration and pH value. Consequently, the activity of SiOH sites is lessened, and ions are subjected to weaker constraints by the gel, resulting in the decline of Cl- adsorption capacity. Moreover, theoretical models for calculating the amount of chloride adsorbed by the C-S-H gels are proposed from the perspectives of thermodynamics and dynamics, and the simulation results are in agreement with the experiment results.

Design, Synthesis, and Biological Evaluation of Marine Lissodendrins B Analogues as Modulators of ABCB1-Mediated Multidrug Resistance

Multidrug resistance (MDR) caused by ATP-Binding Cassette Subfamily B Member 1 (ABCB1, P-glycoprotein, P-gp) is a major barrier for the success of chemotherapy in clinics. In this study, we designed and synthesized a total of 19 Lissodendrins B analogues and tested their ABCB1-mediated MDR reversal activity in doxorubicin (DOX)-resistant K562/ADR and MCF-7/ADR cells. Among all derivatives, compounds D1, D2, and D4 with a dimethoxy-substituted tetrahydroisoquinoline fragment possessed potent synergistic effects with DOX and reversed ABCB1-mediated drug resistance. Notably, the most potent compound D1 merits multiple activities, including low cytotoxicity, the strongest synergistic effect, and effectively reversing ABCB1-mediated drug resistance of K562/ADR (RF = 1845.76) and MCF-7/ADR cells (RF = 207.86) to DOX. As a reference substance, compound D1 allows for additional mechanistic studies on ABCB1 inhibition. The synergistic mechanisms were mainly related to the increased intracellular accumulation of DOX via inhibiting the efflux function of ABCB1 rather than from affecting the expression level of ABCB1. These studies suggest that compound D1 and its derivatives might be potential MDR reversal agents acting as ABCB1 inhibitors in clinical therapeutics and provide insight into a design strategy for the development of ABCB1 inhibitors.

OKL-1111, A modified cyclodextrin as a potential universal reversal agent for anticoagulants

BackgroundAntithrombotic therapy is inevitably associated with a risk for bleeding and these bleeding complications can be life-threatening. Recently, specific reversal agents were developed for the direct factor Xa and thrombin inhibitors (DOACs). However, next to the fact that these agents are relatively expensive, the use of selective reversal agents complicates treatment of bleeding patients in practice. In a series of screening experiments, we discovered a class of cyclodextrins with procoagulant properties. In this study we characterize a lead compound, OKL-1111, and demonstrate its potential use as a universal reversal agent. ObjectivesTo assess the anticoagulant reversal properties of OKL-1111, in vitro and in vivo. MethodsThe effect of OKL-1111 on coagulation in the absence and presence of DOACs was investigated in a thrombin generation assay. Its reversal effect on a variety of anticoagulants in vivo was investigated in a rat tail cut bleeding model. A possible prothrombotic action of OKL-1111 was assessed in a Wessler model in rabbits. ResultsOKL-1111 concentration-dependently reversed the in vitro anticoagulant effects of dabigatran, rivaroxaban, apixaban and edoxaban in the thrombin generation assay. Also in the absence of a DOAC, OKL-1111 concentration-dependently accelerated coagulation in this assay, but did not initiate coagulation. The reversal effect was also seen for all DOACs in the rat tail cut bleeding model. In addition, when tested with other anticoagulants, OKL-1111 also reversed the anticoagulant effect of the vitamin K antagonist warfarin, the low molecular weight heparin enoxaparin, the pentasaccharide fondaparinux and the platelet inhibitor clopidogrel in vivo. OKL-1111 did not have prothrombotic effects in the Wessler model. ConclusionOKL-1111 is a procoagulant cyclodextrin with a currently unknown working mechanism that has potential to become a universal reversal agent for anticoagulants and platelet inhibitors.

Energy Dynamics in Chronic Heart Failure, Chronic Kidney Disease &amp; the Cardiorenal Syndrome: A New Causal Paradigm

In this paper we examine HF and CKD through the lens of a new causal paradigm: as a conjoined energy deficiency syndrome whose progression is governed by impaired energy generation by the cardiovascular system leading to subsequent deterioration of blood energy dynamics. Due to the immense complexity of this topic our intention is not to go into unnecessary and laborious detail on specific cellular and molecular aspects of the syndromes but, instead, to use illustrative examples to establish overarching principles and to highlight the connection between the deteriorating energy field and all resultant aberrations. Indeed, once the energy dynamics are recognized cellular and molecular descriptions become superfluous. Our use of the term 'causal' is meant to imply that future breakthroughs in the treatment (and potential reversal) of these complex disease states necessarily entails recognition and correction of underlying energy deficits.

New Uracil Analog with Exocyclic Methylidene Group Can Reverse Resistance to Taxol in MCF-7 Cancer Cells.

Taxol (Tx), a microtubule-stabilizing drug, has been widely used as a chemotherapeutic in several types of cancer. However, the development of resistance limited its application. One of the strategies used to prevent the emergence of drug resistance is combination treatment, involving at least two drugs. The aim of the current study was to assess if a new uracil analog, 3-p-bromophenyl-1-ethyl-5-methylidenedihydrouracil (U-359) can prevent the development of Tx resistance in breast cancer cells. The cytotoxicity of the new drug was tested in MCF-7 (hormone receptor (ER, PR) positive cell-line) and MCF-10A cell lines using MTT method. For the detection of apoptosis and necrosis, the Wright and Giemsa staining was used. Gene expression was measured by real-time PCR, and changes in the protein levels were evaluated by ELISA and bioluminescent method. We investigated the effect of Tx and U-359 on cancer MCF-7 and normal MCF-10A cells alone and in combination. Tx co-administered with U-359 inhibited proliferation of MCF-7 cells to 7% while the level of ATPase drastically decreased to 14%, compared with effects produced by Tx alone. The apoptosis process was induced through the mitochondrial pathway. These effects were not seen in MCF-10A cells, showing the wide safety margin. The obtained results have shown that U-359 produced a synergistic effect with Tx probably by reducing Tx resistance in MCF-7 cells. To elucidate the possible mechanism of resistance, expression of tubulin III (TUBIII), responsible for microtubule stabilization and tau and Nlp proteins, responsible for microtubule dynamics, was assessed. Combination of Tx with U-359 reduced overexpression of TUBIII and Nlp. Thus, U-359 may stand for a potential reversal agent for the treatment of MDR in cancer cells.