Doxorubicin Impairs Smooth Muscle Cell Contraction: Novel Insights in Vascular Toxicity

Clinical and animal studies have demonstrated that chemotherapeutic doxorubicin (DOX) increases arterial stiffness, a predictor of cardiovascular risk. Despite consensus about DOX-impaired endothelium-dependent vasodilation as a contributing mechanism, some studies have reported conflicting results on vascular smooth muscle cell (VSMC) function after DOX treatment. The present study aimed to investigate the effects of DOX on VSMC function. To this end, mice received a single injection of 4 mg DOX/kg, or mouse aortic segments were treated ex vivo with 1 μM DOX, followed by vascular reactivity evaluation 16 h later. Phenylephrine (PE)-induced VSMC contraction was decreased after DOX treatment. DOX did not affect the transient PE contraction dependent on Ca²⁺ release from the sarcoplasmic reticulum (0 mM Ca²⁺), but it reduced the subsequent tonic phase characterised by Ca²⁺ influx. These findings were supported by similar angiotensin II and attenuated endothelin-1 contractions. The involvement of voltage-gated Ca²⁺ channels in DOX-decreased contraction was excluded by using levcromakalim and diltiazem in PE-induced contraction and corroborated by similar K⁺ and serotonin contractions. Despite the evaluation of multiple blockers of transient receptor potential channels, the exact mechanism for DOX-decreased VSMC contraction remains elusive. Surprisingly, DOX reduced ex vivo but not in vivo arterial stiffness, highlighting the importance of appropriate timing for evaluating arterial stiffness in DOX-treated patients.     

Novel KCND3 Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt KV4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties

KCND3 encodes the voltage-gated potassium channel K_V4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function K_V4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the K_V4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of K_V4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. K_V4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.     

SUL-151 Decreases Airway Neutrophilia as a Prophylactic and Therapeutic Treatment in Mice after Cigarette Smoke Exposure

Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 μg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment.     

High Mobility Group Box 1 Protein in Cerebral Thromboemboli

High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7% (IQR 0.6–6.2%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.     

Tobacco use in six economically disadvantaged communities in the Dominican Republic.

The Dominican Republic is a tobacco-growing country, and tobacco control efforts there have been virtually nonexistent. This study provides a first systematic surveillance of tobacco use in six economically disadvantaged Dominican Republic communities (two small urban, two peri-urban, two rural; half were tobacco growing). Approximately 175 households were randomly selected in each community (total N = 1,048), and an adult household member reported on household demographics and resources (e.g., electricity), tobacco use and health conditions of household members, and household policies on tobacco use. Poverty and unemployment were high in all communities, and significant gaps in access to basic resources such as electricity, running water, telephones/cell phones, and secondary education were present. Exposure to tobacco smoke was high, with 38.4% of households reporting at least one tobacco user, and 75.5% allowing smoking in the home. Overall, 22.5% reported using tobacco, with commercial cigarettes (58.0%) or self-rolled cigarettes (20.1%) the most commonly used types. Considerable variability in prevalence and type of use was found across communities. Overall, tobacco use was higher in males, illiterate groups, those aged 45 or older, rural dwellers, and tobacco-growing communities. Based on reported health conditions, tobacco attributable risks, and World Health Organization mortality data, it is estimated that at least 2,254 lives could potentially be saved each year in the Dominican Republic with tobacco cessation. Although it is expected that the reported prevalence of tobacco use and health conditions represent underestimates, these figures provide a starting point for understanding tobacco use and its prevalence in the Dominican Republic.     

Mass propagation and essential oil analysis of Artemisia vulgaris

Artemisia vulgaris L. (Mugwort) is a threatened and valuable medicinal plant. Attempts have been made in this research to mass propagate its plantlets through in vitro liquid culture technology using Murashige and Skoog (MS) basal medium supplemented with 6-benzyl adenine (BA) (0.44-8.88 microM). Initially, 22.6 shoots (99.9% shooting frequency) developed from shoot tip explants cultured in MS with 4.44 microM BA at 100 ml flask capacity. This was further subcultured at increasing flask capacity (150, 250, and 500 ml) for shoot proliferation. Of the different concentrations of BA and flask capacities tested, 4.44 microM BA and 500 ml flask capacity were found to produce a maximum of 85.5 shoots after 30 d of culture. Shoot proliferation was found to increase with increasing flask capacity whereas shoot number decreased with increasing BA concentration (>4.44 microM). Individual shoots were isolated and rooted on MS medium containing 8.56 microM indole-3-acetic acid (IAA). Then the plantlets were acclimatized under standard laboratory conditions and later under greenhouse conditions. Fresh leaves were collected from greenhouse-grown plants and subjected to essential oil analysis by the simultaneous distillation and extraction method. GC-MS results revealed the presence of 88 components and the extracted oil was rich in camphor (16.8%), alpha-thujone (11.3%), germacrene D (7.2%), camphene (6.5%), 1,8-cineole (5.8%) and beta-caryophyllene (5.4%). This in vitro strategy can be a reliable method for the steady production of a large number of plants for essential oil production, which is reported for the first time for A. vulgaris.     

Impact of climate change on hydropower generation in Rio Jubones Basin,Ecuador

This study attempted to use the soil and water assessment tool(SWAT), integrated with geographic information systems(GIS), for assessment of climate change impacts on hydropower generation. This methodology of climate change impact modeling was developed and demonstrated through application to a hydropower plant in the Rio Jubones Basin in Ecuador. ArcSWAT 2012 was used to develop a model for simulating the river flow. The model parameters were calibrated and validated on a monthly scale with respect to the hydro-meteorological inputs observed from 1985 to 1991 and from 1992 to 1998, respectively. Statistical analyses produced Nash-Sutcliffe efficiencies(NSEs) of 0.66 and 0.61 for model calibration and validation, respectively, which were considered acceptable. Numerical simulation with the model indicated that climate change could alter the seasonal flow regime of the basin, and the hydropower potential could change due to the changing climate in the future.Scenario analysis indicates that, though the hydropower generation will increase in the wet season, the plant will face a significant power shortage during the dry season, up to 13.14% from the reference scenario, as a consequence of a 17% reduction of streamflow under an assumption of a 2.9℃ increase in temperature and a 15% decrease in rainfall. Overall, this study showed that hydrological processes are realistically modeled with SWAT and the model can be a useful tool for predicting the impact of climate change.     

Estimating the Impact of Water Pricing on Water Use Efficiency in Semi-arid Cropping System: An Application of Probabilistically Constrained Nonparametric Efficiency Analysis

By introducing proper pricing instruments, farm level water can be used more efficient. But it demands a proper estimation strategy to analyse the efficiency and the input use behavior of farms under the new pricing system. As most production relationships are stochastic in nature, excluding random errors and noise from model specifications often leads to criticism. By using a probabilistically constrained programming formulation, an empirical estimation of stochastic data envelopment analysis (DEA) is done to analyze the efficiency of irrigation water use in the agricultural production system in the Krishna river basin, India. The results illustrate that water demand is higher for farms at, or close to the frontier and lower for those with low efficiency levels. In a second step, a simulation model is developed by using the frontier and economic efficiency derived from stochastic DEA to analyse the impact of water pricing on water use efficiency and water use behaviour. It is shown that an increase in the water price would not cause sizeable profit loss, if the pricing system is administered on a volumetric basis, but water demand would decrease substantially.     

Novel JPEG 2000 Compliant DWT and IWT VLSI Implementations

This paper proposes two JPEG 2000 compliant architectures: one for DWT (Discrete Wavelet Transform) and one for IWT (Integer Wavelet Transform) implementation. First of all some theoretical issues about DWT and IWT are discussed, then, starting from transforms characteristics, the architectures are presented showing both performance and cost. In the literature many DWT architectures have been proposed; our implementation is a new architecture that computes the DWT using filters of interest for the forthcoming JPEG 2000 standard. Moreover, we propose a Lifting Scheme based architecture for IWT, JPEG 2000 compliant too. The proposed architectures are able to support real-time streams: the DWT one, which is made of 20,000 cells, with an input throughput of 160 Msamples per second and a clock frequency of 160 MHz, the IWT one, consisting of 50,000 cells, with an input throughput of 4.5 Msamples per second and an internal clock frequency of 108 MHz.