Mitigation of Breast Cancer Cells' Invasiveness via Down Regulation of ETV7, Hippo, and PI3K/mTOR Pathways by Vitamin D3 Gold-Nanoparticles.

Metastasis in breast cancer is the major cause of death in females (about 30%). Based on our earlier observation that Vitamin D3 downregulates mTOR, we hypothesized that Vitamin D3 conjugated to gold nanoparticles (VD3-GNPs) reduces breast cancer aggressiveness by downregulating the key cancer controller PI3K/AKT/mTOR. Western blots, migration/invasion assays, and other cell-based, biophysical, and bioinformatics studies are used to study breast cancer cell aggressiveness and nanoparticle characterization. Our VD3-GNP treatment of breast cancer cells (MCF-7 and MDA-MB-231) significantly reduces the aggressiveness (cancer cell migration and invasion rates > 45%) via the simultaneous downregulation of ETV7 and the Hippo pathway. Consistent with our hypothesis, we, indeed, found a downregulation of the PI3K/AKT/mTOR pathway. It is surprising that the extremely low dose of VD3 in the nano formulation (three orders of magnitude lower than in earlier studies) is quite effective in the alteration of cancer invasiveness and cell signaling pathways. Clearly, VD3-GNPs are a viable candidate for non-toxic, low-cost treatment for reducing breast cancer aggressiveness.

Calcineurin inhibition protects against dopamine toxicity and attenuates behavioral decline in a Parkinson's disease model.

BACKGROUND: Parkinson's disease (PD), a highly prevalent neuro-motor disorder is caused due to progressive loss of dopaminergic (DAergic) neurons at substantia nigra region of brain. This leads to depleted dopamine (DA) content at striatum, thus affecting the fine tuning of basal ganglia. In patients, this imbalance is manifested by akinesia, catalepsy and tremor. PD associated behavioral dysfunctions are frequently mitigated by l-DOPA (LD) therapy, a precursor for DA synthesis. Due to progressive neurodegeneration, LD eventually loses applicability in PD. Although DA is cytotoxic, it is unclear whether LD therapy can accelerate PD progression or not. LD itself does not lead to neurodegeneration in vivo, but previous reports demonstrate that LD treatment mediated excess DA can potentiate neurotoxicity when PD associated genetic or epigenetic aberrations are involved. So, minimizing DA toxicity during the therapy is an absolute necessity to halt or slowdown PD progression. The two major contributing factors associated with DA toxicity are: degradation by Monoamine oxidase and DAquinone (DAQ) formation. RESULTS: Here, we report that apoptotic mitochondrial fragmentation via Calcineurin (CaN)-DRP1 axis is a common downstream event for both these initial cues, inhibiting which can protect cells from DA toxicity comprehensively. No protective effect is observed, in terms of cell survival when only PxIxIT domain of CaN is obstructed, demonstrating the importance to block DRP1-CaN axis specifically. Further, evaluation of the impact of DA exposure on PD progression in a mice model reveal that LD mediated behavioral recovery diminishes with time, mostly because of continued DAergic cell death and dendritic spine loss at striatum. CaN inhibition, alone or in combination with LD, offer long term behavioral protection. This protective effect is mediated specifically by hindering CaN-DRP1 axis, whereas inhibiting interaction between CaN and other substrates, including proteins involved in neuro-inflammation, remained ineffective when LD is co-administered. CONCLUSIONS: In this study, we conclude that DA toxicity can be circumvented by CaN inhibition and it can mitigate PD related behavioral aberrations by protecting neuronal architecture at striatum. We propose that CaN inhibitors might extend the therapeutic efficacy of LD treatment.

Corrigendum: USP14 as a therapeutic target against neurodegeneration: a rat brain perspective.

[This corrects the article DOI: 10.3389/fcell.2020.00727.].

Novel Data Transmission Schemes for Inter-WBAN Networks Using Markov Decision Process.

This work proposes a stochastic model of the coordinator units of each wireless body area network (WBAN) in a multi-WBAN scenario. In a Smart Home environment, multiple patients can come into the vicinity of each other while each of them is wearing a WBAN configuration for monitoring body vitals. Thus, while multiple WBANs coexist, the individual WBAN coordinators require adaptive transmission strategies in order to balance between maximizing the likelihood of data transmission and minimizing the chances of packet loss due to inter-BAN interference. Accordingly, the proposed work is divided into two phases. In the offline phase, each WBAN coordinator is modeled stochastically and the problem of their transmission strategy has been modeled as a Markov Decision Process(MDP). The channel conditions and buffer status that influence the transmission decision are taken to be the state parameters in MDP. The formulation is solved offline, prior to deployment of the network to find out the optimal transmission strategies for various input conditions. Such transmission policies for inter-WBAN communication are then incorporated into the coordinator nodes in the post-deployment phase. The work is simulated using Castalia and the results demonstrate the robustness of the proposed scheme in handling both favorable and unfavorable operating conditions.

Total synthesis of haploscleridamine, villagorgin A and an approach towards lissoclin C.

An investigation of asymmetric total syntheses of three indole-imidazole alkaloids from histidine are described. A common advanced piperidinone was contructed via a ring-closing metathesis which was then subjected to a modified Fischer indole synthesis. Deprotection of an N-tosyl group via a dissolving metal reduction affords haploscleridamine which upon reaction with aqueous formaldehyde in trifluoroethanol provided villagorgin A. On closer examination, it was found that villagorgin A was produced as a byproduct during the reductive detosylation in the presence of magnesium and methanol. Attempts to obtain the brominated haploscleridamine congener, lissoclin C through use of bromophenyl hydrazone were thwarted by reductive debromination during deprotection efforts. Investigation of the enantiopurity of the synthetic natural products revealed production of almost racemic materials in some batches as the result of partial racemization of an early stage intermediate. A revised approach routinely provided scalemic haploscleridamine and villagorgin in 30% ee. Analysis of the enantiomer composition of all intermediates by HPLC using columns with chiral stationary phases; this analysis revealed several steps where erosion of enantiomer composition occurred.

Class-Wise Subspace Alignment-Based Unsupervised Adaptive Land Cover Classification in Scene-Level Using Deep Siamese Network.

In this article, an unsupervised domain adaptation strategy has been investigated using a deep Siamese neural network in scene-level land cover classification using remotely sensed images. At the onset, the soft class label and probability scores of each target sample have been obtained using a pretrained model of a deep convolutional neural network. Thereafter, a semiautomatic threshold selection algorithm along with a graph-based approach has been explored to obtain the "most-confident" target samples. Furthermore, the deep Siamese network has been incorporated by training the source and "most-confident" target samples to generate the classwise cross domain common subspace. To assess the effectiveness of the proposed framework, experiments are carried out using three aerial image datasets. The results are found to be encouraging for the proposed scheme in comparison with the other state-of-art techniques.

Direct utilization of industrial carbon dioxide with low impurities for acetate production via microbial electrosynthesis.

The present study aimed to demonstrate the utilization of unpurified industrial CO2 with low impurities for acetate production via microbial electrosynthesis (MES) for the first time. In MES experiments with CO2-rich brewery gas, the enriched mixed culture dominated by Acetobacterium produced 1.8 ± 0.2 g/L acetic acid at 0.26 ± 0.03 g/Lcatholyte/d rate and outperformed a pure culture of Clostridium ljungdahlii (1.1 ± 0.02 g/L; 0.138 ± 0.004 g/Lcatholyte/d). The electron recovery in acetic acid was also more for mixed culture (84 ± 13%) than C. ljungdahlii (42 ± 14%). Electrochemical analysis of biocathodes suggested the role of microbial biofilm in improved hydrogen electrocatalysis. In comparative gas fermentation tests, the mixed culture outperformed C. ljungdahlii and produced acetic acid at a similar level with both industrial and pure CO2 feedstocks. These results suggest the robustness and capability of the mixed microbial community for utilizing slightly impure industrial CO2 for bioproduction and presents a major advancement in MES technology.

Investigating mitochondrial autophagy by routine transmission electron microscopy: Seeing is believing?

Mitochondrial autophagy is affected in many diseases. In the past few years, the multiple-steps process of selective degradation of mitochondria has been dissected in details by combining outcomes from different approaches. Perhaps one of the most rigorous methods to clearly visualise mitochondria undergoing autophagic engulfment and degradation, is transmission electron microscopy (TEM). In this opinion paper, we want to give a brief summary of the mitophagic process, and by which means mitophagy can be addressed, including TEM analysis. We will report examples of autophagy and mitophagy-related TEM images, and discuss how to decipher the different steps of the mitophagic process by routine TEM. In our opinion, this technique can be used as a powerful confirmatory approach for mitochondrial autophagy and can provide details of the organelle fate throughout the course of mitophagy with no substantial sample manipulation.

USP14 as a Therapeutic Target Against Neurodegeneration: A Rat Brain Perspective.

In the recent past, many of the deubiquitinases (DUB) were found to modulate mitochondrial clearance or mitophagy and thus they are currently projected as therapeutic targets against neurodegeneration. Among these DUBs, USP14 stands at a distinctive juncture, since it can influence both proteasome complex activity and autophagy process. USP14 interference can enhance mitochondrial clearance and thus can protect Parkinsonian phenotypes in Drosophila model. However, in higher animal models of neurodegenerative disorders, evaluation of the protective role of USP14 is yet to be done. In this perspective, we pointed out a few of the major considerations that should be classified before designing experiments to evaluate the therapeutic potential of this DUB in rodent models of neurodegeneration. These are mainly: level of USP14 in the concerned brain region and how the level alters in the model system. Because USP14 mediated mitophagy is Prohibitin2 dependent, the anticipated impact of this protein in this aspect is also discussed. To illustrate our view, we show that USP14 levels increases in adult rat brain substantia nigra (SN) and cerebellum compared to the young ones. We also depict that rotenone treatment can immediately lead to increased SN specific USP14 levels. Our perception thus portrays USP14 as a therapeutic target, especially for addressing SN specific neurodegeneration in adult rat brain, but may vary with the disease model.

Designing Transmission Strategies for Enhancing Communications in Medical IoT Using Markov Decision Process.

The introduction of medical Internet of Things (IoT) for biomedical applications has brought about the era of proactive healthcare. Such advanced medical supervision lies on the foundation of a network of energy-constrained wearable or implantable sensors (or things). These miniaturized battery-powered biosensor nodes are placed in, on, or around the human body to measure vital signals to be reported to the sink. This network configuration deployed on a human body is known as the Wireless Body Area Network (WBAN). Strategies are required to restrict energy expenditure of the nodes without degrading performance of WBAN to make medical IoT a green (energy-efficient) and effective paradigm. Direct communication from a node to sink in WBAN may often lead to rapid energy depletion of nodes as well as growing thermal effects on the human body. Hence, multi-hop communication from sources to sink in WBAN is often preferred instead of direct communication with high transmission power. Existing research focuses on designing multi-hop protocols addressing the issues in WBAN routing. However, the ideal conditions for multi-hop routing in preference to single-hop direct delivery is rarely investigated. Accordingly, in this paper an optimal transmission policy for WBAN is developed using Markov Decision Process (MDP) subject to various input conditions such as battery level, event occurrence, packet transmission rate and link quality. Thereafter, a multi-hop routing protocol is designed where routing decisions are made following a pre-computed strategy. The algorithm is simulated, and performance is compared with existing multi-hop protocol for WBAN to demonstrate the viability of the proposed scheme.

Iron-Catalyzed Allylic Amination Directly from Allylic Alcohols.

Allylic amination, directly from alcohols, has been demonstrated without any Lewis acid activators using an efficient and regiospecific molecular iron catalyst. Various amines and alcohols were employed and the reaction proceeded through the oxidation/reduction (redox) pathway. A direct one-step synthesis of common drugs, such as cinnarizine and nafetifine, was exhibited from cinnamyl alcohol that produced water as side product.

Work-exposure to PM10 and aromatic volatile organic compounds, excretion of urinary biomarkers and effect on the pulmonary function and heme-metabolism: A study of petrol pump workers and traffic police personnel in Kolkata City, India.

This study focused work-exposure to particulate matter ≤ 10 µm (PM10), volatile organic compounds (VOCs) and biological monitoring of major VOCs (BTEX) to observe the significant effects of traffic related pollutants on respiratory and hematological systems of workers engaged in two occupational settings, petrol pumps and traffic areas of Kolkata metropolitan city, India. PM10 was assessed by personal sampling and particle size distribution by 8-stage Cascade Impactor. VOCs were analysed by gas chromatography-flame ionization detector (GC-FID) and five urinary metabolites, trans trans- mercapturic acid (tt-MA), S-phenyl mercapturic acid (SPMA), hippuric acid (HA), mandelic acid (MA) and methyl hippuric acid (MHA) of VOCs, benzene, toluene, ethyl benzene and xylenes (BTEX) by reverse phase high performance liquid chromatography (HPLC). Pulmonary functions test (PFT) was measured Spirometrically. ∂-aminoleavulinic acid (ALA) and porphobilinogen (PBG) in lymphocytes were measured spectrophometrically following column chromatographic separation. High exposure to PM10, having 50% of particles, ≤ 5.0 µm in both the occupational settings. Exposure to toluene was highest in petrol pumps whereas benzene was highest (104.6 ± 99.0 µg m-3) for traffic police personnel. Workplace Benzene is found many fold higher than the National ambient standard. Air-benzene is correlated significantly with pre- and post-shift tt-MA (p < 0.001) and SPMA (p < 0.001) of exposed workers. Blood cell counts indicated benzene induced hematotoxicity. ALA and PBG accumulation in lymphocytes indicated alteration in heme-metabolism, especially among traffic police. Significant reduction of force exploratory volume in one second (FEV1) and forced vital capacity (FVC) of fuel fillers are observed with increased tt-MA and SPMA. Study revealed PFT impairments 11.11% (6.66% restrictive and 2.22% obstructive and combined restrictive and obstructive type, each) among petrol pumps and 8.3% obstructive type among traffic police.

Ameliorative effects of glycyrrhizin on streptozotocin-induced diabetes in rats.

OBJECTIVES: Glycyrrhizin is the main water-soluble constituent of the root of liquorice (Glycyrrhiza glabra). The study investigates the effect of glycyrrhizin on streptozotocin (STZ)-induced diabetic changes and associated oxidative stress, including haemoglobin-induced free iron-mediated oxidative reactions. METHODS: Male Wistar rats were grouped as normal control, STZ-induced diabetic control, normal treated with glycyrrhizin, diabetic treated with glycyrrhizin and diabetic treated with a standard anti-hyperglycaemic drug, glibenclamide. Different parameters were studied in blood and tissue samples of the rats. KEY FINDINGS: Glycyrrhizin treatment improved significantly the diabetogenic effects of STZ, namely enhanced blood glucose level, glucose intolerant behaviour, decreased serum insulin level including pancreatic islet cell numbers, increased glycohaemoglobin level and enhanced levels of cholesterol and triglyceride. The treatment significantly reduced diabetes-induced abnormalities of pancreas and kidney tissues. Oxidative stress parameters, namely, serum superoxide dismutase, catalase, malondialdehyde and fructosamine in diabetic rats were reverted to respective normal values after glycyrrhizin administration. Free iron in haemoglobin, iron-mediated free radical reactions and carbonyl formation in haemoglobin were pronounced in diabetes, and were counteracted by glycyrrhizin. Effects of glycyrrhizin and glibenclamide treatments appeared comparable. CONCLUSION: Glycyrrhizin is quite effective against hyperglycaemia, hyperlipidaemia and associated oxidative stress, and may be a potential therapeutic agent for diabetes treatment.

Action of pelargonidin on hyperglycemia and oxidative damage in diabetic rats: implication for glycation-induced hemoglobin modification.

Glycation-modified hemoglobin in diabetes mellitus has been suggested to be a source of enhanced catalytic iron and free radicals causing pathological complications. The present study aims to verify this idea in experimental diabetes. Pelargonidin, an anthocyanidin, has been tested for its antidiabetic potential with emphasis on its role against pathological oxidative stress including hemoglobin-mediated free radical reactions. Male wistar rats were grouped as normal control, streptozotocin-induced diabetic control, normal treated with pelargonidin and diabetic treated with pelargonidin. Pelargonidin-treated rats received one time i.p injection of the flavonoid (3 mg/kg bodyweight). Biochemical parameters were assayed in blood samples of different groups of rats. Liver was used for histological examinations. Pelargonidin treatment normalized elevated blood glucose levels and improved serum insulin levels in diabetic rats. Glucose tolerance test appeared normal after treatment. Decreased serum levels of SOD and catalase, and increased levels of malondialdehyde and fructosamine in diabetic rats were reverted to their respective normal values after pelargonidin administration. Extents of hemoglobin glycation, hemoglobin-mediated iron release, iron-mediated free radical reactions and carbonyl formation in hemoglobin were pronounced in diabetic rats, indicating association between hemoglobin glycation and oxidative stress in diabetes. Pelargonidin counteracts hemoglobin glycation, iron release from the heme protein and iron-mediated oxidative damages, confirming glycated hemoglobin-associated oxidative stress in diabetes.