In silico exploration and in vitro validation of the filarial thioredoxin reductase inhibitory activity of Scytonemin and its derivatives.

Lymphatic filariasis (LF) caused by the vector borne parasitic nematode Wuchereria bancrofti is of major concern of the World Health Organization (WHO). Lack of potential drug candidates worsens the situation. Presently available drugs are promising in killing the microfilaria (mf) but are not effective as adulticidal therapeutics. Previous studies have revealed that routine administration of the available drugs (albendazole, ivermectin and albendazole) sometime is associated with severe adverse effects (SAEs) in co-infection state. Therefore, potential and safe therapeutics are still required. Earlier studies on filarial thioredoxin reductase (TrxR) have shown that successful inhibition of it can lead to apoptotic death of the parasites. TrxR in filarial parasites plays a significant role in disease progression and pathogenesis, hence efficient non-reversible inhibition of TrxR can be a good strategy to treat LF. In this research, inhibitory potential of Scytonemin, a cyanobacterial metabolite on filarial TrxR was evaluated via different in silico methods and validated through in vitro experiments. Parasite death upon exposure to Scytonemin can be correlated with the TrxR inhibiting capacity of the compound. Therefore, this cyanobacterial-derived compound may possibly be used further as novel and safe therapeutic candidate against filarial infection.Communicated by Ramaswamy H. Sarma.

Tracing the human movements of three thousand years ago by volcanic grinding tools in the Final Bronze Age settlement of Monte Croce Guardia (Arcevia-Marche Region, central Italy).

Volcanic rocks were among the most sought-after materials to produce grinding tools in antiquity because lavas lithologies, either mafic or felsic, ensured good wear resistance and grinding capacity with respect to many other kinds of rocks. The interest in findings made of vesciculated lavas, referable to parts of querns, mortars, and/or pestles of the Final Bronze Age site of Monte Croce Guardia (Arcevia) lies in the fact that this settlement was built upon limestones belonging to the sedimentary sequence of the Marche-Umbria Apennines (central Italy) and far away from potential raw materials of volcanic rocks. A petrologic study of 23 grinding tool fragments clearly indicates a provenance from the volcanic provinces of central Italy: Latium and Tuscany Regions. Few leucite tephrites (5) and one leucite phonolite lavas have a clear magmatic affinity with the high-K series of the Roman Volcanic Province (Latium) whereas the most abundant volcanic lithotype (17 samples) is represented by shoshonites (K-series) whose thin section texture, modal mineralogy and major-trace elements contents closely match with the shoshonite lavas from the Radicofani volcanic centre in the Tuscan Magmatic Province. At Radicofani (a volcanic neck in the eastern sector of Tuscany) a Final Bronze Age site coeval to that of Arcevia is present and a potential pathway corridor from that site towards Arcevia (air-line distance of ca. 115 km) is dotted with many settlements of the same age. Through analytical algorithms based on the slope and the different human-dependent cost-functions which can be applied to determine non-isotropic accumulated cost surface, least-cost paths and least-cost corridors, the best route from Radicofani to Monte Croce Guardia, approximately 140 km long, was simulated, with a walking time of 25-30 h, possibly using pack animals and wheel chariots. Three thousand years ago the Apennine Mountains did not thus constitute a barrier for human movements. This study also shed light on some other possible patterns of interactions between Final Bronze Age communities of central Italy through the present-day regions of Tuscany, Umbria and Marche, aimed towards the best performance of strategic economic activities at that time such as that of the transformation of cereals, and accompanied to cultural and social reasons.

Many-Body Molecular Interactions in a Memristor.

Electronic transitions in molecular-circuit elements hinge on complex interactions between molecules and ions, offering a multidimensional parameter space to embed, access, and optimize material functionalities for target-specific applications. This opportunity is not cultivated in molecular memristors because their low-temperature charge transport, which is a route to decipher molecular many-body interactions, is unexplored. To address this, robust, temperature-resilient molecular memristors based on a Ru complex of an azo aromatic ligand are designed, and current-voltage sweep measurements from room temperature down to 2 K with different cooling protocols are performed. By freezing out or activating different components of supramolecular dynamics, the local Coulombic interactions between the molecules and counterions that affect the electronic transport can be controlled. Operating conditions are designed where functionalities spanning bipolar, unipolar, nonvolatile, and volatile memristors with sharp as well as gradual analog transitions are captured within a single device. A mathematical design space evolves, thereof comprising 36 tuneable parameters in which all possible steady-state functional variations in a memristor characteristic can be attainable. This enables a deterministic design route to engineer neuromorphic devices with unprecedented control over the transformation characteristics governing their functional flexibility and tunability.

Petrological footprints of the millstones of Megara Hyblaea (Sicily Island, Italy) highlight the human interactions with Mediterranean volcanoes.

A petrographic and geochemical study of several volcanic millstones, representative of 119 artifacts found in the ancient Greek colony of Megara Hyblaea (Sicily Island) and recording the grinding device evolution from the Archaic to the Hellenistic period, unravelled the volcanoes involved as quarrying and production areas. This was possible also through the comparison with available petrographic and geochemical literature data of ancient volcanic millstones found in the whole Mediterranean. Saddle querns, hopper-rubber, rotary Morgantina- and Delian-type millstones of Megara Hyblaea consist of lithotypes belonging to five magmatic series: Tholeiitic, Na-Alkaline, Tholeiitic Transitional, Calcalkaline and High-K Alkaline. A provenance from the Eastern Sicily, i.e. mugearites from Etna and basalts and basaltic andesites from the Hyblaean Mountains were recognized for all the four investigated grinding devices. By contrast, a sea-trade is involved for several saddle querns made of calcalkaline basaltic andesites and andesites lavas (Aegean Islands) and two Morgantina-type millstones consisting of a calcalkaline rhyodacite ignimbrite from the quarrying site of Mulargia (Sardinia). A wide millstone trade, both local (Eastern Sicily) or maritime (Central-Eastern Mediterranean) was thus constrained through six centuries, from the foundation of the Greek colony up to the destruction of the settlement at the end of third century BCE. Finally, Vulture Volcano (southern Italian peninsula) is the most probable candidate for the only leucite- and haüyne-bearing phonolite of the High-K Alkaline Series.

Crude protein fraction with high thioredoxin reductase (TrxR) enzyme activity from filarial parasite Setaria cervi counters lipopolysaccharide (LPS)-induced inflammation in macrophages.

Host-parasite interaction has always been an area of interest to the parasite biologists. The complex immune interactions between the parasite and/or the parasite-derived products with the host immune cells determine the fate of the disease biology. Parasitic organisms are widely equipped with a vast array of protective machineries including antioxidant enzymes to withstand the hostile condition inside the host body. The reactive oxygen species (ROS) generated inside the host as a result of parasitic intervention can be endured by the parasite by their own tools to ensure their survival. One such antioxidant enzyme in the filarial parasite that plays a significant role in redox homeostasis, survivability and disease progression is the thioredoxin reductase (TrxR). Herein, we have projected a crude lysate of the bovine filarial parasite Setaria cervi enriched with high TrxR enzyme activity has the capacity to downregulate lipopolysaccharide (LPS)-induced inflammatory macrophages. TrxR-mediated inhibition of the TLR4-NF-κB axis resulting into downregulation of the pro-inflammatory cytokines with concomitant upregulation of the anti-inflammatory cytokines supports the filarial parasite to produce an anti-inflammatory milieu which ultimately promotes worm survivability inside the host and pathogenesis.

An efficient CNN based algorithm for detecting melanoma cancer regions in H&E-stained images.

Histopathological images are widely used to diagnose diseases such as skin cancer. As digital histopathological images are typically of very large size, in the order of several billion pixels, automated identification of abnormal cell nuclei and their distribution within multiple tissue sections would enable rapid comprehensive diagnostic assessment. In this paper, we propose a deep learning-based technique to segment the melanoma regions in Hematoxylin and Eosin-stained histopathological images. In this technique, the nuclei in an image are first segmented using a deep learning neural network. The segmented nuclei are then used to generate the melanoma region masks. Experimental results show that the proposed method can provide nuclei segmentation accuracy of around 90% and the melanoma region segmentation accuracy of around 98%. The proposed technique also has a low computational complexity.

Detection of malignant melanoma in H&E-stained images using deep learning techniques.

Histopathological images are widely used to diagnose diseases including skin cancer. As digital histopathological images are typically of very large size, in the order of several billion pixels, automated identification of all abnormal cell nuclei and their distribution within multiple tissue sections would assist rapid comprehensive diagnostic assessment. In this paper, we propose a deep learning-based technique to segment the melanoma regions in Hematoxylin and Eosin (H&E) stained histopathological images. In this technique, the nuclei in the image are first segmented using a Convolutional Neural Network (CNN). The segmented nuclei are then used to generate melanoma region masks. Experimental results with a small melanoma dataset show that the proposed method can potentially segment the nuclei with more than 94 % accuracy and segment the melanoma regions with a Dice coefficient of around 85 %. The proposed technique also has a small execution time making it suitable for clinical diagnosis with a fast turnaround time.

Rise of Informal Slums and the Next Global Pandemic.

Informal slums are growing exponentially in the developing world and these will serve as the breeding ground for a future global pandemic. Virtually every sustainable development goal is unmet in slums around the globe thus we must act now to divert a global humanitarian crisis.

Triggering the downstream apoptotic signal inside human parasitic organisms demonstrates a promising approach for anti-parasitic drug development: A mechanistic perspective.

Parasitic organisms of various genera have threatened humankind. Although they are not always fatal but can damage the well-being of an individual in terms of both economic and societal crisis. Marked progress has been made toward eliminating those pathogenic organisms, however, complete removal is still not possible. Several antiparasitic drug moieties have been largely commercialized and are routinely used at the same time novel drug candidates are still required. Programmed cell death (PCD) is a vital biological phenomenon inside every organism. Particularly, induction of the death signaling inside the parasitic species through selective targeting of effective drug candidates is one of the major strategies to combat these infectious organisms. In this chapter significance of apoptosis induction to eliminate the parasitic disease has been illustrated with suitable references. Moreover, we have shared our own experiences of apoptosis induction in eliminating a World Health Organization enlisted Neglected Tropical Disease, lymphatic filariasis. On the other hand, we have also tried to put some light on the mechanism of apoptosis in different parasites.

Disruption of redox homeostasis with synchronized activation of apoptosis highlights the antifilarial efficacy of novel piperine derivatives: An in vitro mechanistic approach.

A series of novel piperine derivatives were synthesized with high yield and were evaluated for its antifilarial potential against the bovine filarial parasite Setaria cervi. Among 21 (3a-3u) compounds screened, three of them (3k, 3l, 3s) showed significant potential against all the developmental stages (oocytes, microfilariae and adult) of the filarial worm in time and dose dependent manner. 3l showed the highest efficacy among the selected three compounds. These three compounds were further evaluated for both in vitro and in vivo toxicity analyses which further fortified the benign nature of the selected compounds. The antifilarial activities they exhibited were clearly fuelled through disparity of the internal redox homeostasis as evidenced from the alterations in the enzymatic and non-enzymatic antioxidants level which ultimately shifted towards activation of pro-apoptotic signaling cascade eventually leading to the death of the parasites. The ability of the compound 3l to bind thioredoxin reductase and CED-3 protein are the key findings of this study. The present study supported with several biological experiments is therefore a maiden report on the antifilarial effectiveness of these novel piperine derivatives.

Automated proliferation index calculation for skin melanoma biopsy images using machine learning.

The Proliferation Index (PI) is an important diagnostic, predictive and prognostic parameter used for evaluating different types of cancer. This paper presents an automated technique to measure the PI values for skin melanoma images using machine learning algorithms. The proposed technique first analyzes a Mart-1 stained histology image and generates a region of interest (ROI) mask for the tumor. The ROI mask is then used to locate the tumor regions in the corresponding Ki-67 stained image. The nuclei in the Ki-67 ROI are then segmented and classified using a Convolutional Neural Network (CNN), and the PI value is calculated based on the number of the active and the passive nuclei. Experimental results show that the proposed technique can robustly segment (with 94 % accuracy) and classify the nuclei with a low computational complexity and the calculated PI values have less than 4 % average error.

Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions.

Polymeric micelles, i.e. aggregation colloids formed in solution by self-assembling of amphiphilic polymers, represent an innovative tool to overcome several issues related to drug administration, from the low water-solubility to the poor drug permeability across biological barriers. With respect to other nanocarriers, polymeric micelles generally display smaller size, easier preparation and sterilization processes, and good solubilization properties, unfortunately associated with a lower stability in biological fluids and a more complicated characterization. Particularly challenging is the study of their interaction with the biological environment, essential to predict the real in vivo behavior after administration. In this review, after a general presentation on micelles features and properties, different characterization techniques are discussed, from the ones used for the determination of micelles basic characteristics (critical micellar concentration, size, surface charge, morphology) to the more complex approaches used to figure out micelles kinetic stability, drug release and behavior in the presence of biological substrates (fluids, cells and tissues). The techniques presented (such as dynamic light scattering, AFM, cryo-TEM, X-ray scattering, FRET, symmetrical flow field-flow fractionation (AF4) and density ultracentrifugation), each one with their own advantages and limitations, can be combined to achieve a deeper comprehension of polymeric micelles in vivo behavior. The set-up and validation of adequate methods for micelles description represent the essential starting point for their development and clinical success.

Inhibition of thioredoxin reductase (TrxR) triggers oxidative stress-induced apoptosis in filarial nematode Setaria cervi channelized through ASK-1-p38 mediated caspase activation.

Inhibition of an imperative antioxidant enzyme with subsequent death is a victorious and widely accepted strategy to combat various infectious diseases. Among different antioxidant enzymes, thioredoxin reductase (TrxR) is an exclusive one. Studies have revealed that direct inhibition of TrxR by different classes of chemical moieties promptly results in the death of an organism. Especially the structural as well as biochemical modifications of the enzyme upon inhibition project serious threat towards the subject organism. Herein, an attempt was made to inhibit TrxR of filarial species by administering Auranofin, 1 chloro 2,4 dinitrobenzene (CDNB), Curcumin, and a novel carbamo dithioperoxo(thioate) derivative (4a). Our study has revealed that inhibition of TrxR resulted in the induction of the classical CED pathway of apoptosis along with the intrinsic and extrinsic pathways of apoptosis (Caspase mediated) routed through the ASK-1/p38 axis. Druggability analysis of filarial TrxR for the selected compounds was performed in silico through molecular docking studies. Therefore, this study attempts to decipher the mechanism of apoptosis induction following TrxR inhibition. The safety of those four compounds in terms of dose and toxicity was taken under consideration. Thitherto, the mechanism of TrxR mediated initiation of cell death in filarial parasite has remained undercover, and therefore, it is a maiden report on the characterization of apoptosis induction upon TrxR inhibition which will eventually help in generating effective antifilarial drugs in the future.

A review on the interactions between dendritic cells, filarial parasite and parasite-derived molecules in regulating the host immune responses.

Lymphatic filariasis (LF) is the second leading cause of parasitic disabilities that affects millions of people in India and several other tropical countries. The complexity of this disease is endorsed by various immunopathological consequences such as lymphangitis, lymphadenitis and elephantiasis. The immune evasion strategies that a filarial parasite usually follows are chiefly initiated with the communication between the invaded parasites and parasite-derived molecules, with the Toll-like receptors (TLRs) present on the surface of the antigen-presenting cells (APCs). Classically, the filarial parasites interact with the DCs resulting in lowering of CD4+ T-cell responses. These CD4+ T-cell responses are the key players behind the immune-mediated pathologies associated with LF. In chronic stage, the canonical pro-inflammatory immune responses are shifted towards an anti-inflammatory subtype, which is favouring the parasite survivability within the host. The central theme of this review article is to present the overall immune response elicited when an APC, particularly a DC, encounters a filarial parasite.

Adaptive clip-limit-based bi-histogram equalization algorithm for infrared image enhancement.

Infrared (IR) images are basically low-contrast in nature; hence, it is essential to enhance the contrast of IR images to facilitate real-life applications. This work proposes a novel adaptive clip-limit-oriented bi-histogram equalization (bi-HE) method for enhancing IR images. HE methods are simple in implementation but often cause over-enhancement due to the presence of long spikes. To reduce long spikes, this work suggests to apply a log-power operation on the histogram, where the log operation reduces the long spikes, and power transformation regains the shape of the histogram. First, a histogram separation point is generated applying the mean of the multi-peaks of the input histogram. After that, an alteration in the input histogram is done using the log-power process. Subsequently, a clipping operation on the altered histogram followed by redistribution of the clipped portion is performed to restrict over-enhancement. Next, the modified histogram is sub-divided using the histogram separation point. Finally, the modified sub-histograms are equalized independently. Simulation results show that the suggested method effectively improves the contrast of IR images. Visual quality evaluations and quantitative assessment demonstrate that the suggested method outperforms the state-of-the-art algorithms.

Thiol antioxidant thioredoxin reductase: A prospective biochemical crossroads between anticancer and antiparasitic treatments of the modern era.

The thiol-based glutathione reductase (GR) and thioredoxin reductase (TrxR) are the major antioxidant enzymes present in various organisms that maintain the internal redox homeostasis. The thioredoxin system has attracted the attention of researchers from diverse investigation fields of biological sciences. Apart from redox regulation, this system is thought to be the major regulator of various biological processes including transcription, apoptosis, etc. Identification and physicobiochemical characterization of the reductase enzyme i.e. Thioredoxin reductase (TrxR) revealed the potency of it to become a promising target. Novel therapeutic interventions by selective targeting of TrxR in parasitic organisms as well as in the cancer cells have now become a usual treatment approach. However, different isoforms and their variation in the penultimate amino acid (Selenocysteine or cysteine) present in the catalytic site of the enzyme have made this enzyme to respond differently towards various drugs and synthetic and/or natural compounds. Therefore, the present article seeks to highlight the importance and the detailed molecular mechanism, functional perspective underlying the TrxR inhibition in various parasitic protozoans, helminthes as well as in cancer cells for devising suitable anti-TrxR candidates.

Senna plant generates reactive oxygen species (ROS) and induces apoptosis in Hymenolepis diminuta.

Like mammalian cells, helminth parasites are equipped with an array of enzymatic anti-oxidant system which has an adaptive strategy to cope up with several conditions of stress that arise from host immune response or drug treatment. Earlier, we had reported that three species of Senna, viz. S. alata, S. alexandrina and S. occidentalis leaf extracts caused severe morphological and biochemical alterations in the zoonotic parasite Hymenolepis diminuta. To understand whether the leaf extracts of the three species of Senna have any effect on the enzymatic anti-oxidant system in H.diminuta or not, the present study was investigated on the mechanism of action of these leaf extracts on the anti-oxidant system of the parasite. The viability of the parasite was assessed by MTT reduction assay, chromatin condensation through Hoechst staining of tissue and DNA fragmentation assay, and the oxidative enzymes of the parasite were estimated biochemically. Activity of superoxide dismutase, catalase, glutathione S- transferase and glutathione peroxidase were found to be increased in all the treated parasites from that of the control, with S. alata showed the highest increased amongst the three plant species in all the enzymes, at 331.0 %, 215.4 %, 85.4 % and 65.5 % respectively. Upliftment of apoptotic protein CED-3, CED-4 and EGL-1 and down regulation of anti-apototic protein CED-9 was visualised in all treated paraites. The redox imbalance triggered by these leaf extracts resulted in the activation of apoptotic pathway that led to death of the parasite. Our results demonstrated that the leaf extracts of the three Senna plant species could open new insight for an affordable natural anthelmintic with high efficacy and less toxicity.

Charge disproportionate molecular redox for discrete memristive and memcapacitive switching.

Electronic symmetry breaking by charge disproportionation results in multifaceted changes in the electronic, magnetic and optical properties of a material, triggering ferroelectricity, metal/insulator transition and colossal magnetoresistance. Yet, charge disproportionation lacks technological relevance because it occurs only under specific physical conditions of high or low temperature or high pressure. Here we demonstrate a voltage-triggered charge disproportionation in thin molecular films of a metal-organic complex occurring in ambient conditions. This provides a technologically relevant molecular route for simultaneous realization of a ternary memristor and a binary memcapacitor, scalable down to a device area of 60 nm2. Supported by mathematical modelling, our results establish that multiple memristive states can be functionally non-volatile, yet discrete-a combination perceived as theoretically prohibited. Our device could be used as a binary or ternary memristor, a binary memcapacitor or both concomitantly, and unlike the existing 'continuous state' memristors, its discrete states are optimal for high-density, ultra-low-energy digital computing.