Drug resistance is one of the trademark features of Cancer Stem Cells (CSCs). We and others have recently shown that paucity of functional death receptors (DR4/5) on the cell surface of tumour cells ...is one of the major reasons for drug resistance, but their involvement in the context of in CSCs is poorly understood. By harnessing CSC specific cytotoxic function of salinomycin, we discovered a critical role of epigenetic modulator EZH2 in regulating the expression of DRs in colon CSCs. Our unbiased proteome profiler array approach followed by ChIP analysis of salinomycin treated cells indicated that the expression of DRs, especially DR4 is epigenetically repressed in colon CSCs. Concurrently, EZH2 knockdown demonstrated increased expression of DR4/DR5, significant reduction of CSC phenotypes such as spheroid formation in-vitro and tumorigenic potential in-vivo in colon cancer. TCGA data analysis of human colon cancer clinical samples shows strong inverse correlation between EZH2 and DR4. Taken together, this study provides an insight about epigenetic regulation of DR4 in colon CSCs and advocates that drug-resistant colon cancer can be therapeutically targeted by combining TRAIL and small molecule EZH2 inhibitors.
In the current era, one of biggest challenges is to shorten the breeding cycle for rapid generation of a new crop variety having high yield capacity, disease resistance, high nutrient content, etc. ...Advances in the "-omics" technology have revolutionized the discovery of genes and bio-molecules with remarkable precision, resulting in significant development of plant-focused metabolic databases and resources. Metabolomics has been widely used in several model plants and crop species to examine metabolic drift and changes in metabolic composition during various developmental stages and in response to stimuli. Over the last few decades, these efforts have resulted in a significantly improved understanding of the metabolic pathways of plants through identification of several unknown intermediates. This has assisted in developing several new metabolically engineered important crops with desirable agronomic traits, and has facilitated the
domestication of new crops for sustainable agriculture and food security. In this review, we discuss how "omics" technologies, particularly metabolomics, has enhanced our understanding of important traits and allowed speedy domestication of novel crop plants.
Chili (
Capsicum annuum
L.) is an important vegetable and spice crop of tropical and sub-tropical regions. Chili plants showing upward leaf curling, leaf crinkling, and leaf yellowing symptoms, ...collected from Sikar district of Rajasthan, India, were found to be associated with begomovirus and satellite molecules. The presence of virus was confirmed by PCR using virus-specific primer. The full-length genomic DNA-A of three begomovirus (MM-1, CS-1 and RV-1) and two satellites (MM-2 and MM-3) were cloned which was identified from single symptomatic chili plant. The genome organization of isolated three viruses is similar to those of other Old World monopartite begomoviruses. The comparison of the sequences and closest phylogenetic relationships for the begomoviruses, betasatellite and alphasatellite DNAs revealed that MM-1 was designated as DNA-A of
Chili leaf curl virus
(ChiLCV), CS-1 is considered to be a new distinct species of
Tomato leaf curl Gujrat virus
(ToLCGV) whereas RV-1 as a new strain of
Cotton leaf curl Multan virus
(CLCuMuV). The DNA-A component of ChiLCV showed 8.6%, ToLCGV of 16.6% and CLCuMuV of 7.7% average evolutionary divergence, concomitantly, the betasatellite and alphasatellite molecule had 9.9% and 5.9% overall sequence divergence, respectively. Interestingly, most of the begomoviruses were found to be intra-species recombinants. The dN/dS ratio and Tajima
D
value of all viral DNA-A component and their associated betasatellite showed their selective control on evolutionary relationships. The nucleotide substitution rates were determined for the DNA-A genomes of ChiLCV (7.22 × 10
–4
substitutions site
–1
year
–1
), CLCuMuV (1.49 × 10
–4
substitutions site
–1
year
–1
), ToLCGV (7.47 × 10
–4
substitutions site
–1
year
–1
), the genome of associated ChiLCB (4.20 × 10
–4
substitutions site
–1
year
–1
) and CLCuMuA (1.49 × 10
–4
substitutions site
–1
year
–1
). Agro-inoculation studies indicate that the presence of DNA betasatellite induce severe symptoms in
N. benthamiana
and chili, suggesting prerequisite association for typical disease development.
Display omitted
•Integration of the triazole motif as a linker enhances structural and functional support for chemo-sensing applications, creating a predefined scaffold called ..."suprareceptors".•Triazole contributes to the metal ion coordination through its -N hetero atoms and the anion binding through H-bonding interactions.•The hydrophobic cavity of the supramolecular scaffolds and their amenability of diverse chemical modifications, combined with the triazole linker, enable multidimensional sensing applications.
Rapid, reliable, and unbiased detection and quantification of important analytes have drawn rising attention because of the dire need to understand the environmental and the biomedical conditions better. Macrocyclic platforms, such as, calixnarenes (CnA), pillarnarenes (PnA), cyclodextrins (CD) and cucurbiturils (CBn) have been reported recently to build sensitive receptors to selectively recognize the relevant species of importance by primarily eliciting appropriate fluorescence, absorbance, and or colorimetric signals. This review highlights the examples of such suprareceptors based on these four types of macrocyclic scaffolds wherein the attachment of triazole moiety played either a structural or a functional or both the roles in recognizing an ion or a molecule or a species of importance. Notably, the common cations, anions, amino acids and other species having importance in the environmental and biomedical fields were chosen as the guest species of interest for discussion. In addition, this review article emphasizes the role of the pre-defined molecular structures of selected macrocyclic scaffolds, which allows suitable modification to incorporate molecular linkers, ligating groups, and signaling units for selective and sensitive recognition of species of chemical, biological, medical and ecological importance. The article also focusses on their relative utility and importance and thereby provides some futuristic growth potential and dimensions of these four supramolecular platforms. It is to be noted that the integration of triazole moieties into the arms of these supramolecular platforms has been possible with the advent of Click chemistry which revolutionalized the application domains of such conjugates and thereby transformed the Nobel prize winning “Click Chemistry” into “Click Technology” and hence the present article.
The coronavirus disease 2019 (COVID-19) pandemic wreaked havoc worldwide, with more than 20 million confirmed cases and nearly 0. 75 million deaths as of 10th August 2020. Various factors determine ...the severity and symptoms of this infection. Older age and underlying diseases are the challenges being faced in controlling and treating COVID-19. In 2019, 703 million of the global population was older than 65 years of age. The estimated mortality due to COVID-19 in people older than 76 years of age is reportedly 18%. Frequent infections in older people, higher disease severity, and increased mortality are major challenges in the implementation of appropriate preventive measures and future strategies to protect against this disease in geriatric population. Poor health status, weak immune function, lowered organ function, increased probability of multiple underlying diseases, and poor attention to personal health can increase the susceptibility to various diseases in the geriatric population. Concerning inadequate immunity, the decrease expression of receptors and exaggerated pathophysiologic responses can be debilitating. However, future studies will reveal the hidden facets in these aspects in this COVID-19 catastrophe. In this article, we reviewed the main concerns of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the geriatric population, including the risk of acquiring severe COVID-19 resulting in mortality, variation in clinical manifestations, and other pandemic-related concerns. We also discussed the need for increasing attention toward the elderly, taking appropriate prevention and control measures, and considering geriatric-related adjustments in vaccine design and development.
In this article, a new concept of the Complex Neutrosophic Matrix is introduced to solve different problems related to uncertainties. Based on the proposed matrix, we have provided various algebraic ...operations like addition, subtraction, union many others which will be of great help in establishing the fundamental concepts. The results obtained through the above operations will be consequently utilized in solving the higher-dimensional problems due to their matrix properties. This novel concept lays the foundation of various research solutions in the field of the complex neutrosophic matrix, which are yet to be considered by researchers. The matrix norm convergence of the proposed matrix has also been studied for the necessary foundation of the complex neutrosophic matrix. Also, the future studies of the proposed concept have been proposed.
Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and ...increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups.
Display omitted
•Established directly from patients; largest collection to date•Multiple PDX established from immune and targeted therapy-resistant patients•Multiple PDX from brain metastasis samples•Multiple PDX from rare subgroups and rare genetic aberrations
Krepler et al. have established a collection of melanoma patient-derived xenografts (PDX). Melanoma is a very heterogeneous cancer, and this large collection includes even rare subtypes and genetic aberrations in sufficient numbers. Multiple PDX from therapy-resistant patients are characterized and tested in pre-clinical trials for second line therapies.
Chronic inflammation and airway hyperresponsiveness (AHR) in asthmatics are usually managed effectively by treatment with glucocorticoids. However, a subset of patients remains refractory to therapy. ...The underlying mechanisms are largely unknown, although recruitment of neutrophils (rather than eosinophils) is strongly correlated, suggesting a role for nonallergic host defense responses. Increased levels of IFN-gamma and endotoxins are also related to severe asthma and because these activate host defense pathways, we investigated a possible common etiologic link to steroid-resistant disease. To be able to unravel the complexity of asthmatic inflammation, we used two model systems which permitted dissection of the relevant molecular pathways. In the first of these, we transferred transgenic OVA(323-339) peptide-specific IFN-gamma-producing Th1 cells into mice. These animals were subsequently challenge via the airways with OVA(323-339) peptide and/or LPS. Challenge with both components, but not with either one individually, induced AHR. Importantly, AHR was resistant to treatment with dexamethasone. Development of AHR was dependent on IFN-gamma, inhibited by depletion of pulmonary macrophages (but not neutrophils) and abrogated in TLR4- or MyD88-deficient mice. In contrast, in the second model in which we transferred OVA(323-339) peptide-activated Th2 cells, eosinophilic inflammation and AHR were induced, and both were suppressed by steroid treatment. We conclude that cooperative signaling between IFN-gamma and TLR4/MyD88 constitutes a previously unrecognized pathway that regulates macrophage-dependent steroid-resistant AHR.
We examine the co-creation of value by bottom of the pyramid consumers in the health services context. Following a qualitative approach, we use the empirical context of the National Rural Health ...Mission (NRHM) in India, one of the largest healthcare policy interventions in the world. Our grounded theory-based research used semi-structured interviews conducted in 28 villages across three states using a purposive sample (NRHM beneficiaries). The qualitative data were analysed utilising a discovery-oriented approach, in accordance with the value co-creation and service-dominant logic frameworks. We draw insights about the roles of individual agency, the individual's social milieu, and supplementary forces in affecting different types of individual wellbeing. Our results help to explicate the processes of the exploitation, combination and reinforcement of resources within a co-created healthcare ecosystem, and six propositions explain value co-creation-driven health service delivery. We also discuss implications for marketers and policy implementers.
PDF
