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Harnessing genetic diversity in major staple crops through the development of new breeding capabilities is essential to ensure food security1. Here we examined the genetic and phenotypic diversity of the A. E. Watkins landrace collection2 of bread wheat (Triticum aestivum), a major global cereal, by whole-genome re-sequencing of 827 Watkins landraces and 208 modern cultivars and in-depth field evaluation spanning a decade. We found that modern cultivars are derived from two of the seven ancestral groups of wheat and maintain very long-range haplotype integrity. The remaining five groups represent untapped genetic sources, providing access to landrace-specific alleles and haplotypes for breeding. Linkage disequilibrium-based haplotypes and association genetics analyses link Watkins genomes to the thousands of identified high-resolution quantitative trait loci and significant marker-trait associations. Using these structured germplasm, genotyping and informatics resources, we revealed many Watkins-unique beneficial haplotypes that can confer superior traits in modern wheat. Furthermore, we assessed the phenotypic effects of 44,338 Watkins-unique haplotypes, introgressed from 143 prioritized quantitative trait loci in the context of modern cultivars, bridging the gap between landrace diversity and current breeding. This study establishes a framework for systematically utilizing genetic diversity in crop improvement to achieve sustainable food security.
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Variação Genética , Genoma de Planta , Haplótipos , Desequilíbrio de Ligação , Fenótipo , Melhoramento Vegetal , Locos de Características Quantitativas , Triticum , Triticum/genética , Haplótipos/genética , Locos de Características Quantitativas/genética , Desequilíbrio de Ligação/genética , Variação Genética/genética , Genoma de Planta/genética , Alelos , Produtos Agrícolas/genética , Introgressão Genética , Sequenciamento Completo do GenomaRESUMO
Cholesterol derived from the host milieu forms a critical factor for mycobacterial pathogenesis. However, the molecular circuitry co-opted by Mycobacterium tuberculosis (Mtb) to accumulate cholesterol in host cells remains obscure. Here, we report that the coordinated action of WNT-responsive histone modifiers G9a (H3K9 methyltransferase) and SIRT6 (H3K9 deacetylase) orchestrate cholesterol build-up in in vitro and in vivo mouse models of Mtb infection. Mechanistically, G9a, along with SREBP2, drives the expression of cholesterol biosynthesis and uptake genes; while SIRT6 along with G9a represses the genes involved in cholesterol efflux. The accumulated cholesterol in Mtb infected macrophages promotes the expression of antioxidant genes leading to reduced oxidative stress, thereby supporting Mtb survival. In corroboration, loss-of-function of G9a in vitro and pharmacological inhibition in vivo; or utilization of BMDMs derived from Sirt6-/- mice or in vivo infection in haplo-insufficient Sirt6-/+ mice; hampered host cholesterol accumulation and restricted Mtb burden. These findings shed light on the novel roles of G9a and SIRT6 during Mtb infection and highlight the previously unknown contribution of host cholesterol in potentiating anti-oxidative responses for aiding Mtb survival.
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Histona-Lisina N-Metiltransferase , Mycobacterium tuberculosis , Sirtuínas , Animais , Camundongos , Colesterol/metabolismo , Histonas/metabolismo , Macrófagos/metabolismo , Mycobacterium tuberculosis/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismoRESUMO
Over the last two decades, the low-valent compounds of group-14 elements have received significant attention in several fields of chemistry owing to their unique electronic properties. The low-valent group-14 species include tetrylenes, tetryliumylidene, tetrylones, dimetallenes and dimetallynes. These low-valent group-14 species have shown applications in various areas such as organic transformations (hydroboration, cyanosilylation, N-functionalisation of amines, and hydroamination), small molecule activation (e.g. P4, As4, CO2, CO, H2, alkene, and alkyne) and materials. This review presents an in-depth discussion on low-valent group-14 species-catalyzed reactions, including polymerization of rac-lactide, L-lactide, DL-lactide, and caprolactone, followed by their photophysical properties (phosphorescence and fluorescence), thin film deposition (atomic layer deposition and vapor phase deposition), and medicinal applications. This review concisely summarizes current developments of low-valent heavier group-14 compounds, covering synthetic methodologies, structural aspects, and their applications in various fields of chemistry. Finally, their opportunities and challenges are examined and emphasized.
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BACKGROUND: More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time. METHODS: A focused drug synergy screen consisting of 20 drugs was performed by combining EZH2 inhibition with a panel of anti-cancer compounds in mesothelioma cell lines. The compounds used are under preclinical investigation or already used in the clinic. The synergistic potential of the combinations was assessed by using the Bliss model. To validate our findings, in vivo xenograft experiments were performed. RESULTS: Combining EZH2i with ATMi was found to have synergistic potential against BAP1-deficient mesothelioma in our drug screen, which was validated in clonogenicity assays. Tumour growth inhibition potential was significantly increased in BAP1-deficient xenografts. In addition, we observe lower ATM levels upon depletion of BAP1 and hypothesise that this might be mediated by E2F1. CONCLUSIONS: We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker.
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Proteínas Mutadas de Ataxia Telangiectasia , Proteína Potenciadora do Homólogo 2 de Zeste , Mesotelioma , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/deficiência , Humanos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/deficiência , Animais , Camundongos , Mesotelioma/tratamento farmacológico , Mesotelioma/patologia , Mesotelioma/genética , Linhagem Celular Tumoral , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Sinergismo Farmacológico , FemininoRESUMO
In this work, we have developed an efficient method for the intramolecular double hydroamination of aniline by employing o-amino 1,6-diyne as a potential starting material. This protocol enables easy access to bioactive motif 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indole through an intramolecular cascade bicyclization and concomitant isomerization pathway in one pot. This transformation has been effectively achieved by utilizing a stereoelectronically tuned, π-accepting NHC-supported copper(I) system. During ligand optimization trials, naphthoquinone-annulated N-heterocyclic carbene, Nq(IDipp) [1,3-bis(2,6-diisopropylphenyl)-4,5-naphthoquino-imidazolidene]-supported copper(I) complexes of the type Nq(IDipp)CuX (X = Cl or I) were synthesized and fully characterized using various spectroscopic techniques. For this conversion, NHC plays a crucial role in providing the optimum electron density around the metal center. It is a highly regio- and chemoselective transformation with a high atom economy and uses cheap, environmentally benign copper-based catalysts. Furthermore, a plausible mechanism has been proposed on the basis of experimental observations and literature support.
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The present study focuses on the pathological and molecular characterization of African swine fever virus (ASFV) associated with an outbreak in wild boars in two national parks in southern India in 2022-2023. Significant mortality was observed among free-ranging wild boars at Bandipur National Park, Karnataka, and Mudumalai National Park, Tamil Nadu. Extensive combing operations were undertaken in both national parks, spanning an area of around 100 km2, originating from the reported epicenter, to estimate the mortality rate. Recovered carcasses were pathologically examined, and ASFV isolates was genetically characterized. Our findings suggested spillover infection of ASFV from nearby domestic pigs, and the virus was equally pathogenic in wild boars and domestic pigs. ASFV intrusion was reported in the Northeastern region of the country, which borders China and Myanmar, whereas the current outbreak is very distantly located, in southern India. Molecular data will help in tracing the spread of the virus in the country.
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Vírus da Febre Suína Africana , Febre Suína Africana , Surtos de Doenças , Sus scrofa , Animais , Vírus da Febre Suína Africana/genética , Vírus da Febre Suína Africana/isolamento & purificação , Índia/epidemiologia , Suínos , Febre Suína Africana/virologia , Febre Suína Africana/epidemiologia , Febre Suína Africana/mortalidade , Sus scrofa/virologia , Surtos de Doenças/veterinária , Filogenia , Animais Selvagens/virologiaRESUMO
Short-chain fatty acids (SCFAs) are essential molecules produced by gut bacteria that fuel intestinal cells and may also influence overall health. An imbalance of SCFAs can result in various acute and chronic diseases, including diabetes, obesity and colorectal cancer (CRC). This review delves into the multifaceted roles of SCFAs, including a brief discussion on their source and various gut-residing bacteria. Primary techniques used for detection of SCFAs, including gas chromatography, high-performance gas chromatography, nuclear magnetic resonance and capillary electrophoresis are also discussed through this article. This review study also compiles various synthesis pathways of SCFAs from diverse substrates such as sugar, acetone, ethanol and amino acids. The different pathways through which SCFAs enter cells for immune response regulation are also highlighted. A major emphasis is the discussion on diseases associated with SCFA dysregulation, such as anaemia, brain development, CRC, depression, obesity and diabetes. This includes exploring the relationship between SCFA levels across ethnicities and their connection with blood pressure and CRC. In conclusion, this review highlights the critical role of SCFAs in maintaining gut health and their implications in various diseases, emphasizing the need for further research on SCFA detection, synthesis and their potential as diagnostic biomarkers. Future studies of SCFAs will pave the way for the development of novel diagnostic tools and therapeutic strategies for optimizing gut health and preventing diseases associated with SCFA dysregulation.
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Ácidos Graxos Voláteis , Microbioma Gastrointestinal , Humanos , Ácidos Graxos Voláteis/metabolismo , Animais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Obesidade/metabolismoRESUMO
Diploknema butyracea (Roxb) H.J Lam, also referred as " Kalpavriksha", is commonly known as Gophal, Cheura, or Indian butter tree. It is a deciduous tree with straight trunks of 15-20m in height and white-yellow-coloured fragile flowers with fragrance, found at altitudes of 300-1500 m in the sub-Himalayan region of India, China, Nepal, and Bhutan. Diploknema have 11 taxa and 8 species, out of which 3 species are found in Uttarakhand hills, Sikkim, Darjeeling, Arunachal Pradesh, and Assam. The tree holds significant economic importance, serving various purposes within ethnic communities. Its high lipid content makes it valuable for food, medicine, construction, and the production of various value-added products. The ethno-pharmacological applications encompass treating rheumatism, burns, asthma, and skin conditions. The plant's different components-bark, leaves, flowers, seeds, and fruits-contain diverse array of phytoconstituents, including alkaloids, tannins, flavonoids, steroids, terpenoids, and palmitic acid, along with essential nutrients like sodium, calcium, potassium, iron, magnesium, zinc, and various sugars which shows diverse pharmacological and therapeutic activities. Beyond traditional uses, Diploknema is important for diverse industrial application in pharmaceuticals, confectionery, nutraceuticals, and cosmetics. Present paper is an attempt to understand comprehensive details on different aspects of this plant to explore new avenues for various value-added products.
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Aegilops tauschii is the diploid progenitor of the wheat D subgenome and a valuable resource for wheat breeding, yet, genetic analysis of resistance against Fusarium head blight (FHB) and the major Fusarium mycotoxin deoxynivalenol (DON) is lacking. We treated a panel of 147 Ae. tauschii accessions with either Fusarium graminearum spores or DON solution and recorded the associated disease spread or toxin-induced bleaching. A k-mer-based association mapping pipeline dissected the genetic basis of resistance and identified candidate genes. After DON infiltration nine accessions revealed severe bleaching symptoms concomitant with lower conversion rates of DON into the non-toxic DON-3-O-glucoside. We identified the gene AET5Gv20385300 on chromosome 5D encoding a uridine diphosphate (UDP)-glucosyltransferase (UGT) as the causal variant and the mutant allele resulting in a truncated protein was only found in the nine susceptible accessions. This UGT is also polymorphic in hexaploid wheat and when expressed in Saccharomyces cerevisiae only the full-length gene conferred resistance against DON. Analysing the D subgenome helped to elucidate the genetic control of FHB resistance and identified a UGT involved in DON detoxification in Ae. tauschii and hexaploid wheat. This resistance mechanism is highly conserved since the UGT is orthologous to the barley UGT HvUGT13248 indicating descent from a common ancestor of wheat and barley.
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Aegilops , Fusarium , Triticum/genética , Triticum/metabolismo , Glucosiltransferases/genética , Difosfato de Uridina , Melhoramento Vegetal , Doenças das Plantas/genética , Resistência à Doença/genéticaRESUMO
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be over, but its variants continue to emerge, and patients with mild symptoms having long COVID is still under investigation. SARS-CoV-2 infection leading to elevated cytokine levels and suppressed immune responses set off cytokine storm, fatal systemic inflammation, tissue damage, and multi-organ failure. Thus, drug molecules targeting the SARS-CoV-2 virus-specific proteins or capable of suppressing the host inflammatory responses to viral infection would provide an effective antiviral therapy against emerging variants of concern. Evolutionarily conserved papain-like protease (PLpro) and main protease (Mpro) play an indispensable role in the virus life cycle and immune evasion. Direct-acting antivirals targeting both these viral proteases represent an attractive antiviral strategy that is also expected to reduce viral inflammation. The present study has evaluated the antiviral and anti-inflammatory potential of natural triterpenoids: azadirachtin, withanolide_A, and isoginkgetin. These molecules inhibit the Mpro and PLpro proteolytic activities with half-maximal inhibitory concentrations (IC50 ) values ranging from 1.42 to 32.7 µM. Isothermal titration calorimetry (ITC) analysis validated the binding of these compounds to Mpro and PLpro. As expected, the two compounds, withanolide_A and azadirachtin, exhibit potent anti-SARS-CoV-2 activity in cell-based assays, with half-maximum effective concentration (EC50 ) values of 21.73 and 31.19 µM, respectively. The anti-inflammatory roles of azadirachtin and withanolide_A when assessed using HEK293T cells, were found to significantly reduce the levels of CXCL10, TNFα, IL6, and IL8 cytokines, which are elevated in severe cases of COVID-19. Interestingly, azadirachtin and withanolide_A were also found to rescue the decreased type-I interferon response (IFN-α1). The results of this study clearly highlight the role of triterpenoids as effective antiviral molecules that target SARS-CoV-2-specific enzymes and also host immune pathways involved in virus-mediated inflammation.
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The nucleocapsid (N) protein of SARS-CoV-2 plays a pivotal role in encapsulating the viral genome. Developing antiviral treatments for SARS-CoV-2 is imperative due to the diminishing immunity of the available vaccines. This study targets the RNA-binding site located in the N-terminal domain (NTD) of the N-protein to identify the potential antiviral molecules against SARS-CoV-2. A structure-based repurposing approach identified the twelve high-affinity molecules from FDA-approved drugs, natural products, and the LOPAC1280 compound libraries that precisely bind to the RNA binding site within the NTD. The interaction of these potential antiviral agents with the purified NTD protein was thermodynamically characterized using isothermal titration calorimetry (ITC). A fluorescence-based plate assay to assess the RNA binding inhibitory activity of small molecules against the NTD has been employed, and the selected compounds exhibited significant RNA binding inhibition with calculated IC50 values ranging from 8.8 µM to 15.7 µM. Furthermore, the antiviral efficacy of these compounds was evaluated using in vitro cell-based assays targeting the replication of SARS-CoV-2. Remarkably, two compounds, Telmisartan and BMS-189453, displayed potential antiviral activity against SARS-CoV-2, with EC50 values of approximately 1.02 µM and 0.98 µM, and a notable selective index of >98 and > 102, respectively. This study gives valuable insight into developing therapeutic interventions against SARS-CoV-2 by targeting the N-protein, a significant effort given the global public health concern posed due to the virus re-emergence and long COVID-19 disease.
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COVID-19 , SARS-CoV-2 , Humanos , Antivirais/farmacologia , Antivirais/química , Síndrome de COVID-19 Pós-Aguda , Nucleocapsídeo/metabolismo , Termodinâmica , RNA , Simulação de Acoplamento MolecularRESUMO
We report a high rate of seropositivity against SARS-CoV-2 in wild felines in India. Seropositivity was determined by microneutralization and plaque reduction neutralization assays in captive Asiatic lions, leopards, and Bengal tigers. The rate of seropositivity was positively correlated with that of the incidence in humans, suggesting the occurrence of large spillover events.
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COVID-19 , Leões , Panthera , Tigres , Animais , Gatos , Humanos , SARS-CoV-2 , Estudos Retrospectivos , COVID-19/epidemiologia , Índia/epidemiologiaRESUMO
A semi-microscopic theory is developed for heterogeneous electron transfer (HET) kinetics based on the energy level alignment approach at self-assembled monolayer (SAM) covered metal electrodes. Theory provides the electronic and molecular property-dependent equations for the HET rate constant (k0) and the transfer coefficient (α) for potential. k0 is formulated using the activation free energy as a product of the SAM covered metal work function (WF) and fractional electronic charge exchanged at the transition state (attained through the alignment of the frontier molecular orbital (FMO) energy level of the electroactive group with the WF of metal). k0 is a function of the metal jellium electronic screening length and dielectric and of the molecular self-assembly (through its dipole moment, size, and packing density) and the FMO energies of electroactive groups. The operative potential at the transition state is governed by α, which is a function of molecular spacer length and characteristic electronic-dipolar coupling length. The current rectification phenomenon in nanogap molecular devices is theoretically analyzed using equations for k0 and α for SAM covered source and drain electrodes. Theory unravels the LUMO or HOMO dichotomy for a given metal: (i) for the HOMO assisted ET, the metal with a high WF has a high current rectification ratio (RR), while (ii) for the LUMO assisted ET, the metal with a low WF has a high current RR in asymmetrical devices. Theory predicts the reversal in current rectification by altering the dipole moment of the anchoring molecule, the HOMO/LUMO energy of the electroactive groups, and the nature of the metal. Finally, theory shows qualitative and quantitative coherence with the reported experimental current-potential response of molecular device.
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Non-melanoma skin cancer is one of the most common malignancies reported around the globe. Current treatment therapies fail to meet the desired therapeutic efficacy due to high degree of drug resistance. Thus, there is prominent demand in advancing the current conventional therapy to achieve desired therapeutic efficacy. To break the bottleneck, nanoparticles have been used as next generation vehicles that facilitate the efficient interaction with the cancer cells. Here, we developed combined therapy of 5-fluorouracil (5-FU) and cannabidiol (CBD)-loaded nanostructured lipid carrier gel (FU-CBD-NLCs gel). The current investigation has been designed to evaluate the safety and efficacy of developed 5-Flurouracil and cannabidiol loaded combinatorial lipid-based nanocarrier (FU-CBD NLCs) gel for the effective treatment of skin cancer. Initially, confocal microscopy study results showed excellent uptake and deposition at epidermal and the dermal layer. Irritation studies performed by IR camera and HET cam shows FU-CBD NLCs was much more tolerated and less irritant compared to conventional treatment. Furthermore, gamma scintigraphy evaluation shows the skin retention behavior of the formulation. Later, in-ovo tumor remission studies were performed, and it was found that prepared FU-CBD NLCs was able to reduce tumor volume significantly compared to conventional formulation. Thus, obtained results disclosed that permeation and disposition of 5-FU and CBD into different layers of the skin FU-CBD NLCs gel could be more potential carrier than conventional gel. Furthermore, prepared formulation showed greater tumor remission, better survival rate, reduction in tumor number, area, and volume with improved biochemical profile. Thus, prepared gel could serve as a promising formulation approach for the skin cancer treatment.
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Canabidiol , Nanoestruturas , Neoplasias Cutâneas , Humanos , Absorção Cutânea , Canabidiol/metabolismo , Canabidiol/farmacologia , Portadores de Fármacos/metabolismo , Portadores de Fármacos/farmacologia , Pele , Fluoruracila/metabolismo , Fluoruracila/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Lipídeos , Tamanho da PartículaRESUMO
Two cream-coloured strains (JC732T, JC733) of Gram-stain negative, mesophilic, catalase and oxidase positive, aerobic bacteria which divide by budding, form crateriform structures, and cell aggregates were isolated from marine habitats of Andaman and Nicobar Islands, India. Both strains had genome size of 7.1 Mb and G + C content of 58.9%. Both strains showed highest 16S rRNA gene-based similarity with Blastopirellula retiformator Enr8T (98.7%). Strains JC732T and JC733 shared 100% identity of 16S rRNA gene and genome sequences. The coherence of both strains with the genus Blastopirellula was supported by the 16S rRNA gene based and the phylogenomic trees. Further, the chemo-taxonomic characters and the genome relatedness indices [ANI (82.4%), AAI (80.4%) and dDDH (25.2%)] also support the delineation at the species level. Both strains have the capability to degrade chitin and genome analysis shows the ability to fix N2. Based on the phylogenetic, phylogenomic, comparative genomic, morphological, physiological, and biochemical characteristics, strain JC732T is described as a new species of the genus Blastopirellula for which the name Blastopirellula sediminis sp. nov. is proposed, with strain JC733 as an additional strain.
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Ácidos Graxos , Fosfolipídeos , Fosfolipídeos/química , Ácidos Graxos/química , Filogenia , RNA Ribossômico 16S/genética , Ilhas , Análise de Sequência de DNA , DNA Bacteriano/genética , Técnicas de Tipagem BacterianaRESUMO
Availability of iron is a key factor in the survival and multiplication of Mycobacterium tuberculosis (M.tb) within host macrophage phagosomes. Despite host cell iron regulatory machineries attempts to deny supply of this essential micronutrient, intraphagosomal M.tb continues to access extracellular iron. In the current study, we report that intracellular M.tb exploits mammalian secreted Glyceraldehyde 3-phosphate dehydrogenase (sGAPDH) for the delivery of host iron carrier proteins lactoferrin (Lf) and transferrin (Tf). Studying the trafficking of iron carriers in infected cells we observed that sGAPDH along with the iron carrier proteins are preferentially internalized into infected cells and trafficked to M.tb containing phagosomes where they are internalized by resident mycobacteria resulting in iron delivery. Collectively our findings provide a new mechanism of iron acquisition by M.tb involving the hijack of host sGAPDH. This may contribute to its successful pathogenesis and provide an option for targeted therapeutic intervention.
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Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Ferro/metabolismo , Lactoferrina/metabolismo , Mycobacterium tuberculosis/metabolismo , Transferrina/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular Tumoral , Humanos , Células L , Camundongos , Camundongos Endogâmicos C57BL , Fagossomos/metabolismo , Células THP-1 , Tuberculose/patologiaRESUMO
Bovine herpes virus-1 (BoHV-1) is responsible for production losses through decreased milk yields, abortions, infertility, and trade restrictions in the bovine population. The disease is endemic in many countries including India. As the virus harbors a unique feature of latency animals once infected with the virus remain sero-positive for lifetime and can re-excrete the virus when exposed to stressful conditions. Hence, identification and culling of infected animals is only the means to minimize infection-associated losses. In this study, an economical indigenous assay for the detection of BoHV-1 specific antibodies was developed to cater to the huge bovine population of the country. The viral structural gD protein, expressed in the prokaryotic system was used for optimization of an indirect ELISA for bovines followed by statistical validation of the assay. The diagnostic sensitivity and specificity of the indirect ELISA were 82.9% and 91.3% respectively. Systematically collected serum samples representing organized, unorganized and breeding farms of India were tested with the indigenously developed assay for further validation.
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Doenças dos Bovinos , Herpesvirus Bovino 1 , Animais , Bovinos , Proteínas Virais , Ensaio de Imunoadsorção Enzimática , Anticorpos Antivirais , Índia , Doenças dos Bovinos/diagnósticoRESUMO
Multi-drug resistance (MDR) developed in response to chemotherapy is one of the prominent causes of therapeutic failure. The major underlying factors that contribute to such malignancies include tumor microenvironment, genetic alterations, changes at the cellular level and most of all the heterogeneity of tumors. Recent advances in the field of oncology have prompted a mechanistic understanding of the human genome which is responsible for such alterations, upon which the therapy would be designed. Such an approach that administers drugs by targeting the molecular changes is attributed to precision medicine. Precision medicine helps design therapy as per the requirement of patients based on the sharing of similar complex tumor environments. This revolutionized approach would help in early detection, better targeting, improved patient compliance and survival along with much reduced toxicity otherwise evidenced in conventional cancer therapy. This review discusses the cause of MDR, highlighting the role of precision medicine in overcoming such critical events. Major limitations and future prospects are also highlighted.
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Neoplasias , Medicina de Precisão , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Oncologia , Microambiente Tumoral/genética , Resistência a Múltiplos Medicamentos/genéticaRESUMO
OBJECTIVES: To evaluate mitral-aortic flow velocity integral ratio (MAVIR) as an echocardiographic tool to differentiate between severe and nonsevere mitral regurgitation (MR), compared with regurgitant volume (RVol) and effective regurgitant orifice area (EROA), with subgroup analysis in patients with calcific mitral valve, both by transthoracic (TTE) and transesophageal (TEE) echocardiography. Also, whether MAVIR can be used as a screening tool for severe MR. DESIGN: Prospective, cross-sectional, observational. SETTING: Cardiac operating room of a tertiary-care hospital. PARTICIPANTS: One hundred adult patients with chronic mitral regurgitation with at least mild MR by two-dimensional Doppler and with absence of mitral stenosis, aortic valve disease, and rhythm other than sinus scheduled for cardiac surgery. The subgroup (n = 24) consisted specifically of patients with a calcific mitral valve. INTERVENTIONS: Preinduction TTE and postinduction TEE in the operating room. MEASUREMENTS AND RESULTS: MAVIR, RVol, and EROA were measured in all patients both by TTE and TEE. Cohen's kappa statistics was employed to quantify concordance among RVol, EROA, and MAVIR. Diagnostic indices of MAVIR toward diagnosis of severe MR also were quantified. The results showed a strong agreement, in differentiating severe from nonsevere MR, between MAVIR and both RVol and EROA in the whole cohort (n = 100) and the subgroup (n = 24), both by TTE and TEE. Diagnostic indices were high for MAVIR compared with RVol and EROA in detecting severe MR, both by TTE and TEE. CONCLUSION: MAVIR may be used as an echocardiographic tool to differentiate between severe and nonsevere MR, even in patients with calcific valves. It also can be used to screen patients for severe MR.
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Ecocardiografia Tridimensional , Insuficiência da Valva Mitral , Adulto , Humanos , Insuficiência da Valva Mitral/diagnóstico por imagem , Ecocardiografia Tridimensional/métodos , Ecocardiografia Doppler em Cores/métodos , Estudos Prospectivos , Estudos Transversais , Velocidade do Fluxo Sanguíneo , Índice de Gravidade de DoençaRESUMO
Transition metal oxide has emerged as one of the most potential candidates for environment remediation by utilizing solar energy through photocatalysis. This study compares the optical characteristics of zinc oxide (ZnO) and ceria-doped zinc oxide (CeZnO) nanoparticles synthesized through a facile chemical precipitation method without using any assistant catalyst. The present work investigates the consequences of ceria (cerium dioxide, CeO2 ) intrusion on the photocatalytic activity of ZnO nanoparticles using methylene blue (MB) as a probe pollutant. The CeZnO showed an increase in photoactivity when compared to ZnO nanoparticles for degradation of MB in an aqueous solution under ultraviolet (UV) irradiance. The resulting heterojunction between ZnO and that of ceria enhances the charge separation efficiency showing a strong correlation between ZnO and CeO2 heterojunction on the charge transfer mechanism across the interface.