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Most social species self-organize into dominance hierarchies1,2, which decreases aggression and conserves energy3,4, but it is not clear how individuals know their social rank. We have only begun to learn how the brain represents social rank5-9 and guides behaviour on the basis of this representation. The medial prefrontal cortex (mPFC) is involved in social dominance in rodents7,8 and humans10,11. Yet, precisely how the mPFC encodes relative social rank and which circuits mediate this computation is not known. We developed a social competition assay in which mice compete for rewards, as well as a computer vision tool (AlphaTracker) to track multiple, unmarked animals. A hidden Markov model combined with generalized linear models was able to decode social competition behaviour from mPFC ensemble activity. Population dynamics in the mPFC predicted social rank and competitive success. Finally, we demonstrate that mPFC cells that project to the lateral hypothalamus promote dominance behaviour during reward competition. Thus, we reveal a cortico-hypothalamic circuit by which the mPFC exerts top-down modulation of social dominance.
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Hipotálamo , Córtex Pré-Frontal , Animais , Região Hipotalâmica Lateral , Camundongos , Recompensa , Comportamento SocialRESUMO
The factors that drive dengue virus (DENV) evolution, and selection of virulent variants are yet not clear. Higher environmental temperature shortens DENV extrinsic incubation period in mosquitoes, increases human transmission, and plays a critical role in outbreak dynamics. In the present study, we looked at the effect of temperature in altering the virus virulence. We found that DENV cultured at a higher temperature in C6/36 mosquito cells was significantly more virulent than the virus grown at a lower temperature. In a mouse model, the virulent strain induced enhanced viremia and aggressive disease with a short course, hemorrhage, severe vascular permeability, and death. Higher inflammatory cytokine response, thrombocytopenia, and severe histopathological changes in vital organs such as heart, liver, and kidney were hallmarks of the disease. Importantly, it required only a few passages for the virus to acquire a quasi-species population harboring virulence-imparting mutations. Whole genome comparison with a lower temperature passaged strain identified key genomic changes in the structural protein-coding regions as well as in the 3'UTR of the viral genome. Our results point out that virulence-enhancing genetic changes could occur in the dengue virus genome under enhanced growth temperature conditions in mosquito cells.
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Vírus da Dengue , Humanos , Animais , Camundongos , Vírus da Dengue/genética , Sorogrupo , Temperatura , Virulência , Regiões 3' não Traduzidas , Modelos Animais de DoençasRESUMO
The industrial production of synthetic fertilizers and the wide-scale combustion of fossil fuels have disrupted the global nitrogen cycle, necessitating a prudent shift towards sustainable nitrogen management. Traditional wastewater treatment methods primarily focus on nitrogen elimination rather than recovery in useable form, exacerbating resource depletion and environmental degradation. This review explores integrated technologies, including bio-electroconcentration cells (BEC), direct ammonia fuel cells (DAFC), solid oxide fuel cells (SOFC), and microbial fuel cells (MFC), for effective nutrient recovery in conjugation with energy recovery. Recovered nitrogen, primarily green ammonia, offers a carbon-free energy carrier for diverse applications, including applications in DAFC and SOFC. This review underscores the importance of synchronously retrieving ammonia from wastewater and efficiently diverting it for energy recovery using an integrated fuel cell approach. The key technical challenges and future perspectives are discussed, highlighting the potential of these integrated systems to advance sustainability and circular economy goals.
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Microbial desalination cells (MDCs) are considered as a sustainable technology for water desalination, wastewater treatment, and power generation. However, this neoteric technology suffers from different challenges, including sluggish oxygen reduction reaction and poor electron transfer from microbes to electrodes, ultimately leading to less power generation and desalination efficiency. This review delves into the intricate roles of both abiotic and biocatalysts in enhancing performance of MDCs through ion removal and charge transfer mechanisms. Detailed discussions highlight the comparative advantages and limitations of different catalyst types and insights into electrode modifications to optimise catalytic activity and biofilm formation. Further, recent advancements in electrode engineering, including surface coatings and integration of nanomaterial, geared towards enhancing efficiency of MDC and performance stability are discussed. Finally, future recommendations are provided, focusing on innovative catalyst designs, material integration, and considerations for scale-up and commercialisation, thereby offering a comprehensive roadmap for the continued advancement of MDC.
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Eletrodos , Purificação da Água , Purificação da Água/métodos , Catálise , Salinidade , Águas Residuárias/química , Biofilmes , Fontes de Energia BioelétricaRESUMO
Extensive vascular leakage and shock is a major cause of dengue-associated mortality. At present, there are no specific treatments available. Sphingolipid pathway is a key player in the endothelial barrier integrity; and is mediated through the five sphingosine-1-phosphate receptors (S1PR1-S1PR5). Signaling through S1PR2 promotes barrier disruption; and in Dengue virus (DENV)-infection, there is overexpression of this receptor. Fingolimod (FTY720) is a specific agonist that targets the remaining barrier-protective S1P receptors, without targeting S1PR2. In the present study, we explored whether FTY720 treatment can alleviate DENV-induced endothelial hyperpermeability. In functional assays, in both in vitro systems and in AG129 animal models, FTY720 treatment was found effective. Upon treatment, there was complete restoration of the monolayer integrity in DENV serotype 2-infected human microvascular endothelial cells (HMEC-1). At the molecular level, the treatment reversed activation of the S1P pathway. It significantly reduced the phosphorylation of the key molecules such as PTEN, RhoA, and VE-Cadherin; and also, the expression levels of S1PR2. In DENV2-infected AG129 mice treated with FTY720, there was significant improvement in weight gain, in overall clinical symptoms, and in survival. Whereas 100% of the DENV2-infected, untreated animals died by day-10 post-infection, 70% of the FTY720-treated animals were alive; and at the end of the 15-day post-infection observation period, 30% of them were still surviving. There was a significant reduction in the Evan's-blue dye permeability in the organs of FTY720-treated, DENV-2 infected animals; and also improvement in the hemogram, with complete restoration of thrombocytopenia and hepatic function. Our results show that the FDA-approved molecule Fingolimod (FTY720) is a promising therapeutic intervention in severe dengue.
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Metal pollution load in soil environment has been enhanced during last few decades due to increasing industrialization and wide application of metals in all sectors. Due to the persistent and hazardous nature of metals, it can accumulate in the living system and cause severe risks to the ecosystem. The abundance of metals in soils from 5 different land use systems (industrial, industrial highway, brick kiln production area, residential highways and botanical gardens) in the Indo-Gangetic Plain region of India was analysed for three consecutive years (2018-2020) to evaluate the effects of metal load on soil properties and ecosystem health. Soil enzymatic activities, moisture, porosity, total nitrogen, and organic carbon were least at the industrial area of Ramnagar site and highest at Botanical garden area of BHU. Geochemical indices were calculated to compare the background status of metals in the soil where Cd, Cu, Cr, Co, Ni, Mn and Zn were increased in recent times. Contamination, enrichment and potential ecological risk factors with respect to Cu and Cd contents in soil were significantly higher at industrial area of Ramnagar and highway near industrial area. Maximum lifetime non-cancer and cancer health hazards were observed for Cd and Ni, respectively. The study clearly indicates that Cd, Cu and Ni are capable of posing health risk and cause imbalance in ecological functioning of soil due to chronic exposure of the potential toxic metals generated through change in land uses in sub-urban areas of Indo-Gangetic Plain region.
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Metais Pesados , Poluentes do Solo , Metais Pesados/toxicidade , Metais Pesados/análise , Estações do Ano , Monitoramento Ambiental , Ecossistema , Cádmio/análise , Poluentes do Solo/toxicidade , Poluentes do Solo/análise , Medição de Risco , Solo/química , ChinaRESUMO
PURPOSE OF REVIEW: Advancements in the next-generation sequencing technologies have identified rare transcripts of long noncoding RNAs (lncRNAs) in the genome of cancers, including in acute myeloid leukemia (AML). The purpose of this review is to highlight the contribution of lncRNAs in AML pathogenesis, prognosis, and chemoresistance. RECENT FINDINGS: Several studies have recently reported that deregulated lncRNAs are novel key players in the development of AML and are associated with AML pathophysiology and may serve as prognostic indicators. A few aberrantly expressed lncRNAs that correlated with the recurrent genetic mutations in AML such as NPM1 and RUNX1 have recently been characterized. Moreover, a few lncRNAs in MLL-rearranged leukemia have been described. Additionally, the involvement of lncRNAs in AML chemoresistance has been postulated. SUMMARY: Investigating the functional roles of the noncoding regions including lncRNAs, may provide novel insights into the pathophysiology, refine the prognostic schema, and provide novel therapeutic treatment strategies in AML.
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Leucemia Mieloide Aguda , RNA Longo não Codificante , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , RNA Longo não Codificante/genéticaRESUMO
The intake of fruits has proven to reduce the risk and incidence of cancer worldwide and plays a crucial role in cancer prevention. Pomegranate (Punica granatum), which belongs to the Punicaceae family, is one such plant that contains beneficial nutrients as well as many bioactive components and important phytochemicals that can be attributed to cancer-related therapeutic purposes. Pomegranate possesses antioxidant, anti-inflammatory, anti-proliferative, anti-angiogenic, anti-invasive, and anti-metastatic properties, and induces apoptosis. It also down-regulates various signaling pathways such as NF-κB, PI3K/AKT/mTOR, and Wnt, and down-regulates the expression of genes that are responsible in cancer development, such as anti-apoptotic genes, MMPs, VEGF, c-met, cyclins, Cdks, and pro-inflammatory cytokines. Therefore, inclusion of the fruit in one's diet would assist in a healthy life protected from cancer and also act as an effective chemotherapeutic with no toxic side effects.
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Antineoplásicos/uso terapêutico , Lythraceae , Neoplasias/tratamento farmacológico , Fitoterapia , Preparações de Plantas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Humanos , Preparações de Plantas/farmacologiaRESUMO
Despite tremendous progress made during the last few decades in the treatment options for cancer, compounds isolated from Mother Nature remain the mainstay for therapy of various malignancies. Fangchinoline, initially isolated from the dried root of Stephaniae tetrandrine, has been found to exhibit diverse pharmacological effects including significant anticancer activities both in tumor cell lines and selected preclinical models. This alkaloid appears to act by modulating the activation of various important oncogenic molecules involved in tumorigenesis leading to a significant decrease in aberrant proliferation, survival and metastasis of tumor cells. This mini-review briefly describes the potential effects of fangchinoline on important hallmarks of cancer and highlights the molecular targets modulated by this alkaloid in various tumor cell lines and preclinical models.
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Benzilisoquinolinas/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Alcaloides/química , Alcaloides/uso terapêutico , Apoptose/efeitos dos fármacos , Benzilisoquinolinas/química , Linhagem Celular Tumoral , Humanos , Neoplasias/patologia , Stephania tetrandra/químicaRESUMO
Embelin is a naturally-occurring benzoquinone compound that has been shown to possess many biological properties relevant to human cancer prevention and treatment, and increasing evidence indicates that embelin may modulate various characteristic hallmarks of tumor cells. This review summarizes the information related to the various oncogenic pathways that mediate embelin-induced cell death in multiple cancer cells. The mechanisms of the action of embelin are numerous, and most of them induce apoptotic cell death that may be intrinsic or extrinsic, and modulate the NF-κB, p53, PI3K/AKT, and STAT3 signaling pathways. Embelin also induces autophagy in cancer cells; however, these autophagic cell-death mechanisms of embelin have been less reported than the apoptotic ones. Recently, several autophagy-inducing agents have been used in the treatment of different human cancers, although they require further exploration before being transferred from the bench to the clinic. Therefore, embelin could be used as a potential agent for cancer therapy.
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Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia , Benzoquinonas/química , Produtos Biológicos/química , Sinergismo Farmacológico , Humanos , Neoplasias/metabolismo , Oxirredução/efeitos dos fármacos , Transdução de SinaisRESUMO
Neuropathic pain is a state of chronic pain arising after peripheral or central nerve injury. These injuries can be mediated through the activation of various cells (astrocytes, microglia and Schwann cells), as well as the dissolution of distal axons. Recent studies have suggested that after nerve injury, Toll-like receptors (TLRs) involved in Wallerian degeneration and generation of neuropathic pain. Furthermore, these TLRs are responsible for the stimulation of astrocytes and microglia that can cause induction of the proinflammatory mediators and cytokines in the spinal cord, thereby leading to the generation and maintenance of neuropathic pain. Indeed considering the prevalence of neuropathic pain and suffering of the affected patients, insights into the diverse mechanism(s) of activation of TLR signaling cascades may open novel avenues for the management of this chronic condition. Moreover, existing therapies like antidepressants, anticonvulsants, opiates and other analgesic are not sufficiently effective in reducing the pain. In this review, we present substantial evidences highlighting the diverse roles of TLRs and their signaling pathways involved in the progression of neuropathic pain. Furthermore, an elaborate discussion on various existing treatment regimens and future targets involving TLRs has also been included.
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Analgésicos/farmacologia , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Receptores Toll-Like/metabolismo , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismoRESUMO
Rho kinase inhibitors (ROCK II) play a key role in glaucoma management attributed to their IOP lowering ability and neuroprotective effects. In the present study, a series of novel benzimidazole derivatives (9a-m) has been synthesized and evaluated for their IOP lowering, Rho kinase inhibitory and antioxidant properties. The synthesized compounds were found to be lipophilic and showed a significant IOP lowering effect both in the treated and the contralateral eye comparable to the reference standard fasudil. The nitrophenyl piperazine substituted compound 9j exhibited significant IOP lowering (51.56%) and an inhibition of 57.25 and 77.92% towards ROCK II enzyme at a concentration of 0.5 and 1â¯mM respectively. It possessed a considerable free radical scavenging activity exhibiting an IC50 value of 95.49⯵g/mL in DPPH assay. The molecular docking studies of compound 9j indicated the binding of the compound at the active site of recombinant human ROCK II which makes it a promising antiglaucoma agent.
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Anti-Hipertensivos/farmacologia , Benzimidazóis/farmacologia , Desenho de Fármacos , Glaucoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Glaucoma/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Quinases Associadas a rho/metabolismoRESUMO
Plant community structure under different land uses provides an important understanding of vegetation dynamics to safeguard future restoration programmes and balance ecosystem services. Therefore, this study was carried out to estimate the alterations in soil properties and contamination by potentially toxic metals at different land uses (industrial, brick kiln, highway, and residential areas) compared to the reference (botanical garden area) site coupled with their subsequent influence on herbaceous community structure, bioconcentration, translocation, and extraction amount of metals in different plant species. Most of the total and phytoavailable metals (Co, Cr, Cd, Cu, Ni, Pb, Mn, and Zn) were higher at the contaminated sites compared to the reference site. The number of herbaceous species was highest at the reference site and minimum at the industrial site. Dominant and tolerant species were Cyanodon dactylon, Croton bonaplandianus, Achyranthus aspera, Malvestrum coromendelianum, Dicanthium annulatum, Nicotiana hindostana, Sporobolus virginicus, and Parthenium hysterophorus, found at the industrial, brick kiln, and highway sites. Based on transfer coefficients, C. bonaplandianus, D. annulatum, and Eleusine indica were recognized as potential accumulators, whereas C. dactylon, Commelina benghalensis, A. aspera, Amaranthus sessilis, and M. coromendelianum were found as excluder species for different metals. The identified tolerant herbaceous species could be used for future phytoremediation strategies and the prevention of hazardous risks to living components of contaminated sites.
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Metais Pesados , Poluentes do Solo , Metais Pesados/análise , Ecossistema , Plantas , Biodegradação Ambiental , Poaceae , Solo/química , Poluentes do Solo/análiseRESUMO
Bipolar disorder (BD) is a severe mental illness that can result from neurodevelopmental aberrations, particularly in familial BD, which may include causative genetic variants. In the present study, we derived cortical organoids from BD patients and healthy (control) individuals from a clinically dense family in the Indian population. Our data reveal that the patient organoids show neurodevelopmental anomalies, including organisational, proliferation and migration defects. The BD organoids show a reduction in both the number of neuroepithelial buds/cortical rosettes and the ventricular zone size. Additionally, patient organoids show a lower number of SOX2-positive and EdU-positive cycling progenitors, suggesting a progenitor proliferation defect. Further, the patient neurons show abnormal positioning in the ventricular/intermediate zone of the neuroepithelial bud. Transcriptomic analysis of control and patient organoids supports our cellular topology data and reveals dysregulation of genes crucial for progenitor proliferation and neuronal migration. Lastly, time-lapse imaging of neural stem cells in 2D in vitro cultures reveals abnormal cellular migration in BD samples. Overall, our study pinpoints a cellular and molecular deficit in BD patient-derived organoids and neural stem cell cultures.
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CONTEXT: Molecular dynamics-based investigation has been carried out to simulate the nano-indentation loading in crystalline Al-amorphous Al90Sm10 metallic glass (MG) with an aim to investigate the effect orientation of crystalline-amorphous (C/A) interface orientation on the nano-indentation behavior of the C/A Al-Al90Sm10 nanolaminate for varying indenter speeds. Post-analysis techniques like adaptive-common neighbor analysis (a-CNA), atomic strain, dislocation extraction algorithm (DXA), and Voronoi polyhedral analysis (VP) have been employed to capture the structural evolution during simulated nano-indentation loading. C/A Al-Al90Sm10 nanolaminate with C/A interface orientated perpendicular to the indenter exhibits the presence of elastic regime followed by plastic curve, whereas load versus depth curve behaves plastically since the beginning in case of C/A Al-Al90Sm10 nanolaminate with C/A interface orientated parallel to the indenter. The dislocation density growth is slower in case of C/A Al-Al90Sm10 nanolaminate with C/A interface orientated perpendicular to the indenter attributed to the sinking of dislocations into MG counterpart of the nanolaminate, thereby triggering shear transformation zone activation. Whereas, the dislocation generation is delayed in case of C/A Al-Al90Sm10 nanolaminate with C/A interface orientated parallel to the indenter by virtue of amorphous Al90Sm10 MG coating on crystalline Al but is extensive and rapid. The disintegration of ICO-like structures and mixed clusters and growth of crystal-like clusters is discernible in C/A Al-Al90Sm10 nanolaminate with C/A interface orientated perpendicular to the indenter. On the other hand, the VP population exhibits cyclic variation in C/A Al-Al90Sm10 nanolaminate with C/A interface orientated parallel to the indenter. A transformation pathway of VPs has been mapped out for C/A Al-Al90Sm10 nanolaminate under nano-indentation loading. METHODS: The simulations have been carried out by employing Molecular Dynamics using the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) platform. Post-analysis techniques like adaptive-common neighbor analysis (a-CNA), atomic strain, dislocation extraction algorithm (DXA), and Voronoi polyhedral analysis (VP) have been employed to capture the structural evolution during simulated nano-indentation loading.
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The prognostic impact of Wilms tumor 1 (WT1) mutations remains controversial for patients with acute myeloid leukemia (AML). Here, we aimed to determine the clinical implication of WT1 mutations in a large cohort of pediatric AML. The clinical data of 870 pediatric patients with AML were downloaded from the therapeutically applicable research to generate effective treatment (TARGET) dataset. We analyzed the prevalence, clinical profile, and prognosis of AML patients with WT1 mutations in this cohort. Our results showed that 6.7% of total patients harbored WT1 mutations. These WT1 mutations were closely associated with normal cytogenetics (P<0.001), FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutations (P<0.001), and low complete remission induction rates (P<0.01). Compared to the patients without WT1 mutations, patients with WT1 mutations had a worse 5-year event-free survival (21.7 ± 5.5% vs 48.9 ± 1.8%, P<0.001) and a worse overall survival (41.4 ± 6.6% vs 64.3 ± 1.7%, P<0.001). Moreover, patients with both WT1 and FLT3/ITD mutations had a dismal prognosis. Compared to chemotherapy alone, hematopoietic stem cell transplantation tended to improve the prognoses of WT1-mutated patients. Multivariate analysis demonstrated that WT1 mutations conferred an independent adverse impact on event-free survival (hazard ratio 1.910, P = 0.001) and overall survival (hazard ratio 1.709, P = 0.020). In conclusion, our findings have demonstrated that WT1 mutations are independent poor prognostic factors in pediatric AML.
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Constitutive activation of NF-κB is associated with proinflammatory diseases and suppression of the NF-κB signaling pathway has been considered as an effective therapeutic strategy in the treatment of various cancers including hepatocellular carcinoma (HCC). Herein, we report the synthesis of 1,2 oxazines and their anticancer potential. The antiproliferative studies presented 3-((4-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)methyl)-4-phenyl-4,4a,5,6,7,7a-hexahydrocyclopenta [e][1,2]oxazine(3i) as a lead cytotoxic agent against HCC cells. Flow cytometric analysis showed that 3i caused a substantial increase in the subG1 cell population. Annexin-V-FITC-PI staining showed a significant increase in the percentage of apoptotic cells on treatment with 3i. Transfection with p65 siRNA significantly reduced the 3i induced DNA fragmentation indicating that 3i may primarily mediate its proapoptotic effects by abrogating the NF-κB signaling. In addition, treatment of HCC cells with 3i decreased the DNA binding ability of NF-κB and NF-κB-dependent luciferase expression. Taken together, this report introduces 1,2-oxazine that potently targets the NF-κB signaling pathway in HCC cells.
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A large-scale molecular dynamics (MD) simulation of nano-indentation was carried out to provide insight into the influence of the Al-Al2O3 interface on dislocation evolution and deformation behavior of Al substrate coated with Al2O3 thin film. Adaptive common neighbor analysis (a-CNA), centro-symmetry parameter (CSP) estimation, and dislocation extraction algorithm (DXA) were implemented to represent structural evolution during nano-indentation deformation. The absence of elastic regime was observed in the P-h curve for this simulated nano-indentation test of Al2O3 thin film coated Al specimen. The displacement of oxygen atoms from Al2O3 to Al partly through the interface greatly influences the plastic deformation behavior of the specimen during nano-indentation. Prismatic dislocation loops, which are formed due to pinning of Shockley partials (1/6 < 112>) by Stair-rod (1/6 < 110>) and Hirth dislocation (1/3 < 001>), were observed in all cases studied in this work. Pile-up of atoms was also observed and the extent of the pile-up was found to vary with the test temperature. A distorted stacking fault tetrahedron (SFT) is formed when a nano-indentation test is carried out at 100 K. The presence of a prismatic dislocation loop, SFT and dislocation forest caused strain hardening and, consequently, there is an increase in hardness as indentation depth increases. Graphical abstract Figure illustrates nano-indentation model set up along with load vs. depth curve and distorted stacking fault tetrahedron.
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Aberrant activation of NF-κB is linked with the progression of human malignancies including hepatocellular carcinoma (HCC), and blockade of NF-κB signaling could be a potential target in the treatment of several cancers. Therefore, designing of novel small molecule inhibitors that target NF-κB activation is of prime importance in the treatment of several cancers. In the present work, we report the synthesis of series of 1,3,4-oxadiazoles, investigated their anticancer potential against HCC cells, and identified 2-(3-chlorobenzo[b]thiophen-2-yl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (CMO) as the lead compound. Further, we examined the effect of CMO on cell cycle distribution (flow cytometry), apoptosis (annexin V-propidium iodide-FITC staining), and phosphorylation of NF-κB signaling pathway proteins (IκB and p65) in HCC cells. We found that CMO induced antiproliferative effect in dose- and time-dependent manner. Also, CMO significantly increased the percentage of sub-G1 cell population and induced apoptosis. Furthermore, CMO found to decrease the phosphorylation of IκB (Ser 32) in the cytoplasmic extract and p65 (Ser 536) in the nuclear extract of HCC cells. It also abrogated the DNA binding ability and transcriptional activity of NF-κB. CMO induced the cleavage of PARP and caspase-3 in a time-dependent manner. In addition, transfection with p65 small interfering RNA blocks CMO-induced caspase-3/7 activation. Molecular docking analysis revealed that CMO interacts with the hydrophobic region of p65 protein. Thus, we are reporting CMO as an inhibitor of NF-κB signaling pathway.
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Increased intestinal absorption of oxalate causes hyperoxaluria, a major risk factor for kidney stone disease. Intestinal colonization of recombinant probiotic bacteria expressing oxalate-degrading gene (OxdC) is an effective therapeutic option for recurrent calcium oxalate (CaOx) stone disease. Therefore, we aimed to develop food-grade probiotic L. plantarum secreting OxdC using lactococcal group II intron, Ll.LtrB and evaluate its oxalate degradation ability in vivo. Male Wistar albino rats were divided into four groups. The rats of group I received normal rat chow and drinking water. Groups II, III and IV rats received 5% potassium oxalate containing diet for 28 days. Groups III and IV rats received L. plantarum and food-grade recombinant L. plantarum respectively from 15 to 28 days. Biochemical parameters and crystalluria were analysed in 24â¯h urine samples. At the end of experimental period, rats were sacrificed; intestine and kidneys were dissected out for colonization studies and histopathological analysis. Herein, we found that the administration of recombinant probiotics significantly reduced the urinary oxalate, calcium, urea, and creatinine levels in rats of group IV compared to group II. Furthermore, colonization studies indicated that recombinant probiotics have gastrointestinal transit and intestinal colonization ability similar to that of wild-type bacteria. In addition, gene expression studies revealed down-regulation of OPN and KIM-1 among group IV rats. Histopathological analysis showed less evidence of nephrocalcinosis in group IV rats. In conclusion, the study demonstrates that food-grade L. plantarum secreting OxdC is capable of degrading intestinal oxalate and thereby prevent CaOx stone formation in experimental rats.