Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against
, a mutation present in an overwhelming majority ...of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K
successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1a
;LSL-Kras
;Tgfbr2
(PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.
The treatment for COVID-19 often utilizes immune-modulating drugs. These drugs are also used in immune mediated inflammatory diseases (IMIDs). We performed a systematic review about seroconversion ...after SARS-CoV-2 vaccination in patients with IMIDs and impact of various drugs on seroconversion rates.
Electronic databases were searched to identify relevant studies reporting seroconversion rates following SARS-CoV-2 vaccination in IMIDs. We calculated the pooled seroconversion rates after a single or two doses of vaccination, pooled seroconversion rates in patients with specific IMIDs, and rates in patients on various drugs/drug classes.
Twenty-five studies were included in the systematic review. The pooled seroconversion rates after two doses of mRNA vaccination were higher (83.1, 95%CI: 74.9–89.0, I2 = 90%) as compared to a single dose (69.3, 52.4–82.3, I2 = 95%). The odds of seroconversion were lower in IMIDs as compared to healthy controls (0.05, 0.02–0.13, I2 = 21%). The seroconversion rates in patients with inflammatory bowel disease (95.2, 95%CI: 92.6–96.9, I2 = 0%), spondyloarthropathy (95.6, 95% CI: 83.4–98.9, I2 = 35%), and systemic lupus erythematosus (90.7, 95%CI: 85.4–94.2, I2 = 0%) were higher as compared to rheumatoid arthritis (79.5, 95% CI: 65.1–88.9, I2 = 85%), and vasculitis (70.5, 95% CI: 52.9–83.5, I2 = 51%). The seroconversion rates following double dose of mRNA were excellent (>90%) in those on anti-tumour necrosis factor (TNF), anti-integrin (vedolizumab), anti-IL 17 (secukinumab), anti-IL6 (Tocilizumab) and anti-IL12/23 (Ustekinumab) therapies but attenuated (<70%) in patients on anti-CD20 (Rituximab) or anti-cytotoxic T lymphocyte associated antigen (CTLA-4) therapies (Abatacept). The seroconversion rates were good (70–90%) with steroids, hydroxychloroquine, JAK inhibitors, mycophenolate mofetil and leflunomide. Combination of anti-TNF with immunomodulators (azathioprine, 6-meracptopurine, methotrexate) resulted in an attenuated vaccine response as compared to anti-TNF monotherapy.
Seroconversion rates after SARS-CoV-2 vaccination are lower in patients with IMIDs. Certain therapies (anti-TNF, anti-integrin, anti-IL 17, anti-IL6, anti-12/23) do not impact seroconversion rates while others (anti-CD20, anti-CTLA-4) result in poorer responses.
•Immune mediated inflammatory diseases (IMIDs) require immune-modulating therapies which impair responses to vaccination.•Seroconversion rates after SARS-CoV-2 vaccination are lower in IMIDs as compared to healthy controls•A two-dose regimen of mRNA vaccine is associated with a better seroconversion rate in IMIDs•Certain classes of drugs (anti-CD20, anti-CTLA-4) are associated with a poor seroconversion rate•Assessment of seroconversion may be necessary in patients on some classes of immune modulating therapies.•Vaccination schedules for patients need to be individualized depending on underlying IMID and current treatment.
Iron-sulfur (Fe-S) clusters are versatile cofactors involved in regulating multiple physiological activities, including energy generation through cellular respiration. Initially, the Fe-S clusters ...are assembled on a conserved scaffold protein, iron-sulfur cluster scaffold protein (ISCU), in coordination with iron and sulfur donor proteins in human mitochondria. Loss of ISCU function leads to myopathy, characterized by muscle wasting and cardiac hypertrophy. In addition to the homozygous ISCU mutation (g.7044G→C), compound heterozygous patients with severe myopathy have been identified to carry the c.149G→A missense mutation converting the glycine 50 residue to glutamate. However, the physiological defects and molecular mechanism associated with G50E mutation have not been elucidated. In this report, we uncover mechanistic insights concerning how the G50E ISCU mutation in humans leads to the development of severe ISCU myopathy, using a human cell line and yeast as the model systems. The biochemical results highlight that the G50E mutation results in compromised interaction with the sulfur donor NFS1 and the J-protein HSCB, thus impairing the rate of Fe-S cluster synthesis. As a result, electron transport chain complexes show significant reduction in their redox properties, leading to loss of cellular respiration. Furthermore, the G50E mutant mitochondria display enhancement in iron level and reactive oxygen species, thereby causing oxidative stress leading to impairment in the mitochondrial functions. Thus, our findings provide compelling evidence that the respiration defect due to impaired biogenesis of Fe-S clusters in myopathy patients leads to manifestation of complex clinical symptoms.
Background: Muscle-specific deficiency of iron-sulfur (Fe-S) cluster scaffold protein (ISCU) leads to myopathy.
Results: Cells carrying the myopathy-associated G50E ISCU mutation demonstrate impaired Fe-S cluster biogenesis and mitochondrial dysfunction.
Conclusion: Reduced mitochondrial respiration as a result of diminished Fe-S cluster synthesis results in muscle weakness in myopathy patients.
Significance: The molecular mechanism behind disease progression should provide invaluable information to combat ISCU myopathy.
Abstract The study investigates the heat transfer and friction factor properties of ethylene glycol and glycerol-based silicon dioxide nanofluids flowing in a circular tube under continuous heat flux ...circumstances. This study tackles the important requirement for effective thermal management in areas such as electronics cooling, the automobile industry, and renewable energy systems. Previous research has encountered difficulties in enhancing thermal performance while handling the increased friction factor associated with nanofluids. This study conducted experiments in the Reynolds number range of 1300 to 21,000 with particle volume concentrations of up to 1.0%. Nanofluids exhibited superior heat transfer coefficients and friction factor values than the base liquid values. The highest enhancement in heat transfer was 5.4% and 8.3% for glycerol and ethylene glycol -based silicon dioxide Nanofluid with a relative friction factor penalty of ∼30% and 75%, respectively. To model and predict the complicated, nonlinear experimental data, five machine learning approaches were used: linear regression, random forest, extreme gradient boosting, adaptive boosting, and decision tree. Among them, the decision tree-based model performed well with few errors, while the random forest and extreme gradient boosting models were also highly accurate. The findings indicate that these advanced machine learning models can accurately anticipate the thermal performance of nanofluids, providing a dependable tool for improving their use in a variety of thermal systems. This study's findings help to design more effective cooling solutions and improve the sustainability of energy systems.
Commercial malaria rapid diagnostic tests (RDTs) detect P. falciparum histidine rich protein 2 (PfHRP2) and cross react with PfHRP3, a structural homologue. Here, we analysed natural variations in ...PfHRP2 and PfHRP3 sequences from Indian isolates and correlated these variations with RDT reactivity. A total 1392 P. falciparum positive samples collected from eight endemic states were PCR amplified for Pfhrp2 and Pfhrp3 genes and were sequenced. The deduced protein sequences were analysed for repeat variations and correlated with RDT reactivity. Out of 1392 PCR amplified samples, a single sample was Pfhrp2 negative and two samples were Pfhrp3 negative. Complete Pfhrp2 and Pfhrp3 sequences were obtained for 769 samples and 750 samples, respectively. A total of 16 distinct repeat motifs were observed for Pfhrp2 and 11 for Pfhrp3, including some new repeat types. No correlation was found between variations in the size of Pfhrp2 repeat types 2 and 7, nor between any combinations of repeat motifs, and performance of a commercial RDT at low parasite densities. The findings suggest that sequence diversity in Pfhrp2 and Pfhrp3 genes in Indian isolates is not likely to negatively influence performance of currently used PfHRP2 RDTs.
ObjectivesThe COVID-19 pandemic has profound negative impacts on people’s lives, but little is known on its effect on household food insecurity (HFI) in poor setting resources. This study assessed ...changes in HFI during the pandemic and examined the interlinkages between HFI with child feeding practices and coping strategies.DesignA longitudinal survey in December 2019 (in-person) and August 2020 (by phone).SettingCommunity-based individuals from 26 blocks in 2 districts in Uttar Pradesh, India.ParticipantsMothers with children <2 years (n=569).Main outcomes and analysesWe measured HFI by using the HFI Access Scale and examined the changes in HFI during the pandemic using the Wilcoxon matched-pairs signed-rank tests. We then assessed child feeding practices and coping strategies by HFI status using multivariable regression models.ResultsHFI increased sharply from 21% in December 2019 to 80% in August 2020, with 62% households changing the status from food secure to insecure over this period. Children in newly or consistently food-insecure households were less likely to consume a diverse diet (adjusted OR, AOR 0.57, 95% CI 0.34 to 0.95 and AOR 0.51, 95% CI 0.23 to 1.12, respectively) compared with those in food-secure households. Households with consistent food insecurity were more likely to engage in coping strategies such as reducing other essential non-food expenditures (AOR 2.2, 95% CI 1.09 to 4.24), borrowing money to buy food (AOR 4.3, 95% CI 2.31 to 7.95) or selling jewellery (AOR 5.0, 95% CI 1.74 to 14.27) to obtain foods. Similar findings were observed for newly food-insecure households.ConclusionsThe COVID-19 pandemic and its lockdown measures posed a significant risk to HFI which in turn had implications for child feeding practices and coping strategies. Our findings highlight the need for further investment in targeted social protection strategies and safety nets as part of multisectoral solutions to improve HFI during and after COVID-19.
Integration of the latest technological advancements such as Internet of Things (IoT) and Computational Intelligence (CI) techniques is an active research area for various industrial applications. ...The rapid urbanization and exponential growth of vehicles has led to crowded traffic in cities. The deployment of IoT infrastructures for building smart and intelligent traffic management system greatly improves the quality and comfort of city dwellers. This work aims at building a cost effective IoT enabled traffic forecasting system using deep learning techniques. The case study experimentation is done in a real time traffic environment. The main contributions of this work include: (i) deploying road side sensor station built with ultrasonic sensor and Arduino Uno controller for obtaining traffic flow data (ii) building an IoT cloud system based on open source Thingspeak cloud platform for monitoring real time traffic (iii) performing short term traffic forecast using Recurrent Neural Network (RNN) models such as Long Short Term Memory (LSTM) and Gated Recurrent Unit (GRU). The performance of the prediction model is compared with the traditional statistical methods such as Autoregressive Integrated Moving Average (ARIMA), Seasonal ARIMA (SARIMA) and Convolutional Neural Network (CNN). The results show good performance metrics with RMSE of 5.8, 7.9, 10.2 for LSTM model and 6.7, 8.6, 10.9 for GRU model for three different scenarios such as whole day, morning congested hour and evening congested hour datasets.
Solar photovoltaic system is one of the growing renewable energy sources in the energy market. The performance of the PV system is mainly affected by the partial shading which is inevitable. It ...creates mismatch losses between the PV rows that reduce the power generation. Many research works proposed solutions like Maximum Power Point Tracking (MPPT) and static & dynamic reconfiguration methods. These methods can enhance the power conversion rate of the PV system. However, this power conversion rate can be enhanced by the proposed mismatch loss mitigation algorithm. A current compensation converter has been developed to operate the PV system with even current generating rows. The PV row currents have been measured by using the current sensor and fed to the controller. The controller performs the algorithm and generates the triggering signals to the DIDO converter and it operates the PV rows with even current generation. The performance of the proposed system has been simulated under five kinds of shading patterns using the MATLAB/Simulink® and the corresponding PV curves were plotted. This work is also validated using the 200Watts PV system, which is constructed with the four polycrystalline PV modules as a 2 × 2 PV array. The performance of the proposed system with the corresponding results and waveforms are presented in this work.
•A current compensation converter has been developed to operate the PV system with even current generating rows.•The performance of the proposed system has been simulated under six kinds of shading patterns.•The experimental hardware setup of the proposed configurations has been developed and investigated.•Various performance parameters have been considered to assess the excellency of the proposed concept.
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•CuO NPs have been synthesized by green synthesis method using black tea.•UV–Vis, XRD, FTIR characterisation techniques confirm the synthesis of CuO NPs.•CuO NPs have been dispersed ...in a nematic liquid crystal at various concentrations.•Thermodynamic, optical and dielectric studies have been carried out.•Results show enhancement in the stability of the nematic phase.
Green synthesis of nanoparticles is a biological, eco-friendly and less expensive method which is free from chemical contaminants. In this work, copper oxide nanoparticles (CuO NPs) have been synthesized via green synthesis method. This method proved to be efficient for preparing CuO NPs at room temperature without using any inert atmosphere. The CuO NPs have been characterized using X-Ray Diffraction, Ultraviolet–Visible Spectroscopy and Fourier Transform Infrared Spectroscopy techniques which confirmed the proper synthesis of CuO NPs of the size 2–3 nm. Two different weight percents (0.2 and 0.5) of the synthesized CuO NPs have been dispersed in the nematogenic liquid crystalline material 4-pentyl-4′-cyanobiphenyl (5CB). The physical properties of pure 5CB and its nanocomposites were studied by differential scanning calorimetry, ultraviolet–visible spectroscopy and impedance spectroscopy. Thermodynamic and dielectric results show enhancement in the nematic to isotropic transition temperature of nanocomposites along with enhancement in conductivity as compared to its value for the pure 5CB. Through optical studies, the band gap has been estimated by the Tauc plots which suggest decrease in the optical band gaps of dispersed samples.
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