Molecular mechanisms of thalidomide effectiveness on COVID-19 patients explained: ACE2 is a new ΔNp63α target gene.

COVID-19 pandemic is caused by the SARS-CoV-2 virus, whose internalization and infection are mediated by the angiotensin-converting enzyme 2 (ACE2). The identification of novel approaches to tackle this step is instrumental for the development of therapies for the management of COVID-19 and other diseases with a similar mechanism of infection. Thalidomide, a drug sadly known for its teratogenic effects, has potent immunomodulatory and anti-inflammatory properties. Treatment with this drug has been shown to improve the immune functions of COVID-19 patients and proposed for the management of COVID-19 in clinical practice through drug repositioning. Here, we investigated the molecular details linking thalidomide to ACE2 and COVID-19, showing that in conditions mimicking SARS-CoV-2-associated cytokine storm, the transcription factor ΔNp63α and ACE2 are stabilized, and IL-8 production is increased. In such conditions, we found p63 to bind to and regulate the expression of the ACE2 gene. We previously showed that ΔNp63α is degraded upon thalidomide treatment and now found that treatment with this drug-or with its analogue lenalidomide-downregulates ACE2 in a p63-dependent manner. Finally, we found that thalidomide treatment reduces in vitro infection by pseudo-SARS-CoV-2, a baculovirus pseudotyped with the SARS-CoV-2 spike protein. Overall, we propose the dual effect of thalidomide in reducing SARS-CoV-2 viral re-entry and inflammation through p63 degradation to weaken SARS-CoV-2 entry into host cells and mitigate lung inflammation, making it a valuable option in clinical management of COVID-19. KEY MESSAGES: Thalidomide treatment results in p63-dependent ACE2 downregulation. ACE2 is a p63 transcriptional target. Thalidomide reduces the "cytokine storm" associated to COVID-19. Thalidomide prevents viral re-entry of SARS-CoV-2 by p63-dependent ACE2 downregulation. Thalidomide is a modulator of SARS-CoV-2 or other ACE2-dependent infections. ACE2 is modulated by a pharmacological substance.

Dynamic response of sandwich functionally graded nanoplate under thermal environments and elastic foundations using dynamic stiffness method.

The present paper introduces the development of dynamic stiffness method for analyzing small-scale sandwich functionally graded nanoplates resting on elastic foundation in thermal environments. The mathematical formulation is based on classical plate theory in conjunction with nonlocal elasticity theory. The governing equation is derived using Hamilton's principle. The dynamic stiffness matrix is obtained through the application of the Levy displacement approach and assembled to form the global stiffness matrix. The final matrix is solved for natural frequency of the plates using the Wittrick-Williams algorithm. The proposed methodology is validated against existing literature, demonstrating a strong agreement. Various parametric studies explore the effects of thermal environments, volume fraction index, sandwich configurations, elastic foundation characteristics, nonlocal parameter and boundary conditions. The results show the versatility of the proposed approach in addressing small scaled complex engineering structures. This research significantly contributes to the understanding and analysis of sandwich functionally graded nanoplates, providing valuable insights for applications in aerospace, structural systems, sensors, actuators, and energy harvesting devices.

Fascin Inhibitor NP-G2-044 Decreases Cell Metastasis and Increases Overall Survival of Mice-Bearing Lung Cancers.

AIM: Fascin is an actin-binding protein that promotes tumor metastasis. The inhibition of fascin on the progress of non-small cell lung cancer (NSCLC) is not very clear. Hence, this study explored the potential effect of NP-G2-044, a novel fascin inhibitor, in human NSCLC lines and the Lewis lung cancer (LCC) mice model. METHODS: The growth of cells was analyzed via CCK-8 assays, and the flow cytometry was adopted for cell cycle and apoptosis analysis, as well as the migration and invasion of NSCLC cells with or without NP-G2-044. The therapy of NP-G2-044, which synergizes with cisplatin and PD-1, was evaluated in the established xenograft Lewis's lung cancer of mice. RESULTS: Fascin was overexpressed in human NSCLC cells, and inhibition of fascin by NP-G2-044 attenuated NSCLC cell growth and remarkably undermined the ability of migration and invasion in vitro, which was related to the reduced epithelialmesenchymal transition (EMT) including downregulation of N-cadherin and vimentin, and upregulation of E-cadherin. Further results implied that the above changes may be partially mediated by the Wnt/ß-catenin pathway. In vivo, NP-G2-044 slowed down tumor development and enhanced overall survival alone, leading to synergistic anticancer effects with cisplatin or PD-1 inhibitor. CONCLUSION: Fascin inhibition could inhibit the metastasis of NSCLC and has the potential to enhance the efficacy of cisplatin and PD-1 inhibitors by blocking the Wnt/ß- catenin pathway.

Silver Nanoparticles: Synthesis, Structure, Properties and Applications.

Silver nanoparticles (Ag NPs) have accumulated significant interest due to their exceptional physicochemical properties and remarkable applications in biomedicine, electronics, and catalysis sensing. This comprehensive review provides an in-depth study of synthetic approaches such as biological synthesis, chemical synthesis, and physical synthesis with a detailed overview of their sub-methodologies, highlighting advantages and disadvantages. Additionally, structural properties affected by synthesis methods are discussed in detail by examining the dimensions and surface morphology. The review explores the distinctive properties of Ag NPs, including optical, electrical, catalytic, and antimicrobial properties, which render them beneficial for a range of applications. Furthermore, this review describes the diverse applications in several fields, such as medicine, environmental science, electronics, and optoelectronics. However, with numerous applications, several kinds of issues still exist. Future attempts need to address difficulties regarding synthetic techniques, environmental friendliness, and affordability. In order to ensure the secure utilization of Ag NPs, it is necessary to establish sustainability in synthetic techniques and eco-friendly production methods. This review aims to give a comprehensive overview of the synthesis, structural analysis, properties, and multifaceted applications of Ag NPs.

Long-lasting anti-corrosion direct-to-metal polyurethane NP-GLIDE coatings based on the coordination effect and dual cross-linking of polyphenol.

Aluminum and its alloys have been widely used in our lives. However, Aluminum and its alloys is prone to corrosion, especially in harsh environment. In recent years, hydrophobic coatings were used in the corrosion protection of metal. But, the low surface tension of resins made them have a worse wettability on metal which had high surface tension, resulting in a worse adhesion of these coatings. Herein, we developed a long-lasting anti-corrosion direct-to-metal polyurethane NP-Glide coating based on the coordination effect of polyphenol and dual cross-linking. In comparative evaluation, the corrosion protection and anti-contamination performances of direct-to-metal polyurethane NP-Glide coating are significantly improved by the introduction of functional monomer dopamine methacrylamide (DMA) and TEMAc-8. The PU coatings with 10 wt% TEMAc-8 possesses high impedance value (|Z|0.01Hz > 109 Ω•cm2) after 40 days of immersion in 3.5 wt% NaCl solution, exhibiting a great pull-off adhesion both in dry and wet coating, and a long-term anti-corrosion performance for aluminum alloy protection.

Activation of GPR55 alleviates neuropathic pain and chronic inflammation.

Neuropathic pain (NP) significantly impacts the quality of life due to its prolonged duration and lack of effective treatment. Recent findings suggest that targeting neuroinflammation is a promising approach for treating NP. G protein-coupled receptor 55 (GPR55), a member of the GPCR family, plays an important role in neuroinflammatory regulation. CID16020046, a GPR55 agonist, possesses promising anti-neuroinflammatory effects. Herein, the therapeutic effect of CID16020046 on NP was investigated in an NP rat model. The NP model was established using the unilateral sciatic nerve chronic constriction injury (CCI) assay. Both sham and CCI rats were intraperitoneally administered with 20 mg/kg CID16020046. NP was assessed using paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). First, we showed that GPR55 was downregulated in the spinal dorsal horn of CCI rats. After CCI rats were treated with CID16020046, the values of PWT and PWL were increased, indicating their effect on pain relief. The treated rats had attenuated release of inflammatory cytokines in the spinal cord, decreased spinal malondialdehyde (MDA) levels, and increased spinal glutathione peroxidase (GSH-PX) activity. Additionally, the increased levels of phosphorylated nuclear factor (NF)-κB p65 in CCI rats were significantly alleviated by CID16020046 treatment. Mechanistically, we showed that CID16020046 significantly suppressed the activation of the Janus kinase (JAK2)/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in the spinal cord of CCI-treated rats. However, Colivelin TFA (a STAT3 agonist) abolished the effect of CID16020046 on JAK2/STAT3 activation. In conclusion, our data demonstrate that the activation of GPR55 by CID16020046 alleviates NP and neuroinflammation in CCI rats by mediating the JAK2/STAT3 pathway.

Establishment of Reference Intervals for Bone Turnover Biomarkers in Healthy Populations in Northern China.

Aim: This study was intended to establish the reference intervals of bone turnover markers (BTMs) for healthy populations. Methods: According to the Clinical Laboratory Standards Institute (CLSI) EP28-A3c, we recruited 774 healthy Chinese and investigated their clinical characteristics and relationships among gender, age, season and BTMs. The reference intervals of BTMs for healthy populations in Hebei of China were established through defining the central 95% range of all observations. Results: We found that gender were associated with 25(OH)D, OC, ß-CTX, and P1NP (P < 0.05), but not PTH1-84 (P=0.138). All serum BTMs showed differences among different age groups (P < 0.01). The level of 25 (OH) D in winter showed statistical differences with spring, summer, and autumn (P<0.05). The OC level showed statistical difference between summer and winter (P=0.000). The P1NP levels showed statistical difference between spring and winter (P=0.019), summer and winter (P=0.000), and summer and autumn (P=0.012), respectively. The PTH1-84 levels in winter showed statistical differences with spring, and summer (all P=0.000), while there was no statistically significant difference in ß- CTX levels between seasons. Conclusion: We have established the reference intervals of several BTMs for healthy individuals in Hebei of China, which have statistical significance across different age groups and genders, and there are also significant differences between different seasons. Therefore, the Chinese medical laboratories in different locations should group individuals according to gender and age groups in different seasons, and establish corresponding biological reference intervals.

Intracellular lipid droplets are exploited by Junín virus: a nucleoprotein-dependent process.

Lipid droplets (LDs) are organelles involved in lipid storage, maintenance of energy homeostasis, protein sequestration, signaling events and inter-organelle interactions. Recently, LDs have been shown to favor the replication of members from different viral families, such as the Flaviviridae and Coronaviridae. In this work, we found that LDs are essential organelles for members of the Arenaviridae family. A virus-driven reduction of LDs number was observed in cultures infected with Junín mammarenavirus (JUNV), caused in part by action of the viral nucleoprotein. To note, we identified a new pool of nucleoprotein and viral RNA that localize in the vicinity of LDs, suggesting that LDs play a role during the viral replication cycle. Regarding the mechanism behind LDs exhaustion, we found evidence that lipophagy is involved in LD degradation with the resulting fatty acids being substrates of fatty acid ß-oxidation which fuels viral multiplication. This work highlights the importance of LDs during the replication cycle of JUNV, contributing to the knowledge of the metabolic changes these mammarenaviruses cause in their hosts.

Viral, Immunologic, and Laboratory Parameters in Patients With and Without Post-Acute Sequelae of SARS-CoV-2 Infection (PASC).

BACKGROUND: The pathophysiological mechanisms underlying the post-acute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) are not well understood. Our study aimed to investigate various aspects of theses mechanisms, including viral persistence, immunological responses, and laboratory parameters in patients with and without PASC. METHODS: We prospectively enrolled adults aged ≥ 18 years diagnosed with coronavirus disease 2019 (COVID-19) between August 2022 and July 2023. Blood samples were collected at three time-points: within one month of diagnosis (acute phase) and at 1 month, and 3 months post-diagnosis. Following a recent well-designed definition of PASC, PASC patients were defined as those with a questionnaire-based PASC score ≥ 12 persisting for at least 4 weeks after the initial COVID-19 diagnosis. RESULTS: Of 57 eligible COVID-19 patients, 29 (51%) had PASC, and 28 (49%) did not. The PASC group had significantly higher nucleocapsid protein (NP) antigenemia 3 months after COVID-19 diagnosis (P = 0.022). Furthermore, several cytokines, including IL-2, IL-17A, VEGF, RANTES, sCD40L, IP-10, I-TAC, and granzyme A, were markedly elevated in the PASC group 1 and/or 3 month(s) after COVID-19 diagnosis. In contrast, the median values of several serological markers, including thyroid markers, autoimmune indicators, and stress-related hormones, were within the normal range. CONCLUSION: Levels of NP antigen and of various cytokines involved in immune responses become significantly elevated over time after COVID-19 diagnosis in PASC patients compared to non-PASC patients. This suggests that PASC is associated with prolonged immune dysregulation resulting from heightened antigenic stimulation.

Diagnostic Test Precision of Modified Carbapenem Inactivation Method and Carbapenemase Nordmann-Poirel Test for Phenotypic Detection of Carbapenemase Production in Enterobacterales: A Systematic Review.

Carbapenem-resistant Enterobacterales, particularly those that produce carbapenemases, pose a significant public health concern due to very limited treatment options. The timely identification of carbapenemase-producing Enterobacterales (CPE) is essential for putting in place efficient infection control measures and selecting appropriate antimicrobial therapies, thereby improving the clinical outcome of the patient. The purpose of this systematic review is to compare the diagnostic accuracy and practicality between two phenotypic tests, namely the modified carbapenem inactivation method (mCIM) and carbapenemase Nordmann-Poirel (Carba NP) test, in detecting carbapenemase production by Enterobacterales and thereby aiding the clinician in making a decision to choose an appropriate test for their phenotypic detection. This systematic review involved combining sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, diagnostic odds ratio with 95% confidence interval (CIs), Forest plot for sensitivity and specificity, and plotting suitable summary receiver operating characteristic curve with the area under the curve. Of the 20 studies included in this review, the overall effect sizes of Carba NP and mCIM with 95% CIs were as follows: sensitivity, 91% (86-96%) and 97% (95-99%); specificity, 93% (88-97%) and 97% (93-100%); PPV, 97% and 98%; NPV, 79% and 90%; accuracy, 93% and 97%; diagnostic odds ratio, 1487.8879 and 8527.5541; and AUC, 0.85 and 1, respectively. In conclusion, the mCIM method showed superior sensitivity (97%), specificity (97%), and accuracy compared to the Carba NP test in detecting carbapenemase production, even though both these methods had a few technical limitations. The Carba NP test is rapid, affordable, and dependable, whereas mCIM is more accurate and cost-effective but time-consuming. We propose that both tests can be reliably used for screening of carbapenemase production in Enterobacterales, as endorsed by the Clinical and Laboratory Standards Institute even in resource-limited clinical laboratories, in the order of prioritizing the mCIM method first and then followed by the Carba NP test when situation demands expedited results.

Nrf2-dependent hepatoprotective effect of ellagic acid in titanium dioxide nanoparticles-induced liver injury.

BACKGROUND AND AIMS: Previous studies suggest that titanium dioxide nanoparticles (TiO2 NPs) induce liver injury, possibly due to oxidative stress and inflammation. Ellagic acid (EA) is a dietary polyphenol extracted from natural sources and possesses antioxidant and anti-inflammatory properties. Nonetheless, the efficacy of EA in mitigating liver injury induced by TiO2 NPs remains to be elucidated. METHODS: Primary hepatocytes and L02 cells were cultured with 45 µM EA and 10 µg/ml TiO2 NPs. Mice were orally administered TiO2 NPs (150 mg kg-1) and EA (25/50/100 mg kg-1) for eight weeks. sulforaphane (SFN) as a positive control to evaluate the inhibitory effect of EA on TiO2 NP-induced liver injury (SFN 10 mg kg-1). RNA sequencing (RNA-seq) was employed to elucidate the mechanisms underlying oxidative stress, inflammation, and liver fibrosis. RESULTS: We assessed the impact of EA on cytotoxicity, oxidative stress, inflammation, and fibrosis in both cells and mice exposed to TiO2 NPs for an extended period. Our findings indicated that EA had a protective effect on TiO2 NP-exposed hepatocytes, reducing cytotoxicity, oxidative stress, and inflammation. Furthermore, EA treatment markedly reduced serum aminotransferase levels in mice exposed to TiO2 NPs. Furthermore, EA treatment notably reduced hepatic stress response, inflammation, and fibrosis in mice. The treatment of EA demonstrates non-inferiority compared to SFN. The protective effects of EA were attributed to the upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), EA promoted the translocation and phosphorylation of Nrf2, as indicated by the finding that Nfe2l2 shRNA and inhibition of Nrf2 by ML385 reversed the EA-induced hepatoprotective effects in TiO2 NP-exposed hepatocytes and mice. CONCLUSION: EA significantly mitigated liver injury induced by TiO2 NPs. Importantly, we identified that the nuclear translocation and phosphorylation of Nrf2 are the primary mechanisms through which EA alleviates liver injury resulting from exposure to TiO2 NPs. As a natural activator of Nrf2, EA emerges as a promising therapeutic candidate for treating TiO2 NPs-induced liver injury, further enhancing our understanding of its potential as a hepatoprotective agent and its underlying molecular mechanisms.

The antioxidant and selective apoptotic activities of modified auraptene-loaded graphene quantum dot nanoparticles (M-AGQD-NP).

BACKGROUND: Pancreatic and Gastric cancers are very aggressive and deadly types of cancer that require effective treatment strategies to stop their progression. Nano-drug delivery systems, like those using Auraptene-loaded GQD nanoparticles, play a crucial role in addressing this need by delivering targeted and controlled treatments to cancer cells, making treatment more effective, and reducing side effects. The study focused on investigating the effects of Auraptene, an efficient anticancer compound when loaded into Graphene Quantum Dots (GQDs) on types of human cancer cells. METHODS: To create auraptene-loaded graphene quantum dot nanoparticles (AGQD-NP) (Unmodified and modified types) a combination of hydrothermal and high-energy homogenization methods was used. The nanoparticles were characterized by conducting DLS (Dynamic light scattering), FTIR (Fourier-transform infrared spectroscopy), FESEM (Field Emission Scanning Electron microscopy), and zeta potential analysis. bioactivity of AGQD-NP was assessed through tests, including antioxidant capacity measured by ABTS and DPPH scavenging abilities well as cytotoxicity tested using MTT assay on both human cancer cell lines and normal human vascular endothelial cells. RESULTS: The modified AGQD-NP (M-AGQD-NP) demonstrated antioxidant properties by neutralizing free radicals. They also displayed selective toxicity, towards human gastric adenocarcinoma cell-line (AGS) and human pancreatic adenocarcinoma (PANC) cancer cells with IC50 values recorded at 78.8 µg/mL and 89.72 µg/mL respectively. The specific targeting of gastric cancer cells was evident from the differing IC50 values compared to the Human breast adenocarcinoma cell line (MCF-7), Human hepatocellular carcinoma cell line (Hella), and normal vascular endothelial cells (Huvec). Additionally, the induced apoptotic death, in the human pancreatic adenocarcinoma (PANC) cancer cells was confirmed through AO/PI staining and Annexin-based flow cytometry revealing increased expression levels of P53, Caspase3, BAX, and Caspase8. CONCLUSION: In summary, the M-AGQD-NP have shown encouraging effects displaying antioxidant capabilities and a specific focus, on pancreatic and gastric cancer cells. These findings indicate uses for AGQD-NP as an efficient apoptosis inducer in cancer treatment. Additional In-vivo researches are required to validate their effectiveness, in living organisms.

Comparison of the immunogenicity of mRNA-encoded and protein HIV-1 Env-ferritin nanoparticle designs.

Nucleoside-modified mRNA technology has revolutionized vaccine development with the success of mRNA COVID-19 vaccines. We used modified mRNA technology for the design of envelopes (Env) to induce HIV-1 broadly neutralizing antibodies (bnAbs). However, unlike SARS-CoV-2 neutralizing antibodies that are readily made, HIV-1 bnAb induction is disfavored by the immune system because of the rarity of bnAb B cell precursors and the cross-reactivity of bnAbs targeting certain Env epitopes with host molecules, thus requiring optimized immunogen design. The use of protein nanoparticles (NPs) has been reported to enhance B cell germinal center responses to HIV-1 Env. Here, we report our experience with the expression of Env-ferritin NPs compared with membrane-bound Env gp160 when encoded by modified mRNA. We found that well-folded Env-ferritin NPs were a minority of the protein expressed by an mRNA design and were immunogenic at 20 µg but minimally immunogenic in mice at 1 µg dose in vivo and were not expressed well in draining lymph nodes (LNs) following intramuscular immunization. In contrast, mRNA encoding gp160 was more immunogenic than mRNA encoding Env-NP at 1 µg dose and was expressed well in draining LN following intramuscular immunization. Thus, analysis of mRNA expression in vitro and immunogenicity at low doses in vivo are critical for the evaluation of mRNA designs for optimal immunogenicity of HIV-1 immunogens.IMPORTANCEAn effective HIV-1 vaccine that induces protective antibody responses remains elusive. We have used mRNA technology for designs of HIV-1 immunogens in the forms of membrane-bound full-length envelope gp160 and envelope ferritin nanoparticle. Here, we demonstrated in a mouse model that the membrane-bound form induced a better response than envelope ferritin nanoparticle because of higher in vivo protein expression. The significance of our research is in highlighting the importance of analysis of mRNA design expression and low-dose immunogenicity studies for HIV-1 immunogens before moving to vaccine clinical trials.

Understanding the impact of soil components on the environmental existence of Nonylphenol:From the perspective of soil aggregates.

Nonylphenol (4-NP) has significant adverse effects on the male reproductive system. 4-NP is commonly used in agriculture as a plasticizer and pesticide emulsifier. In the current study, two soil samples with different textures were collected to evaluate the impact of soil components on the environmental existence of 4-NP among soil aggregates. It was found that the presence of soil POM resulted in 4-NP exhibiting a significantly polarized distribution in soil aggregates, instead of the expected increase in content with decreasing particle size. High levels of organic matter and metal oxides result in a high carrying capacity of small aggregates for 4-NP in both soil textures, while POM results in a higher carrying capacity of large aggregates for 4-NP in clay soil. Another important finding is that the existence of 4-NP in soil was regulated by the percentage of aggregates. The results of contribution shown that although small aggregates in sand presented stronger 4-NP carrying capacity, whereas 4-NP was mainly distributed in large aggregates in sand. For clay soil, 4-NP was predominantly located in small aggregates with the 4-NP contributions of small aggregates amounting to 63.17%, despite the highest carrying capacity of 4-NP was observed in large aggregates. These results provide a theoretical basis to investigate the transport and transformation of 4-NP in the soil environment.

Scaffold overlay of flavonoid-inspired molecules: Discovery of 2,3-diaryl-pyridopyrimidin-4-imine/ones as dual hTopo-II and tubulin targeting anticancer agents.

Almost half of all medicines approved by the U.S. Food and Drug Administration have been found to be developed based on inspiration from natural products (NPs). Here, we report a novel strategy of scaffold overlaying of scaffold-hopped analogs of bioactive flavones and isoflavones and installation of drug-privileged motifs, which has led to discovery of anticancer agents that surpass the functional efficiency of the original NPs. The analogs, 2,3-diaryl-pyridopyrimidin-4-imine/ones were efficiently synthesized by an approach of a nitrile-stabilized quaternary ammonium ylide as masked synthon and Pd-catalyzed activation-arylation methods. Compared to the NPs, these NP-analogs exhibited differentiated functions; dual inhibition of human topoisomerase-II (hTopo-II) enzyme and tubulin polymerization, and pronounced antiproliferative effect against various cancer cell lines, including numerous drug-resistant cancer cells. The most active compound 5l displayed significant inhibition of migration ability of cancer cells and blocked G1/S phase transition in cell cycle. Compound 5l caused pronounced effect in expression patterns of various key cell cycle regulatory proteins; up-regulation of apoptotic proteins, Bax, Caspase 3 and p53, and down-regulation of apoptosis-inhibiting proteins, BcL-xL, Cyclin D1, Cyclin E1 and NF-κB, which indicates high efficiency of the molecule 5l in apoptosis-signal axis interfering potential. Cheminformatics analysis revealed that 2,3-diaryl-pyridopyrimidin-4-imine/ones occupy a distinctive drug-relevant chemical space that is seldom represented by natural products and good physicochemical, ADMET and pharmacokinetic-relevant profile. Together, the anticancer potential of the investigated analogs was found to be much more efficient compared to the original natural products and two anticancer drugs, Etoposide (hTopo-II inhibitor) and 5-Flurouracile (5-FU).

Novel approach for green synthesis of stable gold nanoparticles with dried turmeric root extract: investigations on sensor and catalytic applications.

In this study, we present the synthesis of gold nanoparticles (AuNPs) using a completely green synthesis method without the use of any additional functionalizing agent, except dried turmeric root extract. The significant synthesis parameters were optimized, and the applicability of AuNPs was investigated in areas such as plasmonic and fluorescent sensing of aluminum (Al3⁺) and chromium (Cr3⁺) ions, reduction of 4-nitrophenol (4-NP), and degradation of methylene blue (MB) and methyl orange (MO) dyes. Characterization studies were performed using UV-Vis spectroscopy, TEM, FTIR, and XRD, revealing that the AuNPs predominantly had a spherical morphology and a very small particle size of 8.5 nm, with stability maintained up to 120 days. The developed AuNP-based plasmonic sensors relied on aggregation-induced decreases in absorption, along with a red shift in the spectra. Fluorescence sensing demonstrated a linear increase in intensity with increasing concentrations of Al3⁺ and Cr3⁺, with detection limits of 0.83 and 1.19 nM, respectively. The catalytic activities of AuNPs were tested in reducing 4-NP and degradations of MB and MO dyes (binary system) in tap water and wastewater, with the reactions following pseudo-first-order kinetics. This study highlights the potential of AuNPs synthesized from turmeric roots for various environmental and sensing applications.

Natural product-derived ALK inhibitors for treating ALK-driven lung cancers: an in silico study.

Anaplastic lymphoma kinase (ALK)-driven lung cancer represents a critical therapeutic target, demanding innovative approaches for the identification of effective inhibitors. Anaplastic lymphoma kinase (ALK), a key protein involved in the pathogenesis of ALK-driven lung cancers, has been the focus of extensive drug discovery efforts. This study employed a comprehensive computational drug discovery approach, integrating virtual screening with the Lipinski filter, re-docking, molecular dynamics (MD) simulations, and free energy calculations to identify potential inhibitors from a natural compound library. Utilizing the MTiOpenScreen web server, we screened for compounds that exhibit favorable interactions with ALK, resulting in 1227 compounds with virtual screening scores ranging from - 10.2 to - 3.7 kcal/mol. Subsequent re-docking of three selected compounds (ZINC000059779788, ZINC000043552589, and ZINC000003594862) and one reference compound against ALK yielded docking scores - 10.4, - 10.2, - 10.2, and - 10.1 kcal/mol, respectively. These compounds demonstrated promising interactions with ALK, suggesting potential inhibitory effects. Advanced analyses, including MD simulation and binding free energy calculations, further supported the potential efficacy of these compounds. MD simulations, particularly the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analyses, revealed that compounds ZINC000059779788 and ZINC000003594862 achieved better stability compared to compound ZINC000043552589. These stable conformations suggest effective binding over time. Free energy calculations using the MM/GBSA method showed that ZINC000059779788 had the most favorable binding energy, indicating a strong and stable interaction with the ALK protein. The promising computational findings from this study emphasize the necessity for additional experimental testing to verify the therapeutic efficacy of these natural compounds for treating lung cancers.

Rhizosphere effects and microbial N limitations drive the root N limitations in the rhizosphere during secondary succession in a Pinus tabuliformis forest in North China.

Introduction: Rhizosphere effects (REs) have recently been identified as important regulators of root and microbial nutrient acquisition and are positively involved in nutrient cycling of belowground carbon (C), nitrogen (N), and phosphorus (P). Nutrient conditions of the fine roots and soil N are likely to influence REs. Still, it is unclear how REs of soil nutrients themselves variably impact the supply of nutrients to plants in terms of the responses to soil N due to succession. Methods: In this study, we applied both fine roots and extracellular enzymes for vector analysis and stoichiometry of N:P to explore the metabolic limitations of roots and rhizospheric soil microbes and their relationships with REs across five levels of soil N (0, 5, 10, 15, and 20 kg N m-2 year-1) along successional age classes of 42, 55, and 65 years in a Pinus tabuliformis forest. Results: Overall, the metabolism of root and rhizospheric soil microbes was mediated by soil N. N limitation of roots initially decreased before increasing, whereas that of microbes demonstrated opposite trends to the N levels owing to competition for inorganic N between them by REs of NO3 --N. However, N limitations of both roots and microbes were alleviated in young stands and increased with succession after the application of N. In addition, root N limitations were manipulated by REs of three different soil N-related indicators, i.e., total N, NH4 +-N, and NO3 --N. Rhizospheric soil microbial N limitation was almost unaffected by REs due to their strong homeostasis but was an important driver in the regulation of root N limitation. Discussion: Our results indicated that successional age was the most critical driver that directly and indirectly affected root N metabolism. However, the level of N application had a slight effect on root N limitation. Microbial N limitation and variations in the REs of N indicators regulated root N limitation in the rhizosphere. As a result, roots utilized REs to sequester N to alleviate N limitations. These findings contribute to novel mechanistic perspectives on the sustainability of N nutrition by regulating N cycling in a system of plant-soil-microbes in the rhizosphere to adapt to global N deposition or the heterogeneous distribution of bioavailable soil N with succession.

HERV-K np9 and HERV-R env: Two endogenous retrovirus products with potential Pathogenic roles in pediatric acute lymphoblastic leukemia.

OBJECTIVES: Human endogenous retroviruses (HERVs) are integral components of the human genome, and their reactivation has been implicated in the pathogenesis of some malignancies. External viral co-infections are suspected to play a role in HERV transactivation. This study aimed to investigate the expression of HERV-K np9 elements and HERV-R env gene in pediatric acute lymphoblastic leukemia (ALL) patients. Additionally, we explored potential correlations between HERV expression and common viral infections prevalent in this group of patients. METHODS: Blood samples were collected from 43 pediatric ALL patients and 48 age- and sex-matched healthy controls. Quantitative real-time PCR (qRT-PCR) was used to assess the expression of HERV-K np9 and HERV-R env, along with herpes simplex virus (HSV), parvovirus B19, and polyomavirus BK. RESULTS: HERV-K np9 and HERV-R env showed significantly higher expression in the peripheral blood of ALL patients compared to healthy controls (p < .001 and p = .003, respectively). HSV positivity was associated with significantly increased HERV-K np9 expression. No significant correlations were observed between other investigated viruses and HERV gene expression. CONCLUSION: The overexpression of HERV-K np9 and HERV-R env in pediatric ALL patients suggest their potential role in leukemogenesis. Our findings also suggest a possible link between HSV infection and HERV reactivation in this population. Future investigations are needed to understand the precise roles of these genes and viral infections in the development of ALL.

Fast Reduction of 4-Nitrophenol and Photoelectrochemical Hydrogen Production by Self-Reduced Bi/Ti3C2Tx/Bi2S3 Nanocomposite: A Combined Experimental and Theoretical Study.

The distinctive properties of 2D MXenes have garnered significant interest across various fields, including wastewater treatment and photo/electro-catalysis. The integration of inexpensive semiconductor nanostructures with 2D MXenes offers a promising strategy for applications such as wastewater treatment and photoelectrochemical hydrogen production. In this study, we employed an in situ hydrothermal method to immobilize 1D Bi2S3 nanorods and self-reduced metallic bismuth nanoparticles (Bi NPs) onto Ti3C2Tx MXene nanosheets, resulting in the formation of a Bi/Bi2S3/Ti3C2Tx (0D/1D/2D) composite catalyst, which demonstrates an outstanding efficacy in both the reduction of 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) and photoelectrochemical hydrogen production. Remarkably, a 4-NP reduction efficiency of 100% was achieved only in 4 min with a reduction rate of 1.14 min-1, which is outstanding, and it is ∼3.8 times faster than pristine Bi2S3 nanorods (0.3 min-1). Furthermore, the photoelectrochemical assessment reveals that the Bi/Bi2S3/Ti3C2Tx catalyst displays remarkable hydrogen evolution reaction (HER) efficiency in an alkaline electrolyte. It exhibits a significantly lower overpotential and Tafel slope of 73 mV and 84 mV/dec, respectively, compared to pristine Bi2S3 nanorods, which are found to be 129 mV and 145 mV/dec under light illumination. The superior reduction performance of 4-NP and charge transfer mechanism is further investigated through density functional theory (DFT) calculations, alongside validation using various microscopic and spectroscopic techniques. Interestingly, the DFT analysis revealed modifications in the partial density of states of Bi2S3 within the band gap region due to the successful anchoring of Ti3C2Tx nanosheets and metallic Bi NPs, facilitating efficient charge transport and separation across the local junctions. Ultraviolet photoelectron spectroscopy provided insights into band alignment and interfacial charge transfer across the Bi/Bi2S3/Ti3C2Tx junction on a microscopic scale. This work is significant for the development of MXene-based hybrid catalysts, and it provides a deeper understanding of the reduction mechanism of organic pollutants and superior charge transport in the hybrid system for photoelectrochemical hydrogen production.