Angiopoietin-like 4 is upregulated by amphiregulin and activates cell proliferation and migration through p38 kinase in head and neck squamous cell carcinoma.

BACKGROUND: Angiopoietin-like 4 is a molecular hallmark that correlates with the growth and metastasis of head and neck squamous cell carcinoma, one of the most prevalent cancers worldwide. However, the molecular mechanisms by which angiopoietin-like 4 promotes head and neck squamous cell carcinoma tumorigenesis are unclear. METHODS: Using well-characterized cell lines of head and neck squamous cell carcinoma development, including human normal oral keratinocytes, dysplastic oral keratinocytes, oral leukoplakia-derived oral keratinocytes, and head and neck squamous cell carcinoma cell lines, HN13, HN6, HN4, HN12, and CAL27, we investigated the signaling pathways upstream and downstream of angiopoietin-like 4-induced head and neck squamous cell carcinoma tumorigenesis. RESULTS: We found that both epidermal growth factor receptor ligands, epithelial growth factor, and amphiregulin led to angiopoietin-like 4 upregulation in normal oral keratinocytes and dysplastic oral keratinocytes and cooperated with the activation of hypoxia-inducible factor-1 in this effect. Interestingly, amphiregulin and angiopoietin-like 4 were increased in dysplastic oral keratinocytes and head and neck squamous cell carcinoma cell lines, and amphiregulin-induced activation of cell proliferation was dependent on angiopoietin-like 4. Although both p38 mitogen-activated protein kinases (p38 MAPK) and protein kinase B (AKT) were activated by angiopoietin-like 4, only pharmacological inhibition of p38 MAPK was sufficient to prevent head and neck squamous cell carcinoma cell proliferation and migration. We further observed that angiopoietin-like 4 promoted the secretion of interleukin 11 (IL-11), interleukin 12 (IL-12), interleukin-1 alpha (IL-1α), vascular endothelial growth factor, platelet-derived growth factor (PDGF), and tumour necrosis factor alpha (TNF-α), cytokines and chemokines previously implicated in head and neck squamous cell carcinoma pathogenesis. CONCLUSION: Our results demonstrate that angiopoietin-like 4 is a downstream effector of amphiregulin and promotes head and neck squamous cell carcinoma development both through direct activation of p38 kinase as well as paracrine mechanisms.

Assessment of Artificial Intelligence Platforms With Regard to Medical Microbiology Knowledge: An Analysis of ChatGPT and Gemini.

The performance of two artificial intelligence (AI) platforms, ChatGPT 3.5 (OpenAI, California, United States) and Gemini (Google AI, California, United States) was assessed by answering 200 questions of microbiology drawn from validated sources. The questions were selected from topics such as General Microbiology, Immunology, and Microbiology Applied to Infectious Diseases. The study was conducted from December 2023 to March 2024, and the responses of the different AI platforms were compared with an answer key. Statistical analysis was performed to assess accuracy. ChatGPT 3.5 and Gemini had comparable accuracy with correct response scores of 71% and 70.5%, respectively. Their performance varied across different sections. Gemini performed better in General Microbiology and Immunology, and ChatGPT 3.5 had a better score in the Applied Microbiology section. The study's findings highlight that AI platforms such as ChatGPT and Gemini can be utilized in microbiology and medical education. The evolution and continuous updating of AI platforms are required to improve their performance.

ADME/PK Insights of Crocetin: A Molecule Having an Unusual Chemical Structure with Druglike Features.

Crocetin is a promising phyto-based molecule to treat Alzheimer's disease (AD). The chemical structure of crocetin is incongruent with various standard structural features of CNS drugs. As poor pharmacokinetic behavior is the major hurdle for any candidate to become a drug, we elucidated its druggable characteristics by implementing in silico, in vitro, and in vivo approaches, as limited ADME/PK information is available. Results demonstrate several attributes of crocetin based on rules of drug-likeness, lipophilicity, pKa, P-gp inhibitory activity, plasma stability, RBC partitioning, metabolic stability, CYP inhibitory action, blood-brain barrier (BBB) permeability, oral bioavailability, and pharmacokinetic interaction with marketed anti-Alzheimer's drugs (memantine, donepezil, galantamine, and rivastigmine). However, aqueous solubility, chemical stability, plasma protein binding, and P-gp induction are some concerns associated with this molecule that should be taken into consideration during its further development. Overall results indicate favorable ADME/PK behavior and potential druggable candidature of crocetin.

Nanoconfinement Effect in Water Processable Discrete Molecular Complex-Based Hybrid Piezo- and Thermo-Electric Nanogenerator.

Water-processable hybrid piezo- and thermo-electric materials have an increasing range of applications. We use the nanoconfinement effect of ferroelectric discrete molecular complex [Cu(l-phe)(bpy)(H2O)]PF6·H2O (1) in a nonpolar polymer 1D-nanofiber to envision the high-performance flexible hybrid piezo- and thermo-electric nanogenerator (TEG). The 1D-nanoconfined crystallization of 1 enhances piezoelectric throughput with a high degree of mechano-sensitivity, i.e., 710 mV/N up to 3 N of applied force with 10,000 cycles of unaffected mechanical endurance. Thermoelectric properties analysis shows a noticeable improvement in Seebeck coefficient (∼4 fold) and power factor (∼6 fold) as compared to its film counterpart, which is attributed to the enhanced density of states near the Fermi edges as evidenced by ultraviolet photoelectric spectroscopy and density functional based theoretical calculations. We report an aqueous processable hybrid TEG that provides an impressive magnitude of Seebeck coefficient (∼793 µV/K) and power factor (∼35 mWm-1K-2) in comparison to a similar class of materials.

Evidence-based effectiveness of Ozone therapy in the treatment for oral lichen planus - A systematic review.

Oral lichen planus is a common, chronic mucocutaneous condition of uncertain origin. Early treatment of OLP can dramatically reduce the risk of further development, which in turn reduces the risk of developing cancer. Numerous methods can be used to treat OLP. Since the significance of ozone in treating this disease is still uncertain. This systematic review was conducted based on english databases, including PUBMED, SCOPUS, Embase, Ovid, and Journal of Web up to July 2022. We used the search phrases "ozone," "ozone in the treatment of oral lichen planus," "oral lichen planus," and "ozone therapy." Finally, five papers were selected for qualitative analysis. This review included a total of five papers, four of which were clinical trials and one was a longitudinal study. All studies included the erosive form of OLP, also ozone therapy was applied to patients who did not respond to conventional treatment. Ozone showed significant therapeutic effects in terms of reduction in pain and size of the lesion. The signs and symptoms associated with OLP such as burning sensation, lesion size, and scarring all considerably improved with ozone therapy.

Response to Ceftriaxone in Asymptomatic Neurosyphilis Refractory to Doxycycline and Benzathine Penicillin.

An asymptomatic male in his mid-30s presented with a positive Venereal Disease Research Laboratory (VDRL) test report. He was investigated and detected to be reactive for human immunodeficiency virus (HIV)-1 antibodies. A lumbar puncture revealed cerebrospinal fluid (CSF) VDRL to be reactive at a titer of 1:160 which led to a diagnosis of asymptomatic neurosyphilis. The unavailability of first-line antibiotics necessitated the search for alternative regimens. The patient was administered oral doxycycline 200 mg twice daily for 28 days along with intramuscular benzathine penicillin 2.4 million units once weekly for three weeks. A repeat CSF-VDRL performed six months later with raised titers of 1:320 indicated treatment failure. The patient was then administered ceftriaxone 1 g intramuscularly for 14 consecutive days. A final CSF-VDRL examination performed six months later showed non-reactive titers.

EIDD-1931 Treatment Tweaks CYP3A4 and CYP2C8 in Arthritic Rats to Expedite Drug Interaction: Implication in Oral Therapy of Molnupiravir.

EIDD-1931 is the active form of molnupiravir, an orally effective drug approved by the United States Food and Drug Administration (USFDA) against COVID-19. Pharmacokinetic alteration can cause untoward drug interaction (drug-drug/disease-drug), but hardly any information is known about this recently approved drug. Therefore, we first investigated the impact of the arthritis state on the oral pharmacokinetics of EIDD-1931 using a widely accepted complete Freund's adjuvant (CFA)-induced rat model of rheumatoid arthritis (RA) after ascertaining the disease occurrence by paw swelling measurement and X-ray examination. Comparative oral pharmacokinetic assessment of EIDD-1931 (normal state vs arthritis state) showed that overall plasma exposure was augmented (1.7-fold) with reduced clearance (0.54-fold), suggesting its likelihood of dose adjustment in arthritis conditions. In order to elucidate the effect of EIDD-1931 treatment at a therapeutic regime (normal state vs arthritis state) on USFDA-recommended panel of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) for drug interaction using the same disease model, we monitored protein and mRNA expressions (rat homologs) in liver tissue by western blotting (WB) and real time-polymerase chain reaction (RT-PCR), respectively. Results reveal that EIDD-1931 treatment could strongly influence CYP3A4 and CYP2C8 among experimental proteins/mRNAs. Although CYP2C8 regulation upon EIDD-1931 treatment resembles similar behavior under the arthritis state, results dictate a potentially reverse phenomenon for CYP3A4. Moreover, the lack of any CYP inhibitory effect by EIDD-1931 in human/rat liver microsomes (HLM/RLM) helps to ascertain EIDD-1931 treatment-mediated disease-drug interaction and the possibility of drug-drug interaction with disease-modifying antirheumatic drugs (DMARDs) upon coadministration. As elevated proinflammatory cytokine levels are prevalent in RA and nuclear factor-kappa B (NF-kB) and nuclear receptors control CYP expressions, further studies should focus on understanding the regulation of affected CYPs to subside unexpected drug interaction.

Rice false smut pathogen: implications for mycotoxin contamination, current status, and future perspectives.

Rice serves as a staple food across various continents worldwide. The rice plant faces significant threats from a range of fungal, bacterial, and viral pathogens. Among these, rice false smut disease (RFS) caused by Villosiclava virens is one of the devastating diseases in rice fields. This disease is widespread in major rice-growing regions such as China, Pakistan, Bangladesh, India, and others, leading to significant losses in rice plantations. Various toxins are produced during the infection of this disease in rice plants, impacting the fertilization process as well. This review paper lightens the disease cycle, plant immunity, and infection process during RFS. Mycotoxin production in RFS affects rice plants in multiple ways, although the exact phenomena are still unknown.

MOFs as versatile scaffolds to explore environmental contaminants based on their luminescence bustle.

Metal-Organic Frameworks (MOFs) with luminescent properties hold significant promise for environmental remediation. This review critically examines recent research on these materials design, synthesis, and applications, mainly focusing on their role in combating environmental pollutants. Through a comprehensive analysis of metal ions, ligands, and framework compositions, the review discusses the importance of tailored design and synthesis approaches in achieving desired luminescent characteristics. Key findings highlight the effectiveness of luminous MOFs as fluorescent sensors for a wide range of contaminants, including heavy metals, reactive species, antibiotics, and explosives. Considering all this, the review discusses future research needs and opportunities in the field of luminous MOFs. It emphasizes the importance of developing multifunctional materials, refining design methodologies, exploring sensing mechanisms, and ensuring environmental compatibility, scalability, and affordability. By providing insights into the current state of research and outlining future directions, this review is a valuable resource for researchers seeking to address environmental challenges using MOF-based solutions.

Isoprenyl diphosphate synthases of terpenoid biosynthesis in rose-scented geranium (Pelargonium graveolens).

The essential oil of Pelargonium graveolens (rose-scented geranium), an important aromatic plant, comprising mainly mono- and sesqui-terpenes, has applications in food and cosmetic industries. This study reports the characterization of isoprenyl disphosphate synthases (IDSs) involved in P. graveolens terpene biosynthesis. The six identified PgIDSs belonged to different classes of IDSs, comprising homomeric geranyl diphosphate synthases (GPPSs; PgGPPS1 and PgGPPS2), the large subunit of heteromeric GPPS or geranylgeranyl diphosphate synthases (GGPPSs; PgGGPPS), the small subunit of heteromeric GPPS (PgGPPS.SSUI and PgGPPS.SSUII), and farnesyl diphosphate synthases (FPPS; PgFPPS).All IDSs exhibited maximal expression in glandular trichomes (GTs), the site of aroma formation, and their expression except PgGPPS.SSUII was induced upon treatment with MeJA. Functional characterization of recombinant proteins revealed that PgGPPS1, PgGGPPS and PgFPPS were active enzymes producing GPP, GGPP/GPP, and FPP respectively, whereas both PgGPPS.SSUs and PgGPPS2 were inactive. Co-expression of PgGGPPS (that exhibited bifunctional G(G)PPS activity) with PgGPPS.SSUs in bacterial expression system showed lack of interaction between the two proteins, however, PgGGPPS interacted with a phylogenetically distant Antirrhinum majus GPPS.SSU. Further, transient expression of AmGPPS.SSU in P. graveolens leaf led to a significant increase in monoterpene levels. These findings provide insight into the types of IDSs and their role in providing precursors for different terpenoid components of P. graveolens essential oil.

Influence of obesity on load-transfer mechanism, contact mechanics, and longevity of cemented acetabular cup.

Objective: This investigation aimed to assess the impact of obesity on the load-transfer mechanism, longevity, and contact mechanics of cemented acetabular cups. Methods: Three obesity scenarios were considered: obese case-I (100-110 kg), obese case-II (120-130 kg), and obese case-III (140-150 kg). Utilising six finite element models, the effects of different bodyweights on load transfer, contact mechanics, and cup longevity during normal walking conditions were assessed. Muscle forces and hip joint reaction forces were adjusted and linearly calibrated based on obesity cases. Results: Elevated stresses in cortical and cancellous bones, as well as the cement mantle, were observed in obese cases, suggesting a heightened risk of loosening and failure of the cemented fixation of the acetabular cup. Additionally, increased contact pressure and micromotion between articulating surfaces were noted in obese individuals, with a gradual escalation from obese case-I to obese case-III. Conclusions: These findings highlight the significant negative impact of obesity on the performance of cemented acetabular cups, emphasizing the importance of considering bodyweight variations in the design and assessment of orthopaedic implants for optimal functionality and durability.

Iron-arsenide monolayers as an anode material for lithium-ion batteries: a first-principles study.

This theoretical investigation delves into the structural, electronic, and electrochemical properties of two hexagonal iron-arsenide monolayers, 1T-FeAs and 1H-FeAs, focusing on their potential as anode materials for lithium-ion batteries. Previous studies have highlighted the ferromagnetic nature of 1T-FeAs at room temperature. Our calculations reveal that both phases exhibit metallic behaviour with spin-polarized electronic band structures. Electrochemical studies show that the 1T-FeAs monolayer has better ionic conductivity for Li ions than the 1H-FeAs phase, attributed to a lower activation barrier of 0.38 eV. This characteristic suggests a faster charge/discharge rate. Both FeAs phases exhibit comparable theoretical capacities (374 mA h g-1), outperforming commercial graphite anodes. The average open-circuit voltage for maximum Li atom adsorption is 0.61 V for 1H-FeAs and 0.44 V for 1T-FeAs. The volume expansion over the maximum adsorption of Li atoms on both phases is also remarkably less than the commercially used anode material such as graphite. Furthermore, the adsorption of Li atoms onto 1H-FeAs induces a remarkable transition from ferromagnetism to anti-ferromagnetism, with minimal impact on the electronic band structure. In contrast, the original state of 1T-FeAs remains unaffected by Li adsorption. To summarize, both 1T-FeAs and 1H-FeAs monolayers have potential as promising anode materials for lithium-ion batteries, offering valuable insights into their electrochemical performance and phase transition behaviour upon Li adsorption.

Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.

In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.

177 Lu-DOTATATE Salvage Therapy in Rapidly Progressing Neuroendocrine Tumor With Poor Performance Status.

ABSTRACT: Peptide receptor radionuclide therapy (PRRT) has shown to be effective and safe in metastatic gastroenteropancreatic and nongastroenteropancreatic neuroendocrine tumors. However, the selection criteria for PRRT are restricted to patients with good performance status (Eastern Cooperative Oncology Group score ≤2 or Karnofsky performance score ≥60). This denies many patients with adequate somatostatin receptor expression and biochemical profiles from the beneficial effects of PRRT on the quality of life, daily function, and overall survival. The 2 cases highlight the favorable response of PRRT in patients with metastatic neuroendocrine tumor having a very poor performance status initially.

Mutagenic primer-based novel multiplex PCR-RFLP technique to genotype BECN1 SNPs rs10512488 and rs11552192.

BACKGROUND: Single Nucleotide Polymorphisms (SNPs) in candidate autophagy gene BECN1 could influence its functions thereby autophagy process. BECN1 noncoding SNPs were found to be significantly associated with neurodegenerative disease and type 2 diabetes mellitus. This study aimed to develop a simultaneous genotyping technique for two BECN1 SNPs (rs10512488 and rs11552192). METHODS: A mutagenic primer-based approach was used to introduce a NdeI restriction site to genotype rs10512488 by Artificial-Restriction Fragment Length Polymorphism (A-RFLP) along with rs11552192 by Polymerase Chain Reaction (PCR)-RFLP. Multiplexing PCR and restriction digestion reactions were set up for simultaneous genotyping of both SNPs in 100 healthy individuals. Genotypic and allele frequencies were manually calculated, and the Hardy-Weinberg Equilibrium was assessed using the chi-square test. RESULTS: We successfully developed PCR and RFLP conditions for the amplification and restriction digestion of both SNPs within the same tube for genotyping. The results of genotyping by newly developed multiplexing PCR-RFLP technique were concordant with the genotypes obtained by Sanger sequencing of samples. Allelic frequencies of rs10512488 obtained were 0.15 (A) and 0.85 (G), whereas allelic frequencies of rs11552192 were 0.16 (T) and 0.84 (A). CONCLUSION: The newly developed technique is rapid, cost-effective and time-saving for large-scale applications compared to sequencing methods and would play an important role in low-income settings. For the first time, allelic frequencies of rs10512488 and rs11552192 were reported among the North Indian population.

Decoding seasonal changes: soil parameters and microbial communities in tropical dry deciduous forests.

In dry deciduous tropical forests, both seasons (winter and summer) offer habitats that are essential ecologically. How these seasonal changes affect soil properties and microbial communities is not yet fully understood. This study aimed to investigate the influence of seasonal fluctuations on soil characteristics and microbial populations. The soil moisture content dramatically increases in the summer. However, the soil pH only gradually shifts from acidic to slightly neutral. During the summer, electrical conductivity (EC) values range from 0.62 to 1.03 ds m-1, in contrast to their decline in the winter. The levels of soil macronutrients and micronutrients increase during the summer, as does the quantity of soil organic carbon (SOC). A two-way ANOVA analysis reveals limited impacts of seasonal fluctuations and specific geographic locations on the amounts of accessible nitrogen (N) and phosphorus (P). Moreover, dehydrogenase, nitrate reductase, and urease activities rise in the summer, while chitinase, protease, and acid phosphatase activities are more pronounced in the winter. The soil microbes were identified in both seasons through 16S rRNA and ITS (Internal Transcribed Spacer) gene sequencing. Results revealed Proteobacteria and Ascomycota as predominant bacterial and fungal phyla. However, Bacillus, Pseudomonas, and Burkholderia are dominant bacterial genera, and Aspergillus, Alternaria, and Trichoderma are dominant fungal genera in the forest soil samples. Dominant bacterial and fungal genera may play a role in essential ecosystem services such as soil health management and nutrient cycling. In both seasons, clear relationships exist between soil properties, including pH, moisture, iron (Fe), zinc (Zn), and microbial diversity. Enzymatic activities and microbial shift relate positively with soil parameters. This study highlights robust soil-microbial interactions that persist mainly in the top layers of tropical dry deciduous forests in the summer and winter seasons. It provides insights into the responses of soil-microbial communities to seasonal changes, advancing our understanding of ecosystem dynamics and biodiversity preservation.

Unmasking the long-term effects: unravelling neuropsychiatric and neurological consequences of COVID-19.

The COVID-19 pandemic has not only burdened healthcare systems but has also led to a new emerging medical enigma that is post-COVID-19 syndrome or "long COVID." Characterized by persistent symptoms that extend beyond the acute phase of the illness, long COVID has rapidly become a public health concern with ambiguous neurological and neuropsychiatric dimensions. This narrative review aims at synthesizing available research to decode the long-term impacts of COVID-19 on neurological and mental health. Drawing from a multitude of studies, this review synthesizes evidence on various neuropsychiatric and neurological symptoms, including cognitive deficits, mood disorders, and more. The narrative delves into potential pathogenic mechanisms, hoping to fill existing research gaps and offering directions for future inquiry. The objective is not just academic; it has immediate real-world implications. Understanding these long-term effects is crucial for developing effective treatments and interventions, thereby better serving the millions of individuals living with these lingering symptoms. As healthcare systems continue to grapple with the fallout from the pandemic, this review provides much-needed context and insights into an area that demands urgent research and action.

Revisiting the ethnomedicinal, ethnopharmacological, phytoconstituents and phytoremediation of the plant Solanum viarum Dunal.

Solanum viarum, a perennial shrub, belongs to the family Solanaceae known for its therapeutic value worldwide. As a beneficial remedial plant, it is used for treating several disorders like dysentery, diabetes, inflammation, and respiratory disorders. Phytochemistry studies of this plant have shown the presence of steroidal glycoside alkaloids, including solasonine, solasodine, and solamargine. It also has flavonoids, saponins, minerals, and other substances. S. viarum extracts and compounds possess a variety of pharmacological effects, including antipyretic, antioxidant, antibacterial, insecticidal, analgesic, and anticancer activity. Most of the heavy metals accumulate in the aerial sections of the plant which is considered a potential phytoremediation, a highly effective method for the treatment of metal-polluted soils. We emphasize the forgoing outline of S. viarum, as well as its ethnomedicinal and ethnopharmacological applications, the chemistry of its secondary metabolites, and heavy metal toxicity. In addition to describing the antitumor activity of compounds and their mechanisms of action isolated from S. viarum, liabilities are also explained and illustrated, including any significant chemical or metabolic stability and toxicity risks. A comprehensive list of information was compiled from Science Direct, PubMed, Google Scholar, and Web of Science using different key phrases (traditional use, ethnomedicinal plants, western Himalaya, Himachal Pradesh, S viarum, and biological activity). According to the findings of this study, we hope that this review will inspire further studies along the drug discovery pathway of the chemicals extracted from the plant of S. viarum. Further, this review shows that ethnopharmacological information from ethnomedicinal plants can be a promising approach to drug discovery for cancer and diabetes.