Recent advancements in nanomaterial-mediated ferroptosis-induced cancer therapy: Importance of molecular dynamics and novel strategies.

Ferroptosis is a novel type of controlled cell death resulting from an imbalance between oxidative harm and protective mechanisms, demonstrating significant potential in combating cancer. It differs from other forms of cell death, such as apoptosis and necrosis. Molecular therapeutics have hard time playing the long-acting role of ferroptosis induction due to their limited water solubility, low cell targeting capacity, and quick metabolism in vivo. To this end, small molecule inducers based on biological factors have long been used as strategy to induce cell death. Research into ferroptosis and advancements in nanotechnology have led to the discovery that nanomaterials are superior to biological medications in triggering ferroptosis. Nanomaterials derived from iron can enhance ferroptosis induction by directly releasing large quantities of iron and increasing cell ROS levels. Moreover, utilizing nanomaterials to promote programmed cell death minimizes the probability of unfavorable effects induced by mutations in cancer-associated genes such as RAS and TP53. Taken together, this review summarizes the molecular mechanisms involved in ferroptosis along with the classification of ferroptosis induction. It also emphasized the importance of cell organelles in the control of ferroptosis in cancer therapy. The nanomaterials that trigger ferroptosis are categorized and explained. Iron-based and noniron-based nanomaterials with their characterization at the molecular and cellular levels have been explored, which will be useful for inducing ferroptosis that leads to reduced tumor growth. Within this framework, we offer a synopsis, which traverses the well-established mechanism of ferroptosis and offers practical suggestions for the design and therapeutic use of nanomaterials.

Adaptive activation Functions with Deep Kronecker Neural Network optimized with Bear Smell Search Algorithm for preventing MANET Cyber security attacks.

An Adaptive activation Functions with Deep Kronecker Neural Network optimized with Bear Smell Search Algorithm (BSSA) (ADKNN-BSSA-CSMANET) is proposed for preventing MANET Cyber security attacks. The mobile users are enrolled with Trusted Authority Using a Crypto Hash Signature (SHA-256). Every mobile user uploads their finger vein biometric, user ID, latitude and longitude for confirmation. The packet analyser checks if any attack patterns are identified. It is implemented using adaptive density-based spatial clustering (ADSC) that deems information from packet header. Geodesic filtering (GF) is used as a pre-processing method for eradicating the unsolicited content and filtering pertinent data. Group Teaching Algorithm (GTA)-based feature selection is utilized for ideal collection of features and Adaptive Activation Functions along Deep Kronecker Neural Network (ADKNN) is used to categorizing normal and attack packets (DoS, Probe, U2R, and R2L). Then BSSA is utilized for optimizing the weight parameters of ADKNN classifier for optimal classification. The proposed technique is executed in python and its efficiency is evaluated by several performances metrics, such as Accuracy, Attack Detection Rate, Detection Delay, Packet Delivery Ratio, Throughput, and Energy Consumption. The proposed technique provides 36.64%, 33.06%, and 33.98% lower Detection Delay on NSL-KDD dataset compared with the existing methods.

A novel staging system to consolidate silent sinus syndrome and chronic maxillary atelectasis: A systematic review and case series.

KEY POINTS: Silent sinus syndrome (SSS) and chronic maxillary atelectasis (CMA) represent an overlapping clinical entity, both likely lying on the spectrum of one disease process. There is widespread inconsistency of diagnosis in the literature of reported cases of SSS and CMA. We propose a novel, comprehensive staging system to simplify diagnosis and inform management.

Safety of Ambulatory Surgery For Obstructive Sleep Apnea: A Retrospective Review.

OBJECTIVE: Assess the safety of ambulatory surgery performed for obstructive sleep apnea. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care hospital. METHODS: Demographic data including age, gender, race, body mass index, insurance status, socioeconomic status, and distance traveled for surgery was collected, as well as comorbidities, and apnea-hypopnea index (AHI). Outcome variables included continuous positive airway pressure reinitiation, planned/unplanned postoperative admission, emergency department (ED) presentation, or readmission within 7 and 14 days of surgery. RESULTS: A total of 601 patients were included, who underwent sleep surgery between 2017 and 2022. The median age was 55 years [interquartile range: 19]. A total of 437 patients (73%) were male, 502 (84%) were Caucasian, and the median distance traveled was 20 miles [27]. The median AHI was 27.1 [26]. A total of 286 hypoglossal nerve stimulators, 12 tonsillectomies, 160 expansion sphincteroplasties (ESP), and 201 nasal procedures were performed. There were 9 (1%) planned and 23 (4%) total admissions postoperatively. Sixteen patients (2%) presented to ED within 7 days, and 22 (3%) within 14 days. Nine (1%) were readmitted within 7 days, and 12 (2%) within 14 days. There were significantly more planned admissions, unplanned admissions, ED presentations, and readmissions for ESP. There were no significant differences in demographic or clinical data between patients who underwent single versus multiple surgeries. CONCLUSION: Outpatient sleep surgery is generally safe. Close postoperative monitoring is necessary and overnight observation should be considered in those with very severe sleep apnea and/or significant comorbidities. The distance a patient travels should also be considered for overnight admission.

Long-Term Kinetics of SARS-CoV-2 Neutralizing and Anti-Receptor Binding Domain Antibodies among Laboratory-Confirmed COVID-19 Cases in Delhi National Capital Region, India: A Prospective, One-Year Follow-Up Study.

Background: This study was conducted with the objective of measuring the neutralizing and anti-receptor binding domain antibody levels against SARS-CoV-2 among laboratory-confirmed COVID-19 cases and exploring its long-term kinetics over a period of 1 year. Methods: One hundred laboratory-confirmed COVID-19 cases were recruited. Serum samples of the participants were collected within three months from the date of the positive COVID-19 report. The participants were prospectively followed up every three months for symptoms and the collection of blood samples for three additional rounds. The presence of anti-SARS-CoV-2 antibodies (IgA, IgG, and IgM antibodies), anti-receptor binding domain antibodies (anti-RBD), and neutralizing antibodies were measured. Findings: Median plaque reduction neutralization test (PRNT) titers showed a rising trend in the first three rounds of follow-up. The quantitative anti-receptor binding domain ELISA (QRBD) values showed a declining trend in the initial three rounds. However, both the PRNT titers and QRBD values showed significantly higher values for the fourth round of follow-up. Total antibody (WANTAI) levels showed an increasing trend in the initial three rounds (statistically significant). Interpretation: Neutralizing antibodies showed an increasing trend. The anti-receptor binding domain antibodies showed a decreasing trend. Neutralizing antibodies and anti-RBD antibodies persisted in the majority.

Intratumoral Heterogeneity, Chemoresistance and Lymph Node Landing Zone Prognosis in Testicular Tumors Based on Histopathological Characteristics.

BACKGROUND: Existing data on the histopathological correlation of testicular tumors with lymph node prognosis have been poorly explored. We aimed to investigate the relationship of the histopathological properties of testicular tumors with lymph nodes and their involvement with chemoresistance and heterogeneity of testicular tumors. METHODS: Patients with non-seminomatous germ cell tumor (NSGCT) were selected for histopathological correlation of testicular tumor with lymph nodes and its relationship with chemoresistance and heterogeneity. Histopathological and radiological parameters associated with the risk of chemoresistance and tumor progression were measured pre- and post-chemotherapy. Binomial logistic regression and Kaplan-Meier analysis were implemented to determine the predictors of progression and adverse overall patient survival. All categorical variables were analyzed using the Chi-square test, while Pearson's R coefficient determined the correlation. RESULTS: Male patients who were diagnosed with NSGCT from March 2017 to December 2018 at Guwahati Medical College, Guwahati, India, were included in this study. Lymph node groups were predominantly incriminated with the EYST or EYS groups and minimally linked with the pure E and YCS groups. Furthermore, the highest number of lymph node stations was associated with pre-chemotherapy. In salvage chemotherapy in the form of VIP, we found exciting outcomes, as approximately 41% of cases responded positively, especially in the EYS group. CONCLUSION: Our study classifies NSGCT according to the most favorable histopathological grouping and explores the tumoral response in different intrinsic and extrinsic variables. Our analysis can serve as a triumphant histopathological nomogram for a sublime management protocol to deal with the onerous histological pairing in NSGCT.

Standardised quantitative assays for anti-SARS-CoV-2 immune response used in vaccine clinical trials by the CEPI Centralized Laboratory Network: a qualification analysis.

BACKGROUND: Accurate quantitation of immune markers is crucial for ensuring reliable assessment of vaccine efficacy against infectious diseases. This study was designed to confirm standardised performance of SARS-CoV-2 assays used to evaluate COVID-19 vaccine candidates at the initial seven laboratories (in North America, Europe, and Asia) of the Coalition for Epidemic Preparedness Innovations (CEPI) Centralized Laboratory Network (CLN). METHODS: Three ELISAs (pre-spike protein, receptor binding domain, and nucleocapsid), a microneutralisation assay (MNA), a pseudotyped virus-based neutralisation assay (PNA), and an IFN-γ T-cell ELISpot assay were developed, validated or qualified, and transferred to participating laboratories. Immune responses were measured in ELISA laboratory units (ELU) for ELISA, 50% neuralisation dilution (ND50) for MNA, 50% neutralisation titre (NT50) for PNA, and spot-forming units for the ELISpot assay. Replicate assay results of well characterised panels and controls of blood samples from individuals with or without SARS-CoV-2 infection were evaluated by geometric mean ratios, standard deviation, linear regression, and Spearman correlation analysis for consistency, accuracy, and linearity of quantitative measurements across all laboratories. FINDINGS: High reproducibility of results across all laboratories was demonstrated, with interlaboratory precision of 4·1-7·7% coefficient of variation for all three ELISAs, 3·8-19·5% for PNA, and 17·1-24·1% for MNA, over a linear range of 11-30 760 ELU per mL for the three ELISAs, 14-7876 NT50 per mL for PNA, and 21-25 587 ND50 per mL for MNA. The MNA was also adapted for detection of neutralising antibodies against the major SARS-CoV-2 variants of concern. The results of PNA and MNA (r=0·864) and of ELISA and PNA (r=0·928) were highly correlated. The IFN-γ ELISpot interlaboratory variability was 15·9-49·9% coefficient of variation. Sensitivity and specificity were close to 100% for all assays. INTERPRETATION: The CEPI CLN provides accurate quantitation of anti-SARS-CoV-2 immune response across laboratories to allow direct comparisons of different vaccine formulations in different geographical areas. Lessons learned from this programme will serve as a model for faster responses to future pandemic threats and roll-out of effective vaccines. FUNDING: CEPI.

Identification of a glutathione transporter in A. actinomycetemcomitans.

IMPORTANCE: Microbes produce a large array of extracellular molecules, which serve as signals and cues to promote polymicrobial interactions and alter the function of microbial communities. This has been particularly well studied in the human oral microbiome, where key metabolites have been shown to impact both health and disease. Here, we used an untargeted mass spectrometry approach to comprehensively assess the extracellular metabolome of the pathogen Aggregatibacter actinomycetemcomitans and the commensal Streptococcus gordonii during mono- and co-culture. We generated and made publicly available a metabolomic data set that includes hundreds of potential metabolites and leveraged this data set to identify an operon important for glutathione secretion in A. actinomycetemcomitans.

Management of grade II and III furcation defects with intramarrow penetration along with indigenously prepared DFDBA and amniotic membrane: a clinical and radiographic study.

Managing furcation defects constitutes a problem in successful periodontal therapy. Guided tissue regeneration (GTR) is the mainstay for the management of such defects but is expensive. This study makes use of indigenously prepared demineralized freeze-dried bone allograft (DFDBA) and amniotic membrane (AM) as a cost-effective alternative. The purpose of the study was to compare the clinical outcome of grade II and III furcation defects with and without using indigenous DFDBA and AM prepared at Central Tissue Bank, MAIDS. 18 systemically healthy patients with chronic periodontitis displaying either grade II or III furcation defects were treated with open flap debridement (OFD) + intramarrow penetration (IMP) (control group) and OFD + IMP + DFDBA + AM (test group). The clinical and radiographic parameters were recorded at 3 and 6 months postoperatively. All parameters were statistically analyzed. Both treatment modalities resulted in improvement in all clinical variables evaluated. Radiographic dimensions evaluating bone fill showed a statistically significant difference in the test group compared to the control group. Within the limitations of this study, data suggest GTR using indigenously prepared DFDBA and amniotic membrane to be an economical and viable option for treating furcation defects.

A commentary on broader use of preoperative polysomnography in pediatric patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA), characterized by repeated episodes of prolonged airway obstruction during sleep, is a common condition in pediatric patients ages 2 to 6. Polysomnography (PSG) testing can be used to assess the severity of OSA or obstructive sleep-disordered breathing prior to adenotonsillectomy. The article "Characteristics and Frequency of Children With Severe Obstructive Sleep Apnea Undergoing Elective Polysomnography" by Bains et al. notes the variability in guidelines regarding indication for PSG amongst professional societies, making it difficult for physicians to determine which patients require PSG. The purpose of this commentary is to emphasize and elaborate on the potential benefit for preoperative PSG in all patients considering adenotonsillectomy as presented by the aforementioned article. With broader use of preoperative PSG, providers would have a more accurate assessment of OSA severity and to aid in surgical decision-making and postoperative planning.

Factors Predicting Discharge Disposition Following Head and Neck Free Flap Reconstruction.

OBJECTIVES: Patients undergoing head and neck free flap reconstruction (HNFFR) may have significant change to their baseline functional status requiring inpatient rehabilitation (IPR) after discharge. We sought to identify patient/procedure characteristics predictive of discharge destination. METHODS: Patients undergoing elective HNFFR between July 2017 and July 2022 were reviewed for discharge destination. Those discharged to IPR versus home were compared across patient/procedure characteristics and physical/occupational therapy metrics. Significance was assessed via bivariate and multivariable analyses. RESULTS: Of the 531 patients, 102 (19.2%) required IPR postoperatively. Patients discharged to IPR versus home were significantly older (70.1 [11.6] vs. 64.1 [13.1] years; p < 0.001) and more likely to lack family assistance (26.5% vs. 8.6%; p < 0.001), require baseline assistance for activities of daily living (ADLs) (31.4% vs. 9.8%; p < 0.001), have baseline cognitive dysfunction (15.7% vs. 6.1%; p = 0.001), were more likely to have neoplasm as the surgical indication for HNFFR (89.2% vs. 80.0%; p = 0.033) and more likely to have a tracheostomy postop (62.7% vs. 51.7%), and had a significantly longer length of stay (11.2 [8.0] vs. 6.8 [8.3] days; p < 0.001). There was no significant difference in gender, donor site, use of tube feeds, and use of assistive devices between the two groups. Following logistic regression, the strongest predictors of discharge to IPR include lack of family assistance (OR = 3.8; p < 0.001) and baseline assistance for ADLs (OR = 4.0, p < 0.001). CONCLUSION: Certain patient factors predict the need for discharge to rehab after HNFFR. Perioperative identification of these factors may facilitate patient counseling and discharge planning with potential to reduce hospital length of stay and further optimize patient care. LEVEL OF EVIDENCE: III Laryngoscope, 2023.

Intracellular Zn(II) induced turn-on fluorescence of an L-phenylalanine-derived pseudopeptide.

A C2 symmetric L-phenylalanine-derived pseudopeptide has been synthesized for selective and sensitive recognition of Zn(II) ions in aqueous-organic media. The pseudopeptidic probes exhibit intracellular Zn(II) ion-sensing capabilities as demonstrated via live-cell fluorescence studies on RAW264.7 cells. Hence, we present a bioinspired pseudopeptide for potential biological applications involving intracellular Zn(II) ion detection.

The multi-protein targeting potential of bioactive syringin in inflammatory diseases: using molecular modelling and in-silico analysis of regulatory elements.

Inflammation plays a crucial role in the onset or progression of a variety of acute and chronic diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) are the only available FDA-approved therapy. The therapeutic outcome of NSAIDs is still finite due to off-target effects and extreme side effects on other vital organs. Bioactive syringin has been manifested to hold anti-osteoporosis, cardiac hypertrophy, alter autophagy, anti-cancer, neuro-preventive effects, etc. However, its multi-protein targeting potential in inflammation mostly remains unexplored. In the present work, we have checked the multi-protein targeting potential of bioactive glycoside syringin in inflammatory diseases. Based on the binding score of protein-ligand complexes, glycoside syringin scored greater than -7 kcal/mol against 12 inflammatory proteins. Our molecular dynamic simulation study (200 ns) confirmed that bioactive syringin remained inside the binding cavity of inflammatory proteins (JAK1, TYK2, and COX1) in a stable conformation. Further, our co-expression analysis suggests that these genes play an essential role in multiple pathways and are regulated by multiple miRNAs. Our study demonstrates that bioactive glycoside syringin might be a multi-protein targeting potential against inflammatory diseases and could be further investigated utilizing different preclinical approaches.Communicated by Ramaswamy H. Sarma.

Pseudobulbiferamides: Plasmid-Encoded Ureidopeptide Natural Products with Biosynthetic Gene Clusters Shared Among Marine Bacteria of Different Genera.

Ureidopeptidic natural products possess a wide variety of favorable pharmacological properties. In addition, they have been shown to mediate core physiological functions in producer bacteria. Here, we report that similar ureidopeptidic natural products with conserved biosynthetic gene clusters are produced by different bacterial genera that coinhabit marine invertebrate microbiomes. We demonstrate that a Microbulbifer strain isolated from a marine sponge can produce two different classes of ureidopeptide natural products encoded by two different biosynthetic gene clusters that are positioned on the bacterial chromosome and on a plasmid. The plasmid encoded ureidopeptide natural products, which we term the pseudobulbiferamides (5-8), resemble the ureidopeptide natural products produced by Pseudovibrio, a different marine bacterial genus that is likewise present in marine sponge commensal microbiomes. Using imaging mass spectrometry, we find that the two classes of Microbulbifer-derived ureidopeptides occupy different physical spaces relative to the bacterial colony, perhaps implying different roles for these two compound classes in Microbulbifer physiology and environmental interactions.

Artificial intelligence for natural product drug discovery.

Developments in computational omics technologies have provided new means to access the hidden diversity of natural products, unearthing new potential for drug discovery. In parallel, artificial intelligence approaches such as machine learning have led to exciting developments in the computational drug design field, facilitating biological activity prediction and de novo drug design for molecular targets of interest. Here, we describe current and future synergies between these developments to effectively identify drug candidates from the plethora of molecules produced by nature. We also discuss how to address key challenges in realizing the potential of these synergies, such as the need for high-quality datasets to train deep learning algorithms and appropriate strategies for algorithm validation.

Targeted drug delivery using beeswax-derived albendazole-loaded solid lipid nanoparticles in Haemonchus contortus, an albendazole-tolerant nematode.

Targeted delivery has not been achieved for anthelmintic treatment, resulting in the requirement of excess drug dose leading to side effects and therapeutic resistance. Gastrointestinal helminths take up lipid droplets from digestive fluid for energy production, egg development, and defense which inspired us to develop biocompatible and orally administrable albendazole-loaded solid lipid nanoparticles (SLN-A) that were derived from beeswax and showed drug loading efficiency of 83.3 ± 6.5 mg/g and sustained-release properties with 84.8 ± 2.5% of drug released at pH 6.4 within 24 h at 37 °C. Rhodamine B-loaded SLN showed time-dependent release and distribution of dye in-vitro in Haemonchus contortus. The sustained-release property was shown by the particles that caused enhancement of albendazole potency up to 50 folds. Therefore, this formulation has immense potential as an anthelminthic drug delivery vehicle that will be able to reduce the dose and drug-induced side effects by enhancing the bioavailability of the drug.