NOD2 activation enhances macrophage Fcγ receptor function and may increase the efficacy of antibody therapy.

Introduction: Therapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit cytotoxic responses against malignant B cells. However, efficacy is often compromised due to a suppressive microenvironment that interferes with cellular immune responses. To overcome this suppression, agonists of pattern recognition receptors have been studied which promote direct cytotoxicity or elicit anti-tumoral immune responses. NOD2 is an intracellular pattern recognition receptor that participates in the detection of peptidoglycan, a key component of bacterial cell walls. This detection then mediates the activation of multiple signaling pathways in myeloid cells. Although several NOD2 agonists are being used worldwide, the potential benefit of these agents in the context of antibody therapy has not been explored. Methods: Primary cells from healthy-donor volunteers (PBMCs, monocytes) or CLL patients (monocytes) were treated with versus without the NOD2 agonist L18-MDP, then antibody-mediated responses were assessed. In vivo, the Eµ-TCL1 mouse model of CLL was used to test the effects of L18-MDP treatment alone and in combination with anti-CD20 antibody. Results: Treatment of peripheral blood mononuclear cells with L18-MDP led to activation of monocytes from both healthy donors and CLL patients. In addition, there was an upregulation of activating FcγR in monocytes and a subsequent increase in antibody-mediated phagocytosis. This effect required the NF-κB and p38 signaling pathways. Treatment with L18-MDP plus anti-CD20 antibody in the Eµ-TCL model of CLL led to a significant reduction of CLL load, as well as to phenotypic changes in splenic monocytes and macrophages. Conclusions: Taken together, these results suggest that NOD2 agonists help overturn the suppression of myeloid cells, and may improve the efficacy of antibody therapy for CLL.

Perovskite Solar Cells: A Review of the Latest Advances in Materials, Fabrication Techniques, and Stability Enhancement Strategies.

Perovskite solar cells (PSCs) are gaining popularity due to their high efficiency and low-cost fabrication. In recent decades, noticeable research efforts have been devoted to improving the stability of these cells under ambient conditions. Moreover, researchers are exploring new materials and fabrication techniques to enhance the performance of PSCs under various environmental conditions. The mechanical stability of flexible PSCs is another area of research that has gained significant attention. The latest research also focuses on developing tin-based PSCs that can overcome the challenges associated with lead-based perovskites. This review article provides a comprehensive overview of the latest advances in materials, fabrication techniques, and stability enhancement strategies for PSCs. It discusses the recent progress in perovskite crystal structure engineering, device construction, and fabrication procedures that has led to significant improvements in the photo conversion efficiency of these solar devices. The article also highlights the challenges associated with PSCs such as their poor stability under ambient conditions and discusses various strategies employed to enhance their stability. These strategies include the use of novel materials for charge transport layers and encapsulation techniques to protect PSCs from moisture and oxygen. Finally, this article provides a critical assessment of the current state of the art in PSC research and discusses future prospects for this technology. This review concludes that PSCs have great potential as a low-cost alternative to conventional silicon-based solar cells but require further research to improve their stability under ambient conditions in view of their definitive commercialization.

Use of artificial intelligence in determination of bone age of the healthy individuals: A scoping review.

BACKGROUND: Bone age assessment, as an indicator of biological age, is widely used in orthodontics and pediatric endocrinology. Owing to significant subject variations in the manual method of assessment, artificial intelligence (AI), machine learning (ML), and deep learning (DL) play a significant role in this aspect. A scoping review was conducted to search the existing literature on the role of AI, ML, and DL in skeletal age or bone age assessment in healthy individuals. METHODS: A literature search was conducted in PubMed, Scopus, and Web of Science from January 2012 to December 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews (PRISMA-ScR) and Joanna Briggs Institute guidelines. Grey literature was searched using Google Scholar and OpenGrey. Hand-searching of the articles in all the reputed orthodontic journals and the references of the included articles were also searched for relevant articles for the present scoping review. RESULTS: Nineteen articles that fulfilled the inclusion criteria were included. Ten studies used skeletal maturity indicators based on hand and wrist radiographs, two studies used magnetic resonance imaging and seven studies used cervical vertebrae maturity indicators based on lateral cephalograms to assess the skeletal age of the individuals. Most of these studies were published in non-orthodontic medical journals. BoneXpert automated software was the most commonly used software, followed by DL models, and ML models in the studies for assessment of bone age. The automated method was found to be as reliable as the manual method for assessment. CONCLUSIONS: This scoping review validated the use of AI, ML, or DL in bone age assessment of individuals. A more uniform distribution of sufficient samples in different stages of maturation, use of three-dimensional inputs such as magnetic resonance imaging, and cone beam computed tomography is required for better training of the models to generalize the outputs for use in the target population.

Mirror Hypopyon-Corneal Ulcer With Hypopyon in a Silicone Oil-Filled Eye.

This case report describes a woman aged 57 years with a hyperoleon and concomitant hypopyon from a history of silicone oil for retinal detachment and simultaneous Streptococcus pyogenes keratitis.

Brittle cornea syndrome: A tale of three brothers.

Brittle cornea syndrome (BCS) is a genetic connective tissue disorder with discernible ocular features such as blue scleral and thin cornea that predominantly presents in younger children. We herein describe cases of three siblings with BCS, two of whom presented to us with open globe injuries following trivial trauma. Clinical examination of the other eye in both showed diffusely thin corneas and blue sclera. A systemic evaluation revealed sensorineural hearing loss and hyperextensible joints. The third sibling was screened and found to have features concurrent with BCS. This report highlights the challenges faced in the management of ocular injuries and consecutive complications in these patients.

Tonic GABAergic inhibition, via GABAA receptors containing αßƐ subunits, regulates excitability of ventral tegmental area dopamine neurons.

The activity of midbrain dopamine neurons is strongly regulated by fast synaptic inhibitory γ-Aminobutyric acid (GABA)ergic inputs. There is growing evidence in other brain regions that low concentrations of ambient GABA can persistently activate certain subtypes of GABAA receptor to generate a tonic current. However, evidence for a tonic GABAergic current in midbrain dopamine neurons is limited. To address this, we conducted whole-cell recordings from ventral tegmental area (VTA) dopamine neurons in brain slices from mice. We found that application of GABAA receptor antagonists decreased the holding current, indicating the presence of a tonic GABAergic input. Global increases in GABA release, induced by either a nitric oxide donor or inhibition of GABA uptake, further increased this tonic current. Importantly, prolonged inhibition of the firing activity of local GABAergic neurons abolished the tonic current. A combination of pharmacology and immunohistochemistry experiments suggested that, unlike common examples of tonic inhibition, this current may be mediated by a relatively unusual combination of α4ßƐ subunits. Lastly, we found that the tonic current reduced excitability in dopamine neurons suggesting a subtractive effect on firing activity.

Alternative observational designs to estimate the effectiveness of one dose of oral cholera vaccine in Lusaka, Zambia.

We conducted a matched case-control (MCC), test-negative case-control (TNCC) and case-cohort study in 2016 in Lusaka, Zambia, following a mass vaccination campaign. Confirmed cholera cases served as cases in all three study designs. In the TNCC, control-subjects were cases with negative cholera culture and polymerase chain reaction results. Matched controls by age and sex were selected among neighbours of the confirmed cases in the MCC study. For the case-cohort study, we recruited a cohort of randomly selected individuals living in areas considered at-risk of cholera. We recruited 211 suspected cases (66 confirmed cholera cases and 145 non-cholera diarrhoea cases), 1055 matched controls and a cohort of 921. Adjusted vaccine effectiveness of one dose of oral cholera vaccine (OCV) was 88.9% (95% confidence interval (CI) 42.7-97.8) in the MCC study, 80.2% (95% CI: 16.9-95.3) in the TNCC design and 89.4% (95% CI: 64.6-96.9) in the case-cohort study. Three study designs confirmed the short-term effectiveness of single dose OCV. Major healthcare-seeking behaviour bias did not appear to affect our estimates. Most of the protection among vaccinated individuals could be attributed to the direct effect of the vaccine.

Activation of the Intracellular Pattern Recognition Receptor NOD2 Promotes Acute Myeloid Leukemia (AML) Cell Apoptosis and Provides a Survival Advantage in an Animal Model of AML.

TLRs, a family of membrane-bound pattern recognition receptors found on innate immune cells, have been well studied in the context of cancer therapy. Activation of these receptors has been shown to induce inflammatory anticancer events, including differentiation and apoptosis, across a wide variety of malignancies. In contrast, intracellular pattern recognition receptors such as NOD-like receptors have been minimally studied. NOD2 is a member of the NOD-like receptor family that initiates inflammatory signaling in response to the bacterial motif muramyl dipeptide. In this study, we examined the influence of NOD2 in human acute myeloid leukemia (AML) cells, demonstrating that IFN-γ treatment upregulated the expression of NOD2 signaling pathway members SLC15A3 and SLC15A4, downstream signaling kinase RIPK2, and the NOD2 receptor itself. This priming allowed for effective induction of caspase-1-dependent cell death upon treatment with muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic ligand for NOD2. Furthermore, the combination of MTP-PE and IFN-γ on AML blasts generated an inflammatory cytokine profile and activated NK cells. In a murine model of AML, dual treatment with MTP-PE and IFN-γ led to a significant increase in mature CD27- CD11b+ NK cells as well as a significant reduction in disease burden and extended survival. These results suggest that NOD2 activation, primed by IFN-γ, may provide a novel therapeutic option for AML.

Prediction of Human Pharmacokinetics of Ulixertinib, a Novel ERK1/2 Inhibitor from Mice, Rats, and Dogs Pharmacokinetics.

BACKGROUND AND OBJECTIVES: Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. The primary objectives of the study were to evaluate the pharmacokinetics of ulixertinib in mice, rats, and dogs followed by prediction of human pharmacokinetic profile by allometric equations with/without correction factors. METHODS: Oral and intravenous pharmacokinetic profiles of ulixertinib were generated in mice, rats, and dogs. The human intravenous pharmacokinetics profiles [volume of distribution (Vss) and clearance (CL)] were predicted employing simple allometry and using correction factors [maximum life span potential (MLP) and brain weight (BW)]. Pharmacokinetic data obtained from dogs were used to simulate human oral profile [area under the curve (AUC) and maximum plasma concentrations (Cmax)]. RESULTS: Post-intravenous administration the CL was moderate in dogs (15.5 mL/min/kg) and low in mice (6.24 mL/min/kg) and rats (1.67 mL/min/kg). Vss was 0.56, 0.36, and 1.61 L/kg in mice, rats, and dogs, respectively. The half-life (t½) of ulixertinib ranged between 1.0 and 2.5 h across the animal species. Following oral administration ulixertinib attained maximum concentration in plasma (Tmax) within 0.50-0.75 h in mice and rats, indicating that absorption was rapid; however, in dogs, Tmax attained at 2 h. Absolute oral bioavailability in mice and rats was > 92%; however, in dogs, it was 34%. By different allometric approaches, simple method and brain weight correction factor shown clear improvement in the prediction efficiency of allometric scaling for Vss (1.34-1.70 L/kg) and CL (4.18-6.09 mL/min/kg), respectively, comparing with the MLP method and simple method for CL. Similarly, simulation of oral human profile was attained from scaled values and dog data to predict reported human profile (AUC and Cmax). CONCLUSIONS: The derived pharmacokinetic parameters (AUC and Cmax at 600 mg dose) and simulated plasma concentration-time profiles of ulixertinib in humans were predicted with good confidence by allometric approach.

LC-ESI-MS/MS determination of 4-methylpyrazole in dog plasma and its application to a pharmacokinetic study in dogs.

A simple, specific, sensitive and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of 4-methylpyrazole in dog plasma using N-methylnicotinamide-d4 as an internal standard (IS) as per regulatory guidelines. Sample preparation was accomplished through a simple protein precipitation. Chromatographic separation of 4-methylpyrazole and the IS was performed on a monolithic (Chromolith RP18e ) column using an isocratic mobile phase comprising 0.2% formic acid in water and acetonitrile (20:80, v/v) at a flow rate of 1.0 mL/min. Elution of 4-methylpyrazole and the IS occurred at ~1.60 and 1.56 min, respectively. The total chromatographic run time was 3.2 min. A linear response function was established in the concentration range of 4.96-4955 ng/mL. The intra- and inter-day accuracy and precision were in the ranges 1.81-12.9 and 3.80-11.1%, respectively. This novel method has been applied to a pharmacokinetic study in dogs.

Planar silver nanowire, carbon nanotube and PEDOT:PSS nanocomposite transparent electrodes.

Highly conductive, transparent and flexible planar electrodes were fabricated using interwoven silver nanowires and single-walled carbon nanotubes (AgNW:SWCNT) in a PEDOT:PSS matrix via an epoxy transfer method from a silicon template. The planar electrodes achieved a sheet resistance of 6.6 ± 0.0 Ω/□ and an average transmission of 86% between 400 and 800 nm. A high figure of merit of 367 Ω-1 is reported for the electrodes, which is much higher than that measured for indium tin oxide and reported for other AgNW composites. The AgNW:SWCNT:PEDOT:PSS electrode was used to fabricate low temperature (annealing free) devices demonstrating their potential to function with a range of organic semiconducting polymer:fullerene bulk heterojunction blend systems.

Hepatitis E: clinical presentation in disease-endemic areas and diagnosis.

Infection with hepatitis E virus (HEV), mostly genotype 1, is endemic in several developing countries. It can be asymptomatic, be associated with acute hepatitis or fulminant hepatic failure, or present as acute-on-chronic liver disease. Pregnant women are at particular risk of serious outcomes and death. Chronic HEV infection has not been reported from these areas. Diagnosis of acute hepatitis E depends on detection of IgM anti-HEV antibodies or HEV RNA. Current assays for IgM anti-HEV are suboptimal, with high rates of interassay discordance. Though they perform reasonably well in disease-endemic areas, positive test results in low-endemicity areas require confirmation using HEV RNA testing. Detection of IgG anti-HEV antibodies indicates exposure to HEV, either recent or remote. Assays for these too have low concordance, making comparisons of seroprevalence rates using different assays difficult to interpret. There is an urgent need to develop better assays for markers of HEV infection and exposure.

Sudarshan kriya yoga: Breathing for health.

Breathing techniques are regularly recommended for relaxation, stress management, control of psychophysiological states, and to improve organ function. Yogic breathing, defined as a manipulation of breath movement, has been shown to positively affect immune function, autonomic nervous system imbalances, and psychological or stress-related disorders. The aim of this study was to assess and provide a comprehensive review of the physiological mechanisms, the mind-body connection, and the benefits of Sudarshan Kriya Yoga (SKY) in a wide range of clinical conditions. Various online databases searched were Medline, Psychinfo, EMBASE, and Google Scholar. All the results were carefully screened and articles on SKY were selected. The references from these articles were checked to find any other potentially relevant articles. SKY, a unique yogic breathing practice, involves several types of cyclical breathing patterns, ranging from slow and calming to rapid and stimulating. There is mounting evidence to suggest that SKY can be a beneficial, low-risk, low-cost adjunct to the treatment of stress, anxiety, post-traumatic stress disorder, depression, stress-related medical illnesses, substance abuse, and rehabilitation of criminal offenders.

Highly conductive interwoven carbon nanotube and silver nanowire transparent electrodes.

Electrodes fabricated using commercially available silver nanowires (AgNWs) and single walled carbon nanotubes (SWCNTs) produced sheet resistances in the range 4-24 Ω â–¡-1 with specular transparencies up to 82 %. Increasing the aqueous dispersibility of SWCNTs decreased the bundle size present in the film resulting in improved SWCNT surface dispersion in the films without compromising transparency or sheet resistance. In addition to providing conduction pathways between the AgNW network, the SWCNTs also provide structural support, creating stable self-supporting films. Entanglement of the AgNWs and SWCNTs was demonstrated to occur in solution prior to deposition by monitoring the transverse plasmon resonance mode of the AgNWs during processing. The interwoven AgNW/SWCNT structures show potential for use in optoelectronic applications as transparent electrodes and as an ITO replacement.

New diarylmethanofullerene derivatives and their properties for organic thin-film solar cells.

A number of diarylmethanofullerene derivatives were synthesized. The cyclopropane ring of the derivatives has two aryl groups substituted with electron-withdrawing and -donating groups, the latter with long alkyl chains to improve solubility in organic solvents, an important property in processing cells. First reduction potentials of most derivatives were less negative than that of [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), which is possibly ascribed to their electron-withdrawing nature. Organic thin-film photovoltaic cells fabricated with poly(3-hexylthiophene) (P3HT) as the electron-donor and diarylmethanofullerene derivatives as the electron-acceptor material were examined. The {(methoxycarbonyl)phenyl[bis(octyloxy)phenyl]methano}fullerene showed power conversion efficiency as high as PCBM, but had higher solubility in a variety of organic solvents than PCBM. The V(oc) value was higher than that of PCBM, which is derived from the electron-donating (octyloxy)phenyl group, possibly raising the LUMO level. Photovoltaic effects of the devices fabricated with the derivatives having some electron-withdrawing groups were also examined.