Ligand-free biodegradable poly(beta-amino ester) nanoparticles for targeted systemic delivery of mRNA to the lungs.

Non-viral nanoparticles (NPs) have seen heightened interest as a delivery method for a variety of clinically relevant nucleic acid cargoes in recent years. While much of the focus has been on lipid NPs, non-lipid NPs, including polymeric NPs, have the possibility of improved efficacy, safety, and targeting, especially to non-liver organs following systemic administration. A safe and effective systemic approach for intracellular delivery to the lungs could overcome limitations to intratracheal/intranasal delivery of NPs and improve clinical benefit for a range of diseases including cystic fibrosis. Here, engineered biodegradable poly (beta-amino ester) (PBAE) NPs are shown to facilitate efficient delivery of mRNA to primary human airway epithelial cells from both healthy donors and individuals with cystic fibrosis. Optimized NP formulations made with differentially endcapped PBAEs and systemically administered in vivo lead to high expression of mRNA within the lungs in BALB/c and C57 B/L mice without requiring a complex targeting ligand. High levels of mRNA-based gene editing were achieved in an Ai9 mouse model across bronchial, epithelial, and endothelial cell populations. No toxicity was observed either acutely or over time, including after multiple systemic administrations of the NPs. The non-lipid biodegradable PBAE NPs demonstrate high levels of transfection in both primary human airway epithelial cells and in vivo editing of lung cell types that are targets for numerous life-limiting diseases particularly single gene disorders such as cystic fibrosis and surfactant deficiencies.

Dr. Willem Kolff: The Father of the Artificial Kidney.

Dr. Willem J. Kolff (February 14, 1911-February 11, 2009) is widely considered the father of dialysis. In addition, his innovations also included the artificial heart and lung, which earned him the title "the Father of Artificial Organs". In due course, his artificial kidney evolved into modern dialysis, a procedure that filters and purifies blood using an extracorporeal circuit, now a life-sustaining treatment for patients with end-stage kidney failure. Furthermore, his membrane oxygenator, which provided a method to add oxygen to blood as it passed through a machine, is still used in heart-lung machines during open-heart surgery. He is also known for his work in developing the artificial heart (although it now carries the name of his student, Dr. Robert Jarvik), which was used in subsequent designs, as a bridge to heart transplantation. Thanks to his work on the artificial kidney, millions of patients worldwide have benefited from life-sustaining hemodialysis. It can also be argued that Dr. Kolff's introduction of dialysis in 1943 marks the dawn of modern nephrology.

Functional variant rs9344 at 11q13.3 regulates CCND1 expression in multiple myeloma with t(11;14).

Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by cytogenetic abnormalities, such as t(11;14)(q13;q32), resulting in CCND1 overexpression. The rs9344 G allele within CCND1 is the most significant susceptibility allele for t(11;14). Sequencing data from 2 independent cohorts, CoMMpass (n = 698) and Mayo Clinic (n = 661), confirm the positive association between the G allele and t(11;14). Among 80% of individuals heterozygous for rs9344 with t(11;14), the t(11;14) event occurs on the G allele, demonstrating a biological preference for the G allele in t(11;14). Within t(11;14), the G allele is associated with higher CCND1 expression and elevated H3K27ac and H3K4me3. CRISPR/Cas9 mediated A to G conversion resulted in increased H3K27ac over CCND1 and elevated CCND1 expression. ENCODE ChIP-seq data supported a PAX5 binding site within the enhancer region covering rs9344, showing preferential binding to the G allele. Overexpression of PAX5 resulted in increased CCND1 expression. These results support the importance of rs9344 G enhancer in increasing CCND1 expression in MM.

A Practical and Sustainable Ni/Co-Free High-Energy Electrode Material: Nanostructured LiMnO2.

Ni/Co-free high-energy positive electrode materials are of great importance to ensure the sustainability of Li-ion battery production and its supply chain in addition to minimizing environmental impact. Here, nanostructured LiMnO2 with both orthorhombic/monoclinic layered domains is synthesized, and its lithium storage properties and mechanism are examined. High-energy mechanical milling is used to convert the metastable and nanosized LiMnO2 adopting the cation-disordered rocksalt structure to an optimal domain-segregated layered LiMnO2. This positive electrode produces an energy density of 820 W h kg-1, achieved by harnessing a large reversible capacity with relatively small voltage hysteresis on electrochemical cycles. Moreover, voltage decay for cycling, as observed for Li-excess Mn-based electrode materials, is effectively mitigated. Furthermore, by determining the structure-property relationships of different LiMnO2 polymorphs, LiMnO2 with similar domain structure and surface area is successfully synthesized with an alternative and simpler method, without the metastable precursor and high-energy mechanical milling. The cyclability of domain-containing LiMnO2 is also improved with the use of a highly concentrated electrolyte coupled with a lithium phosphate coating due to the suppression of Mn dissolution. These findings maximize the possibility of the development of high-energy, low-cost, and practical rechargeable batteries made from sustainable and abundant Mn sources without Ni/Co.

Vogt striae: Demystified.

Background: To study the correlation of different variables of Vogt striae to other attributes of keratoconus and to suggest a new grading system for Vogt striae to exactly represent the configuration and extent in each individual keratoconic cornea. Methods: The study was an observational and data review study. A total of 386 eyes of 207 keratoconus patients were screened from February 2016 to August 2018. Patients with prior history of collagen cross linking were excluded from the study as measurement of corneal thickness is less reliable for many months after collagen cross linking, and patients may have superficial corneal striae and scarring after collagen cross linking. Patients with history or clinical features suggestive of corneal hydrops or who had undergone lamellar or full thickness corneal transplants and intracorneal ring segments were also excluded from the study. Results: Of total 52 eyes with Vogt striae, 31 eyes (59.6%) had vertical orientation, 3 (5.8%) had horizontal, 11 (21.2%) had oblique while 7 eyes (13.5%) had mixed orientation of Vogt striae. Mean uncorrected distance visual acuity (UCVA) in the vertical group was 0.76 logMAR, horizontal group was 0.80 logMAR, oblique group was 0.65 logMAR, and mixed group was 1.17 logMAR units. Corneal scarring was present in 15 eyes (28.8%) and absent in 37 (71.2%) eyes with Vogt striae. In the mixed Vogt striae group, 85.7% eyes (6 eyes of 7) had corneal scarring, while 16.1% in vertical group (5 eyes of 31), and 27.3% in oblique group (3 of 11) had corneal scarring. Based on three attributes of Vogt striae, that is orientation, number, and corneal scarring, a new grading for Vogt striae was also suggested. Conclusion: This is the first study to report the presence of mixed Vogt striae (combination of horizontal and/or vertical and/or oblique Vogt striae in a single cornea) in cases of keratoconus. For the first time, oblique Vogt striae have been described, and clear limits have been set to call it horizontal, oblique, or vertical striae. A new grading for Vogt striae is also suggested.

Efficacy and safety of Adrenaline-augmented subconjunctival anesthesia in phacoemulsification: A randomized controlled trial.

BACKGROUND/OBJECTIVES: Cataract surgery, particularly phacoemulsification, has evolved significantly, benefiting millions worldwide. The choice of anesthesia technique impacts patient comfort and procedural efficacy. Subconjunctival anesthesia has emerged as an attractive alternative due to its potential to provide effective pain relief and surgeon comfort during surgery. A different aspect of this study is the inclusion of 1:100,000 adrenaline in 2% lignocaine for subconjunctival anesthesia, which has not been previously studied. SUBJECTS/METHODS: A prospective, randomised, comparative study involving 196 eyes evaluated the safety and efficacy of subconjunctival anesthesia in phacoemulsification surgery. Pain scores during surgery and one hour post-surgery, surgeon discomfort, postoperative corneal clarity, complications, and additional anesthesia requirement were assessed. Statistical analysis employed descriptive statistics, t-tests, chi-squared tests, and correlations. RESULTS: Subconjunctival anesthesia significantly lowered pain scores during surgery (p < 0.001) and one hour post-surgery (p < 0.001) compared to topical anesthesia. Surgeon discomfort was notably reduced with subconjunctival anesthesia (p < 0.001). Subconjunctival hemorrhage (p = 0.012) and redness (p = 0.024) were more prevalent postoperatively. No significant difference was observed in intraoperative complications (p = 0.573) or postoperative corneal clarity (p = 0.347). CONCLUSION: Subconjunctival anesthesia, with the inclusion of 1:100,000 adrenaline in 2% lignocaine, provides effective pain relief and reduces surgeon discomfort during phacoemulsification surgery. The addition of adrenaline extends anesthesia duration. While immediate postoperative effects exist, subconjunctival anesthesia holds promise for enhanced patient comfort and procedural efficiency. Further research is needed to validate its long-term benefits and broader implications in evolving ophthalmic surgical practices.

Estimation of depression, anxiety and serum cortisol in patients with oral lichen planus, leukoplakia and oral submucous fibrosis.

Stress and anxiety may be found in patients with oral submucous fibrosis (OSMF), oral leukoplakia (OL) and oral lichen planus (OLP). Cortisol, sometimes referred to as the "stress hormone," has been employed as a stress predictor. Therefore, it is of interest to estimate the levels of depression, anxiety and serum cortisol and establish correlation between them in patients with OL. OLP and OSMF. There were 240 patients, aged 20 years to 45 years, who were divided into four categories (OL, OSMF, OLP and control) of 60 patients apiece. In the supervision of a psychiatrist, the Hamilton Depression Rating Scale (HAM D) and Hamilton Anxiety Rating Scale (HAM (A) questionnaires were filled out. Five millilitres of venous blood were extracted using standard aseptic technique, and all of the samples were examined for serum cortisol level. Anxiety and depression was found in subjects of OL, OSMF and OLP at advanced stages. It was inferred that serum cortisol level was statistically correlated with depression and anxiety in patients with OL, OSMF and OLP.

Nanomechanical inhomogeneities in CVA-deposited titanium nitride thin films: Nanoindentation and finite element method investigations.

Refractory metals that can withstand at high temperatures and harsh conditions are of utmost importance for solar-thermal and energy storage applications. Thin films of TiN have been deposited using cathodic vacuum arc deposition at relatively low temperatures ∼300 °C using the substrate bias âˆ¼ -60 V. The nanomechanical properties of these films were investigated using nanoindentation and the spatial fluctuations were observed. The nanoindentation results were simulated using finite element method through Johnson-Cook model. A parametric study was conducted, and 16 different models were simulated to predict the hardening modulus, hardening exponent, and yield stress of the deposited film. The predicted values of elastic modulus, yield stress, hardening modulus and hardening exponent as 246 GPa, 2500 MPa, 25000 MPa and 0.1 respectively are found to satisfactorily explain the experimental load-indentation curves. We have found the local nitridation plays an important role on nanomechanical properties of TiN thin films and confirms that the nitrogen deficient regions are ductile with low yield stress and hardening modulus. This study further opens the opportunities of modelling the nanoscale system using FEM analysis.

Establishment of a conditionally reprogrammed primary eccrine sweat gland culture for evaluation of tissue-specific CFTR function.

BACKGROUND: Sweat chloride concentration is used both for CF diagnosis and for tracking CFTR modulator efficacy over time, but the relationship between sweat chloride and lung health is heterogeneous and informed by CFTR genotype. Here, we endeavored to characterize ion transport in eccrine sweat glands (ESGs). METHODS: First, ESGs were microdissected from a non-CF skin donor to analyze individual glands. We established primary cultures of ESG cells via conditional reprogramming for functional testing of ion transport by short circuit current measurement and examined cell composition by single-cell RNA-sequencing (scRNA-seq) comparing with whole dissociated ESGs. Secondly, we cultured nasal epithelial (NE) cells and ESGs from two people with CF (pwCF) to assess modulator efficacy. Finally, NEs and ESGs were grown from one person with the CFTR genotype F312del/F508del to explore genotype-phenotype heterogeneity. RESULTS: ESG primary cells from individuals without CF demonstrated robust ENaC and CFTR function. scRNA-seq demonstrated both secretory and ductal ESG markers in cultured ESG cells. In both NEs and ESGs from pwCF homozygous for F508del, minimal baseline CFTR function was observed, and treatment with CFTR modulators significantly enhanced function. Notably, NEs from an individual bearing F312del/F508del exhibited significant baseline CFTR function, whereas ESGs from the same person displayed minimal CFTR function, consistent with observed phenotype. CONCLUSIONS: This study has established a novel primary culture technique for ESGs that allows for functional ion transport measurement to assess modulator efficacy and evaluate genotype-phenoytpe heterogeneity. To our knowledge, this is the first reported application of conditional reprogramming and scRNA-seq of microdissected ESGs.

Investigation of CFTR Function in Human Nasal Epithelial Cells Informs Personalized Medicine.

We broaden the clinical versatility of human nasal epithelial (HNE) cells. HNEs were isolated from 10 participants harboring CFTR variants: nine with rare variants (Q359R [n=2], G480S, R334W [n=5], and R560T) and one person harboring R117H;7T;TG10/5T;TG12. Cultures were differentiated at air-liquid interface. CFTR function was measured in Ussing chambers at three conditions - baseline, ivacaftor, and elexacaftor+tezacaftor+ivacaftor (ETI). Four participants initiated modulators. Q359R HNEs had 5.4% (%WT) baseline CFTR function and 25.5% with ivacaftor. With therapy, sweat [Cl-] decreased and symptoms resolved. G480S HNEs had 4.1% baseline and 32.1% CFTR function with ETI. Clinically, FEV1 increased and sweat [Cl-] decreased (119 to 46mmol/L) with ETI. In vitro cultures derived from five individuals harboring R334W showed a moderate increase in CFTR function with exposure to modulators. For one of these participants, ETI was begun in vivo; symptoms and FEV1 improved. c.1679G>C (R560T) HNEs had <4% baseline CFTR function and no modulator response. RNA analysis confirmed that c.1679G>C completely mis-splices. A symptomatic patient harboring R117H;7T;TG10/5T;TG12 exhibited reduced CFTR function (17.5%) in HNEs, facilitating mild CF diagnosis. HNEs responded to modulators (ivacaftor: 32.8%, ETI: 55.5%) and, since beginning therapy, lung function improved. While reaffirming HNE use for guiding therapeutic approaches, we inform predictions on modulator response (e.g. R334W) and closely assess variants affecting splicing (e.g. c.1679G>C). Notably, functional studies in HNEs harboring R117H;7T;TG10/5T;TG12 facilitated mild CF diagnosis, suggesting use for HNE functional studies as a clinical diagnostic test.

Design and evaluation of fluorescent chitosan-starch hydrogel for drug delivery and sensing applications.

Composite bio-based hydrogels have been obtaining a significant attention in recent years as one of the most promising drug delivery systems. In the present study, the preparation of composite chitosan-starch hydrogel using maleic acid as a cross-linker was optimized with the help of response surface methodology. The synthesized hydrogel was fluorescent owing to clustering of large number of functional groups. Different analytical techniques, including XRD, FTIR, SEM, XPS, fluorescence and BET were utilized to characterize the prepared hydrogel. XRD analysis confirmed the formation of non-crystalline hydrogel with random arrangement of macromolecular chains. The composite hydrogel exhibited good swelling percentage with pH sensitivity, hemocompatibility and degradability. BET analysis confirmed that the variation in concentration of crosslinker significantly influences the pore volume of the hydrogel. The synthesized composite chitosan-starch hydrogel was utilized as a prospective candidate for controlling drug release. Cefixime as a model drug was loaded onto the synthesized hydrogel utilizing the swelling diffusion method. SEM micrographs showed uniform distribution of drug molecules in the drug loaded hydrogel. In vitro drug release experiments indicated the swelling dependent drug release behaviour of chitosan-starch hydrogel with higher drug release at pH 7.4 (93.08 %) compared to pH 1.2 (67.85 %). The composite chitosan-starch hydrogel was able to prolong and control the drug release up to 12 h. The drug release from the hydrogel followed Korsmeyer-Peppas and Makoid-Banakar model with Fickian diffusion mechanism. Further, the composite hydrogel displayed excitation dependent fluorescence emission with most intense blue emission band at 425 nm with an excitation wavelength of 350 nm. The inclusion of cefixime drug in the hydrogel matrix significantly reduced the fluorescence intensity; the decrease was linearly correlated to the concentration of the drug. Moreover, the fluorescence emission the chitosan-starch hydrogel was found to be dependent upon pH. The synthesized hydrogel is expected to be a potential candidate for controlled drug release as well as for fluorescent sensing applications.

Formulation of Phytosomes Containing Rubia cordifolia Extract for Neuropathic Pain: In Vitro and In Vivo Evaluation.

This study aimed to develop a delivery system for the dried aqueous extract of Rubia cordifolia leaves (RCE) that could improve the neuroprotective potential of RCE by improving the bioavailability of the chief chemical constituent rubiadin. Rubiadin, an anthraquinone chemically, is a biomarker phytoconstituent of RCE. Rubiadin is reported to have strong antioxidant and neuroprotective activity but demonstrates poor bioavailability. In order to resolve the problem related to bioavailability, RCE and phospholipids were reacted in disparate ratios of 1:1, 1:2, and 1:3 to prepare phytosome formulations PC1, PC2, and PC3, respectively. The formulation PC2 showed particle size of 289.1 ± 0.21 nm, ζ potential of -6.92 ± 0.10 mV, entrapment efficiency of 72.12%, and in vitro release of rubiadin of 89.42% at pH 7.4 for a period up to 48 h. The oral bioavailability and neuroprotective potential of PC2 and RCE were assessed to evaluate the benefit of PC2 formulation over the crude extract RCE. Formulation PC2 showed a relative bioavailability of 134.14% with a higher neuroprotective potential and significantly (p < 0.05) augmented the nociceptive threshold against neuropathic pain induced by partial sciatic nerve ligation method. Antioxidant enzyme levels and histopathological studies of the sciatic nerves in various treatment groups significantly divulged that PC2 has enough potential to reverse the damaged nerves into a normal state. Finally, it was concluded that encapsulated RCE as a phytosome is a potential carrier system for enhancing the delivery of RCE for the efficient treatment of neuropathic pain.

A Monte Carlo simulation-based decision support system for radiation oncologists in the treatment of glioblastoma multiforme.

In the present research, we have developed a model-based crisp logic function statistical classifier decision support system supplemented with treatment planning systems for radiation oncologists in the treatment of glioblastoma multiforme (GBM). This system is based on Monte Carlo radiation transport simulation and it recreates visualization of treatment environments on mathematical anthropomorphic brain (MAB) phantoms. Energy deposition within tumour tissue and normal tissues are graded by quality audit factors which ensure planned dose delivery to tumour site thereby minimising damages to healthy tissues. The proposed novel methodology predicts tumour growth response to radiation therapy from a patient-specific medicine quality audit perspective. Validation of the study was achieved by recreating thirty-eight patient-specific mathematical anthropomorphic brain phantoms of treatment environments by taking into consideration density variation and composition of brain tissues. Dose computations accomplished through water phantom, tissue-equivalent head phantoms are neither cost-effective, nor patient-specific customized and is often less accurate. The above-highlighted drawbacks can be overcome by using open-source Electron Gamma Shower (EGSnrc) software and clinical case reports for MAB phantom synthesis which would result in accurate dosimetry with due consideration to the time factors. Considerable dose deviations occur at the tumour site for environments with intraventricular glioblastoma, haematoma, abscess, trapped air and cranial flaps leading to quality factors with a lower logic value of 0. Logic value of 1 depicts higher dose deposition within healthy tissues and also leptomeninges for majority of the environments which results in radiation-induced laceration.

Averting H+-Mediated Charge Storage Chemistry Stabilizes the High Output Voltage of LiMn2O4-Based Aqueous Battery.

H+ co-intercalation chemistry of the cathode is perceived to have damaging consequences on the low-rate and long-term cycling of aqueous zinc batteries, which is a critical hindrance to their promise for stationary storage applications. Herein, the thermodynamically competitive H+ storage chemistry of an attractive high-voltage cathode LiMn2O4 is revealed by employing operando and ex-situ analytical techniques together with density functional theory-based calculations. The H+ electrochemistry leads to the previously unforeseen voltage decay with cycling, impacting the available energy density, particularly at lower currents. Based on an in-depth investigation of the effect of the Li+ to Zn2+ ratio in the electrolyte on the charge storage mechanism, a purely aqueous and low-salt concentration electrolyte with a tuned Li+/Zn2+ ratio is introduced to subdue the H+-mediated charge storage kinetically, resulting in a stable voltage output and improved cycling stability at both low and high cathode loadings. Synchrotron X-ray diffraction analysis reveals that repeated H+ intercalation triggers an irreversible phase transformation leading to voltage decay, which is averted by shutting down H+ storage. These findings unveiling the origin and impact of the deleterious H+-storage, coupled with the practical strategy for its inhibition, will inspire further work toward this under-explored realm of aqueous battery chemistry.

Tuning the plasmonic resonance in TiN refractory metal.

Plasmonic coatings can absorb electromagnetic radiation from visible to far-infrared spectrum for the better performance of solar panels and energy saving smart windows. For these applications, it is important for these coatings to be as thin as possible and grown at lower temperatures on arbitrary substrates like glass, silicon, or flexible polymers. Here, we tune and investigate the plasmonic resonance of titanium nitride thin films in lower thicknesses regime varying from ~ 20 to 60 nm. High-quality crystalline thin films of route-mean-square roughness less than ~ 0.5 nm were grown on a glass substrate at temperature of ~ 200 °C with bias voltage of - 60 V using cathodic vacuum arc deposition. A local surface-enhanced-plasmonic-resonance was observed between 400 and 500 nm, which further shows a blueshift in plasmonic frequency in thicker films due to the increase in the carrier mobility. These results were combined with finite-difference-time-domain numerical analysis to understand the role of thicknesses and stoichiometry on the broadening of electromagnetic absorption.

Correlation Between Ultrasonographic Placental Thickness and Adverse Fetal and Neonatal Outcomes.

Introduction The placenta is often overlooked in the routine evaluation of normal gestations, receiving attention only when abnormalities are detected. Placental thickness can serve as a good predictor of fetal growth and birth weight, especially in the second trimester.In this prospective study, we measured placental thickness in the second and third trimesters of singleton pregnancies and identified an association between placental thickness and adverse outcomes such as congenital anomalies, fetal growth restriction (FGR), prematurity, low birth weight, stillbirth, and hydrops fetalis. Methodology A total of 298 patients aged 20 to 33 years with a singleton pregnancy and regular cycles, who were sure of the date of their last menstrual period, were observed. Placental thickness was measured by ultrasound at 18-20 and 30-32 weeks, and patients were divided into three groups. Group A consisted of patients with normal placental thickness. Group B included patients with a thin placenta (below the 10th percentile). Group C consisted of patients with a thick placenta (above the 95th percentile). The correlation between placental thickness and the fetal and neonatal outcome was observed. Results Out of 298 patients, 82 (27.5%) were primigravida and 216 (72.4%) were multigravida. At 18-20 weeks, premature birth was observed in one patient (7.69%) in Group C and six patients (20%) in Group B, compared with eight patients (3.14%) in Group A. At 30-32 weeks, premature birth was seen in two patients (16.67%) in Group C and 11 patients (36.67%) in Group B, compared with two patients (0.78%) in Group A. At 18-20 weeks of gestation, low birth weight was observed for three patients (23.08%) in Group C and 16 patients (53.33%) in Group B, compared with 15 patients (5.88%) in Group A. At 30-32 weeks, low birth weight was observed for four patients (33.33%) in Group C and 19 patients (63.33%) in Group B compared with 11 patients (4.30%) in Group A. A significant association was found between a thin placenta and low birth weight and prematurity at both 18-20 and 30-32 weeks of gestation. Two patients (13.33%) had major congenital abnormalities and a thick placenta at 18-20 weeks. In Group C, hydrops were observed in two patients (15.38%) at 18-20 weeks and two patients (16.67%) at 30-32 weeks. A significant association was found between a thick placenta and hydrops. At 30-32 weeks, 13 patients (43.33%) in Group B had developed FGR compared with six patients (2.34%) with a normal placenta. A significant association was found between a thin placenta and FGR. One patient (7.69%) with a thick placenta had a stillbirth, indicating a nonsignificant association. Conclusions A positive correlation was observed between congenital anomalies and hydrops and a thick placenta, whereas FGR, preterm labor, prematurity, and low birth weight were associated with a thin placenta. Subnormal placental thickness for a particular gestational age may be the earliest sign of FGR. A sonographically identified abnormal placenta should alert clinicians to the possibility of a compromised perinatal outcome and the need for evaluation and close follow-up.

A Review on Pyrazole Derivatives Used in the Treatment of Rheumatoid Arthritis: Recent Advancement and Drug Development.

Rheumatoid arthritis (RA) is an autoimmune disorder where inflammation and destruc-tion of bone are the hallmarks of the disease. This review focuses on the etiology, pathophysiolo-gy, and treatment strategies for RA, along with the different approaches used for the synthesis of pyrazoles, the characterization of various properties, and their biological significance for curing RA. The activated immune system of the body causes inflammation of the synovial joint due to the interaction of immune cells, such as T and B lymphocytes, macrophages, plasma cells, den-dritic cells and mast cells. The treatment for RA has been revolutionized with the discovery of new chemical compounds and an understanding of their mechanism in the treatment of the dis-ease. Pyrazoles are the starting materials for the synthesis of heterocyclic compounds and possess great relevance in the pharmaceutical field for the development of new drugs. They are versatile bio-scaffolds in medicinal chemistry and organic synthesis. This has been followed by a deep analysis of pyrazoles and their derivatives on the basis of medical significance in the treatment of RA. This follow-up and information may help the chemists, scientists, and researchers to generate new pyrazole compounds with high efficacy for better treatment of patients with RA. We summa-rize the review with an understanding of the core of pyrazoles and a claim that their derivatives may be helpful in the development of efficient drugs against RA.

Hydronium Intercalation Enables High Rate in Hexagonal Molybdate Single Crystals.

Rapid proton transport in solid-hosts promotes a new chemistry in achieving high-rate Faradaic electrodes. Exploring the possibility of hydronium intercalation is essential for advancing proton-based charge storage. Nevertheless, this is yet to be revealed. Herein, a new host is reported of hexagonal molybdates, (A2 O)x ·MoO3 ·(H2 O)y (A = Na+ , NH4 + ), and hydronium (de)intercalation is demonstrated with experiments. Hexagonal molybdates show a battery-type initial reduction followed by intercalation pseudocapacitance. Fast rate of 200 C (40 A g-1 ) and long lifespan of 30 000 cycles are achieved in electrodes of monocrystals even over 200 µm. Solid-state nuclear magnetic resonance confirms hydronium intercalations, and operando measurements using electrochemical quartz crystal microbalance and synchrotron X-ray diffraction disclose distinct intercalation behaviours in different electrolyte concentrations. Remarkably, characterizations of the cycled electrodes show nearly identical structures and suggest equilibrium products are minimally influenced by the extent of proton solvation. These results offer new insights into proton electrochemistry and will advance correlated high-power batteries and beyond.