PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells.

The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate.

A RGS7-CaMKII complex drives myocyte-intrinsic and myocyte-extrinsic mechanisms of chemotherapy-induced cardiotoxicity.

Dose-limiting cardiotoxicity remains a major limitation in the clinical use of cancer chemotherapeutics. Here, we describe a role for Regulator of G protein Signaling 7 (RGS7) in chemotherapy-dependent heart damage, the demonstration for a functional role of RGS7 outside of the nervous system and retina. Though expressed at low levels basally, we observed robust up-regulation of RGS7 in the human and murine myocardium following chemotherapy exposure. In ventricular cardiomyocytes (VCM), RGS7 forms a complex with Ca2+/calmodulin-dependent protein kinase (CaMKII) supported by key residues (K412 and P391) in the RGS domain of RGS7. In VCM treated with chemotherapeutic drugs, RGS7 facilitates CaMKII oxidation and phosphorylation and CaMKII-dependent oxidative stress, mitochondrial dysfunction, and apoptosis. Cardiac-specific RGS7 knockdown protected the heart against chemotherapy-dependent oxidative stress, fibrosis, and myocyte loss and improved left ventricular function in mice treated with doxorubicin. Conversely, RGS7 overexpression induced fibrosis, reactive oxygen species generation, and cell death in the murine myocardium that were mitigated following CaMKII inhibition. RGS7 also drives production and release of the cardiokine neuregulin-1, which facilitates paracrine communication between VCM and neighboring vascular endothelial cells (EC), a maladaptive mechanism contributing to VCM dysfunction in the failing heart. Importantly, while RGS7 was both necessary and sufficient to facilitate chemotherapy-dependent cytotoxicity in VCM, RGS7 is dispensable for the cancer-killing actions of these same drugs. These selective myocyte-intrinsic and myocyte-extrinsic actions of RGS7 in heart identify RGS7 as an attractive therapeutic target in the mitigation of chemotherapy-driven cardiotoxicity.

"Deficiency in ELF4, X-Linked": a Monogenic Disease Entity Resembling Behçet's Syndrome and Inflammatory Bowel Disease.

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Characterizing the Conformational Dynamics of Human SUMO2: Insights into its Interaction with Metal Ions and SIMs.

SUMO (Small Ubiquitin-like Modifiers) proteins are involved in a crucial post-translational modification commonly termed as SUMOylation. In this work, we have investigated the native-state conformational flexibility of human SUMO2 and its interaction with Cu2+ and Zn2+ ions using 15N-1H based 2D NMR spectroscopy. After SUMO1, SUMO2 is the most studied SUMO isoform in humans which shares 45 % and ~80 % similarity with SUMO1 in terms of sequence and structure, respectively. In this manuscript, we demonstrate that compared to SUMO1, several amino acids around the α1-helix region of SUMO2 access energetically similar near-native conformations. These conformations could play a crucial role in SUMO2's non-covalent interactions with SUMO interaction motifs (SIMs) on other proteins. The C-terminal of SUMO2 was found to bind strongly with Cu2+ ions resulting in a trimeric structure as observed by gel electrophoresis. This interaction seems to interfere in its non-covalent interaction with a V/I-x-V/I-V/I based SIM in Daxx protein.

tomoCAM: fast model-based iterative reconstruction via GPU acceleration and non-uniform fast Fourier transforms.

X-ray-based computed tomography is a well established technique for determining the three-dimensional structure of an object from its two-dimensional projections. In the past few decades, there have been significant advancements in the brightness and detector technology of tomography instruments at synchrotron sources. These advancements have led to the emergence of new observations and discoveries, with improved capabilities such as faster frame rates, larger fields of view, higher resolution and higher dimensionality. These advancements have enabled the material science community to expand the scope of tomographic measurements towards increasingly in situ and in operando measurements. In these new experiments, samples can be rapidly evolving, have complex geometries and restrictions on the field of view, limiting the number of projections that can be collected. In such cases, standard filtered back-projection often results in poor quality reconstructions. Iterative reconstruction algorithms, such as model-based iterative reconstructions (MBIR), have demonstrated considerable success in producing high-quality reconstructions under such restrictions, but typically require high-performance computing resources with hundreds of compute nodes to solve the problem in a reasonable time. Here, tomoCAM, is introduced, a new GPU-accelerated implementation of model-based iterative reconstruction that leverages non-uniform fast Fourier transforms to efficiently compute Radon and back-projection operators and asynchronous memory transfers to maximize the throughput to the GPU memory. The resulting code is significantly faster than traditional MBIR codes and delivers the reconstructive improvement offered by MBIR with affordable computing time and resources. tomoCAM has a Python front-end, allowing access from Jupyter-based frameworks, providing straightforward integration into existing workflows at synchrotron facilities.

RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21.

BACKGROUND: Prior evidence demonstrated that Regulator of G protein Signaling 6 (RGS6) translocates to the nucleolus in response to cytotoxic stress though the functional significance of this phenomenon remains unknown. METHODS: Utilizing in vivo gene manipulations in mice, primary murine cardiac cells, human cell lines and human patient samples we dissect the participation of a RGS6-nucleolin complex in chemotherapy-dependent cardiotoxicity. RESULTS: Here we demonstrate that RGS6 binds to a key nucleolar protein, Nucleolin, and controls its expression and activity in cardiomyocytes. In the human myocyte AC-16 cell line, induced pluripotent stem cell derived cardiomyocytes, primary murine cardiomyocytes, and the intact murine myocardium tuning RGS6 levels via overexpression or knockdown resulted in diametrically opposed impacts on Nucleolin mRNA, protein, and phosphorylation.RGS6 depletion provided marked protection against nucleolar stress-mediated cell death in vitro, and, conversely, RGS6 overexpression suppressed ribosomal RNA production, a key output of the nucleolus, and triggered death of myocytes. Importantly, overexpression of either Nucleolin or Nucleolin effector miRNA-21 counteracted the pro-apoptotic effects of RGS6. In both human and murine heart tissue, exposure to the genotoxic stressor doxorubicin was associated with an increase in the ratio of RGS6/Nucleolin. Preventing RGS6 induction via introduction of RGS6-directed shRNA via intracardiac injection proved cardioprotective in mice and was accompanied by restored Nucleolin/miRNA-21 expression, decreased nucleolar stress, and decreased expression of pro-apoptotic, hypertrophy, and oxidative stress markers in heart. CONCLUSION: Together, these data implicate RGS6 as a driver of nucleolar stress-dependent cell death in cardiomyocytes via its ability to modulate Nucleolin. This work represents the first demonstration of a functional role for an RGS protein in the nucleolus and identifies the RGS6/Nucleolin interaction as a possible new therapeutic target in the prevention of cardiotoxicity.

Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis.

Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.

Enhanced Therapeutic Efficacy Against Melanoma through Exosomal Delivery of Hesperidin.

Melanoma, characterized as the most aggressive and metastatic form of skin cancer, currently has limited treatment options, predominantly chemotherapy and radiation therapy. However, the drawbacks associated with parenterally administered chemotherapy underscore the urgent need for alternative compounds to combat melanoma effectively. Hesperidin (HES), a flavonoid present in various citrus fruits, exhibits promising anticancer activity. Nevertheless, the clinical utility of HES is hindered by challenges such as poor water solubility, a short half-life, and low oral bioavailability. In response to these limitations, we introduced a novel approach by formulating HES-loaded exosomes (Exo-HES). Isolation of exosomes was achieved through the ultracentrifugation method, and HES was efficiently loaded using the sonication method. The resulting formulations displayed a desirable particle size (∼106 nm) and exhibited a spherical morphology, as confirmed by scanning electron and atomic force microscopy. In vitro studies conducted on B16F10 cell lines demonstrated higher cytotoxicity of Exo-HES compared to free HES, supported by enhanced cellular uptake validated through coumarin-6-loaded exosomes. This superior cytotoxicity was further evidenced by DNA fragmentation, increased generation of free radicals (ROS), loss of mitochondrial membrane potential, and effective inhibition of colony formation. The antimetastatic properties of Exo-HES were confirmed through wound healing and transwell migration assays. Oral pharmacokinetics studies revealed a remarkable increase of approximately 2.5 times in oral bioavailability and half-life of HES when loaded into exosomes. Subsequent in vivo experiments utilizing a B16F10-induced melanoma model in Swiss mice established that Exo-HES exhibited superior anticancer activity compared to HES after oral administration. Importantly, no biochemical, hematological, or histological toxicities were observed in tumor-bearing mice treated with Exo-HES. These findings suggest that exosomes loaded with HES represent a promising nanocarrier strategy to enhance the therapeutic effectiveness of hesperidin in melanoma treatment.

Assessing the synergistic potential of bacteriophage endolysins and antimicrobial peptides for eradicating bacterial biofilms.

Phage-encoded endolysins have emerged as a potential substitute to conventional antibiotics due to their exceptional benefits including host specificity, rapid host killing, least risk of resistance. In addition to their antibacterial potency and biofilm eradication properties, endolysins are reported to exhibit synergism with other antimicrobial agents. In this study, the synergistic potency of endolysins was dissected with antimicrobial peptides to enhance their therapeutic effectiveness. Recombinantly expressed and purified bacteriophage endolysin [T7 endolysin (T7L); and T4 endolysin (T4L)] proteins have been used to evaluate the broad-spectrum antibacterial efficacy using different bacterial strains. Antibacterial/biofilm eradication studies were performed in combination with different antimicrobial peptides (AMPs) such as colistin, nisin, and polymyxin B (PMB) to assess the endolysin's antimicrobial efficacy and their synergy with AMPs. In combination with T7L, polymyxin B and colistin effectively eradicated the biofilm of Pseudomonas aeruginosa and exhibited a synergistic effect. Further, a combination of T4L and nisin displayed a synergistic effect against Staphylococcus aureus biofilms. In summary, the obtained results endorse the theme of combinational therapy consisting of endolysins and AMPs as an effective remedy against the drug-resistant bacterial biofilms that are a serious concern in healthcare settings.

Integrative Modulation of Magnetic Resonance Transverse and Longitudinal Relaxivity in a Cell-Viable Bimagnetic Ensemble, γ-Fe2O3@ZnFe2O4.

The potential application of magnetic nanosystems as magnetic resonance imaging (MRI) contrast agents has been thoroughly investigated. This work seeks to attain robust MRI-contrast efficiency by designing an interacting landscape of a bimagnetic ensemble of zinc ferrite nanorods and maghemite nanoparticles, γ-Fe2O3@ZnFe2O4. Because of competing spin clusters and structural anisotropy triggered by isotropic γ-Fe2O3 and anisotropic ZnFe2O4, γ-Fe2O3@ZnFe2O4 undergoes the evolution of cluster spin-glass state as evident from the critical slowing down law. Such interacting γ-Fe2O3@ZnFe2O4 with spin flipping of 1.2 × 10-8 s and energy barrier of 8.2 × 10-14 erg reflects enhanced MRI-contrast signal. Additionally, γ-Fe2O3@ZnFe2O4 is cell-viable to noncancerous HEK 293 cell-line and shows no pro-tumorigenic activity as observed in MDA-MB-231, an extremely aggressive triple-negative breast cancer cell line. As a result, γ-Fe2O3@ZnFe2O4 is a feasible option for an MRI-contrast agent having longitudinal relaxivity, r1, of 0.46 s-1mM-1 and transverse relaxivity, r2, of 15.94 s-1mM-1, together with r2/r1 of 34.65 at 1.41 T up to a modest metal concentration of 0.1 mM. Hence, this study addresses an interacting isotropic/anisotropic framework with faster water proton decay in MR-relaxivity resulting in phantom signal amplification.

Site-directed mutagenesis at the Glu78 in Ec-NhaA transporter impacting ion exchange: a biophysical study.

Na+/H+ antiporters facilitate the exchange of Na+ for H+ across the cytoplasmic membrane in prokaryotic and eukaryotic cells. These transporters are crucial to maintain the homeostasis of sodium ions, consequently pH, and volume of the cells. Therefore, sodium/proton antiporters are considered promising therapeutic targets in humans. The Na+/H+ antiporter in Escherichia coli (Ec-NhaA), a prototype of cation-proton antiporter (CPA) family, transports two protons and one sodium (or Li+) in opposite direction. Previous mutagenesis experiments on Ec-NhaA have proposed Asp164, Asp163, and Asp133 amino acids with the significant implication in functional and structural integrity and create site for ion-binding. However, the mechanism and the sites for the binding of the two protons remain unknown and controversial which could be critical for pH regulation. In this study, we have explored the role of Glu78 in the regulation of pH by Ec-NhaA. Although we have created various mutants, E78C has shown a considerable effect on the stoichiometry of NhaA and presented comparable phenotypes. The ITC experiment has shown the binding of ~ 5 protons in response to the transport of one lithium ion. The phenotype analysis on selective medium showed a significant expression compared to WT Ec-NhaA. This represents the importance of Glu78 in transporting the H+ across the membrane where a single mutation with Cys amino acid alters the number of H+ significantly maintaining the activity of the protein.

Review on novel targeted enzyme drug delivery systems: enzymosomes.

The goal of this review is to present enzymosomes as an innovative means for site-specific drug delivery. Enzymosomes make use of an enzyme's special characteristics, such as its capacity to accelerate the reaction rate and bind to a particular substrate at a regulated rate. Enzymosomes are created when an enzyme forms a covalent linkage with a liposome or lipid vesicle surface. To construct enzymosomes with specialized activities, enzymes are linked using acylation, direct conjugation, physical adsorption, and encapsulation techniques. By reducing the negative side effects of earlier treatment techniques and exhibiting efficient medication release, these cutting-edge drug delivery systems improve long-term sickness treatments. They could be a good substitute for antiplatelet medication, gout treatment, and other traditional medicines. Recently developed supramolecular vesicular delivery systems called enzymosomes have the potential to improve drug targeting, physicochemical characteristics, and ultimately bioavailability in the pharmaceutical industry. Enzymosomes have advantages over narrow-therapeutic index pharmaceuticals as focusing on their site of action enhances both their pharmacodynamic and pharmacokinetic profiles. Additionally, it reduces changes in normal enzymatic activity, which enhances the half-life of an enzyme and accomplishes enzyme activity on specific locations.

Achieving White Light Emission with High Luminescence Efficiency via Combustion Produced Sr3Y(PO4)3: Dy3+ Nanophosphors for Photonic Applications.

Extensive investigations were conducted on the structural and photoluminescence characteristics of the present nanosamples, encompassing PL, TEM, PXRD, EDAX, CCT, and CIE research. PXRD studies established a single phase, and TEM instruments were used to examine the dimensions and topographical behavior. The EDAX analysis examined the magnitude of the different components that were present. Decay lifetimes, radiative and non-radiative energy transfer rates, and a number of intensity limitations have all been found using PL spectra. Two significant peaks were visible in the blue (B) and yellow (Y) regions of the photoluminescence (PL) spectra upon NUV excitation, at 486 nm and 577 nm. At 7 mol% Dy3+ ions, the PL intensity peaked. After that, it began to decline as a result of the concentration quenching process brought on by multipolar exchanges (s = 4.1445). The values of 0.86423 ms, 81%, and 226 s-1 were discovered to be the decay life time, non radiative rates, and quantum efficiency of the ideal powder, respectively. Further analysis of Sr3Y0.93Dy0.07(PO4)3 nanocrystals revealed that their chromaticity coordinates (0.305, 0.321), and CCT value (6902 K) matched those of NTSE and commercial LEDs, certifying their use in innovative optoelectronic appliances, particularly single phased WLEDs.

RGS7 balances acetylation/de-acetylation of p65 to control chemotherapy-dependent cardiac inflammation.

Cardiotoxicity remains a major limitation in the clinical utility of anthracycline chemotherapeutics. Regulator of G-protein Signaling 7 (RGS7) and inflammatory markers are up-regulated in the hearts of patients with a history of chemotherapy particularly those with reduced left-ventricular function. RGS7 knockdown in either the murine myocardium or isolated murine ventricular cardiac myocytes (VCM) or cultured human VCM provided marked protection against doxorubicin-dependent oxidative stress, NF-κB activation, inflammatory cytokine production, and cell death. In exploring possible mechanisms causally linking RGS7 to pro-inflammatory signaling cascades, we found that RGS7 forms a complex with acetylase Tip60 and deacetylase sirtuin 1 (SIRT1) and controls the acetylation status of the p65 subunit of NF-κB. In VCM, the detrimental impact of RGS7 could be mitigated by inhibiting Tip60 or activating SIRT1, indicating that the ability of RGS7 to modulate cellular acetylation capacity is critical for its pro-inflammatory actions. Further, RGS7-driven, Tip60/SIRT1-dependent cytokines released from ventricular cardiac myocytes and transplanted onto cardiac fibroblasts increased oxidative stress, markers of transdifferentiation, and activity of extracellular matrix remodelers emphasizing the importance of the RGS7-Tip60-SIRT1 complex in paracrine signaling in the myocardium. Importantly, while RGS7 overexpression in heart resulted in sterile inflammation, fibrotic remodeling, and compromised left-ventricular function, activation of SIRT1 counteracted the detrimental impact of RGS7 in heart confirming that RGS7 increases acetylation of SIRT1 substrates and thereby drives cardiac dysfunction. Together, our data identify RGS7 as an amplifier of inflammatory signaling in heart and possible therapeutic target in chemotherapeutic drug-induced cardiotoxicity.

NMR based Serum metabolomics revealed metabolic signatures associated with oxidative stress and mitochondrial damage in brain stroke.

Brain stroke (BS, also known as a cerebrovascular accident), represents a serious global health crisis. It has been a leading cause of permanent disability and unfortunately, frequent fatalities due to lack of timely medical intervention. While progress has been made in prevention and management, the complexities and consequences of stroke continue to pose significant challenges, especially, its impact on patient's quality of life and independence. During stroke, there is a substantial decrease in oxygen supply to the brain leading to alteration of cellular metabolic pathways, including those involved in mitochondrial-damage, leading to mitochondrial-dysfunction. The present proof-of-the-concept metabolomics study has been performed to gain insights into the metabolic pathways altered following a brain stroke and discover new potential targets for timely interventions to mitigate the effects of cellular and mitochondrial damage in BS. The serum metabolic profiles of 108 BS-patients were measured using 800 MHz NMR spectroscopy and compared with 60 age and sex matched normal control (NC) subjects. Compared to NC, the serum levels of glutamate, TCA-cycle intermediates (such as citrate, succinate, etc.), and membrane metabolites (betaine, choline, etc.) were found to be decreased BS patients, whereas those of methionine, mannose, mannitol, phenylalanine, urea, creatine and organic acids (such as 3-hydroxybutyrate and acetone) were found to be elevated in BS patients. These metabolic changes hinted towards hypoxia mediated mitochondrial dysfunction in BS-patients. Further, the area under receiver operating characteristic curve (ROC) values for five metabolic features (methionine, mannitol, phenylalanine, mannose and urea) found to be more than 0.9 suggesting their high sensitivity and specificity for differentiating BS from NC subjects.

Ultra-high-performance liquid chromatography-quadrupole time of flight tandem mass spectrometry based in vitro metabolite profiling of DK-GV-04P, a novel anticancer molecule under drug discovery.

DK-GV-04P, chemically identified as 3-cinnamyl-2-(4-methoxyphenyl) quinazolin-4(3H)-one, is an investigational molecule synthesized at the Chemical Biology Laboratory of the National Institute of Pharmaceutical Education and Research-Ahmedabad. The compound has shown potential anticancer activity against squamous CAL27 cell lines. Metabolite identification and characterization are critical in drug discovery, providing key insights into a compound's pharmacokinetics, pharmacodynamics safety, and metabolic fate. The primary aim of the study was to identify and characterize the in vitro metabolites of DK-GV-04P. In silico identification of the site of metabolism was also carried out using xenosite online software. The molecule was incubated with human liver microsomes and human S9 liver fraction to generate in vitro metabolites, which were further identified and characterized using ultra-high-performance liquid chromatography-quadrupole time of flight tandem mass spectrometry. A total of nine metabolites (four phase I and five phase II) were identified and characterized through tandem mass spectrometry. The major biotransformation pathways involved in metabolism of DK-GV-04P were hydroxylation, O-demethylation and glucuronidation. In addition to this, a detailed biotransformation pathway of DK-GV-04P has been established in this study.

Addition of Surgeon-Administered Adductor Canal Infiltration to the Periarticular Infiltration in Total Knee Arthroplasty: Effect on Pain and Early Outcomes.

BACKGROUND: Our aim was to study the additive effect of surgeon-administered adductor canal infiltration (SACI) over routine periarticular infiltration (PAI) on pain control [morphine consumption and pain score by the visual analog scale (VAS)] and early function [flexion and Timed Up and Go (TUG) test] post-total knee arthroplasty (TKA). METHODS: We prospectively randomized 60 patients into 2 groups. Group I patients received the standard PAI, whereas in Group II, the patients received a SACI in addition to the PAI. The total volume of the injected drug and the postoperative pain management protocol were the same for all. The number of doses of patient-controlled analgesia (PCA) used for breakthrough pain was recorded as PCA consumption. For early function, flexion and the TUG test were used. The VAS score and PCA consumption were compared between the 2 groups by using analyses of variance with post hoc tests as indicated. The TUG test and flexion were compared using Student t tests. The level of significance was set at 0.05. RESULTS: The PCA consumption in the first 6 hours was significantly higher in Group I (P = .04). The VAS at 6 hours was significantly lower in Group II (P = .042). The TUG test was comparable between the 2 groups preoperatively (P = .72) at 24 hours (P = .60) and 48 hours (P = .60) post-TKA. The flexion was comparable between the 2 groups preoperatively (P = .85) at 24 hours (P = .48) and 48 hours (P = .79) post-TKA. CONCLUSIONS: Adding a SACI to PAI provides improved pain relief and reduces opioid consumption without affecting early function post-TKA. A SACI avoids the need for an anesthesiologist or specialized equipment with no added operating time and minimal added cost. We recommend routine use of SACI for all patients undergoing TKA.

Ectomycorrhizas of Rhizopogon himalayensis on Cedrus deodara.

The ectomycorrhizal (EcM) roots of Cedrus deodara associated with a unique hypogeous EcM fungus-Rhizopogon himalayensis is meticulously characterized and comprehensively described based on well-established standard morphological and anatomical features. The mycobiont-R. himalayensis was found organically associated with the roots of C. deodara. The EcM morphotypes are distinguished by differences in the shape and color of the roots, type of ramification, surface texture, type of mantle, as well as different chemical reactions. All the examined morphotypes were having similar mycorrhizal system and anatomically (Mantle and Hartig net) no disparities were seen, that is, nonsignificant (p > 0.05) variations were observed. The majority of mycorrhizal systems were irregularly pinnate, dichotomous type with 0-1 order of ramification and occasional coralloid type. Mantle surface was densely cottony to loosely wooly. The outer and inner mantles were H & Q type. Hartig net was a complex net-like structure with uniseriate to mutiseriate type of hyphal cell arrangement. Rhizomorph were smooth and round, consistently growing along roots. Moreover, extraradical hyphae were hyaline, septate, and without clamp connections. Sclerotia and cystidia were absent. Our findings will contribute to the biology of ectomycorrhizae associated with primitive and economically valuable conifers, thriving in the face of shifting environmental conditions in the northwestern Himalayas.

Preclinical determination of wound-healing activity of halibut oil cream in rat model of burn wound.

This study investigated the effects of halibut oil cream, containing omega-3 fatty acids, vitamins A and D, and hydroxyproline, on burn wound healing in rats. Acute dermal toxicity tests confirmed its nontoxicity. Wistar rats were divided into five groups: a control, a positive control treated with silver sulfadiazine 1% (SSD), and three groups treated with 3%, 9%, and 27% halibut oil cream Formulation (HBOF). The SSD and HBOF groups showed significant healing improvements compared to the control. Histopathological analysis indicated increased collagen production in the HBOF groups, suggesting halibut oil cream's potential as a topical treatment for burn wounds.

Predictive analytics and early intervention in healthcare social work: a scoping review.

This scoping review investigates the untapped potential of predictive analytics in healthcare social work, specifically targeting early intervention frameworks. Despite the escalating attention predictive analytics has garnered across multiple disciplines, its tailored application in social work remains notably sparse. This study endeavors to fill this lacuna by meticulously reviewing the extant literature and delineating the prospective advantages and inherent constraints of integrating predictive analytics into healthcare social work. The outcomes of this inquiry enrich the prevailing dialogue on the utility of predictive analytics in healthcare, offering indispensable perspectives for practitioners and policymakers in the social work domain.