Cell-Engineered Recombinant α-Synuclein: A Gage R&R Validated Protocol.

α-Synuclein (α-Syn) misfolding and its presence in Lewy bodies are observed in almost all Parkinson's disease (PD) patients. Basic biomedical research would benefit from a quick, low-cost approach to purifying α-Syn and developing in vitro and in vivo models for PD. Several research groups utilize PFF-based models, yet the production of α-Syn PFFs is inconsistent, resulting in nonconclusive findings. Some research laboratories prepare recombinant α-Syn (r α-Syn) by molecular cloning to overexpress α-Syn with various purifying techniques. Laboratory-to-laboratory protocols cause considerable variability and sometimes contradictory findings. PD researchers spend more on protein than solving α-Syn's riddles. This article uncovered a novel method for expressing and purifying r α-Syn validated through gage reproducibility and repeatability (Gage R&R). For the production of r α-Syn, we have employed the ability of a high-cell-density-based expression system to overexpress protein in BL21(DE3). A simple, high-throughput, nonchromatographical purification protocol has been devised to facilitate research with higher reproducibility, which was validated through Gage R&R. A crossover experimental design was utilized, and the purified protein was characterized using orthogonal high-end analytical methods, which displayed higher similarity between the isolated r α-Syn. Batch-to-batch variability was the least for produced protein and hence can be utilized for exploring the iceberg of PD.

Validation of metastasis-free survival as a surrogate endpoint for overall survival in localized prostate cancer in the era of docetaxel for castration-resistant prostate cancer.

BACKGROUND: Prior work from the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) consortium (ICECaP-1) demonstrated that metastasis-free survival (MFS) is a valid surrogate for overall survival (OS) in localized prostate cancer (PCa). This was based on data from patients treated predominantly before 2004, prior to docetaxel being available for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). We sought to validate surrogacy in a more contemporary era (ICECaP-2) with greater availability of docetaxel and other systemic therapies for mCRPC. PATIENTS AND METHODS: Eligible trials for ICECaP-2 were those providing individual patient data (IPD) after publication of ICECaP-1 and evaluating adjuvant/salvage therapy for localized PCa, and which collected MFS and OS data. MFS was defined as distant metastases or death from any cause, and OS was defined as death from any cause. Surrogacy was evaluated using a meta-analytic two-stage validation model, with an R2 ≥ 0.7 defined a priori as clinically relevant. RESULTS: A total of 15 164 IPD from 14 trials were included in ICECaP-2, with 70% of patients treated after 2004. The median follow-up was 8.3 years and the median postmetastasis survival was 3.1 years in ICECaP-2, compared with 1.9 years in ICECaP-1. For surrogacy condition 1, Kendall's tau was 0.92 for MFS with OS at the patient level, and R2 from weighted linear regression (WLR) of 8-year OS on 5-year MFS was 0.73 (95% confidence interval 0.53-0.82) at the trial level. For condition 2, R2 was 0.83 (95% confidence interval 0.64-0.89) from WLR of log[hazard ratio (HR)]-OS on log(HR)-MFS. The surrogate threshold effect on OS was an HR(MFS) of 0.81. CONCLUSIONS: MFS remained a valid surrogate for OS in a more contemporary era, where patients had greater access to docetaxel and other systemic therapies for mCRPC. This supports the use of MFS as the primary outcome measure for ongoing adjuvant trials in localized PCa.

The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma.

BACKGROUND: The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG + EV in a phase I trial in mUC (NCT04724018). PATIENTS AND METHODS: Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG + EV were administered on days 1 + 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints. RESULTS: Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months. CONCLUSIONS: The combination of SG + EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.

Choline Derivative as a Multifunctional Interfacial Bridge through Synergistic Effects for Improving the Efficiency and Stability of Perovskite Solar Cells.

The interfacial carrier non-radiative recombination caused by buried defects in electron transport layer (ETL) material and the energy barrier severely hinders further improvement in efficiency and stability of perovskite solar cells (PSCs). In this study, the effect of the SnO2 ETL doped with choline chloride (CC), acetylcholine chloride (AC), and phosphocholine chloride sodium salt (PCSS) are investigated. These dopants modify the interface between SnO2 ETL and perovskite layer, acting as a bridge through synergistic effects to form uniform ETL films, enhance the interface contact, and passivate defects. Ultimately, compared with CC (which with ─OH) and AC (which with C═O), the PCSS with P═O and sodium ions groups is more beneficial for improving performance. The device based on PCSS-doped SnO2 ETL achieves an efficiency of 23.06% with a high VOC of 1.2 V, which is considerably higher than the control device (20.55%). Moreover, after aging for 500 h at a temperature of 25 °C and relative humidity (RH) of 30-40%, the unsealed device based on SnO2-PCSS ETL maintains 94% of its initial efficiency, while the control device only 80%. This study provides a meaningful reference for the design and selection of ideal pre-buried additive molecules.

Multi-modal deep learning improves grain yield prediction in wheat breeding by fusing genomics and phenomics.

MOTIVATION: Developing new crop varieties with superior performance is highly important to ensure robust and sustainable global food security. The speed of variety development is limited by long field cycles and advanced generation selections in plant breeding programs. While methods to predict yield from genotype or phenotype data have been proposed, improved performance and integrated models are needed. RESULTS: We propose a machine learning model that leverages both genotype and phenotype measurements by fusing genetic variants with multiple data sources collected by unmanned aerial systems. We use a deep multiple instance learning framework with an attention mechanism that sheds light on the importance given to each input during prediction, enhancing interpretability. Our model reaches 0.754 ± 0.024 Pearson correlation coefficient when predicting yield in similar environmental conditions; a 34.8% improvement over the genotype-only linear baseline (0.559 ± 0.050). We further predict yield on new lines in an unseen environment using only genotypes, obtaining a prediction accuracy of 0.386 ± 0.010, a 13.5% improvement over the linear baseline. Our multi-modal deep learning architecture efficiently accounts for plant health and environment, distilling the genetic contribution and providing excellent predictions. Yield prediction algorithms leveraging phenotypic observations during training therefore promise to improve breeding programs, ultimately speeding up delivery of improved varieties. AVAILABILITY AND IMPLEMENTATION: Available at https://github.com/BorgwardtLab/PheGeMIL (code) and https://doi.org/doi:10.5061/dryad.kprr4xh5p (data).

High-density mapping of durable and broad-spectrum stripe rust resistance gene Yr30 in wheat.

KEY MESSAGE: The durable stripe rust resistance gene Yr30 was fine-mapped to a 610-kb region in which five candidate genes were identified by expression analysis and sequence polymorphisms. The emergence of genetically diverse and more aggressive races of Puccinia striiformis f. sp. tritici (Pst) in the past twenty years has resulted in global stripe rust outbreaks and the rapid breakdown of resistance genes. Yr30 is an adult plant resistance (APR) gene with broad-spectrum effectiveness and its durability. Here, we fine-mapped the YR30 locus to a 0.52-cM interval using 1629 individuals derived from residual heterozygous F5:6 plants in a Yaco"S"/Mingxian169 recombinant inbred line population. This interval corresponded to a 610-kb region in the International Wheat Genome Sequencing Consortium (IWGSC) RefSeq version 2.1 on chromosome arm 3BS harboring 30 high-confidence genes. Five genes were identified as candidate genes based on functional annotation, expression analysis by RNA-seq and sequence polymorphisms between cultivars with and without Yr30 based on resequencing. Haplotype analysis of the target region identified six haplotypes (YR30_h1-YR30_h6) in a panel of 1215 wheat accessions based on the 660K feature genotyping array. Lines with YR30_h6 displayed more resistance to stripe rust than the other five haplotypes. Near-isogenic lines (NILs) with Yr30 showed a 32.94% higher grain yield than susceptible counterparts when grown in a stripe rust nursery, whereas there was no difference in grain yield under rust-free conditions. These results lay a foundation for map-based cloning Yr30.

Conversion of Failed J-Pouch to Kock Pouch: Indications, Contraindications, and Outcomes.

BACKGROUND: The IPAA has been successful in restoring intestinal continuity and preserving continence in the majority of patients requiring a proctocolectomy. However, a subset of individuals experience significant complications that might result in pouch failure. The conversion of the J-pouch to a continent ileostomy pouch represents a significant surgical procedure. In this article, we discuss the indications and contraindications, present the technical principles applied for the conversion, and describe the outcomes of such conversion in the literature. OBJECTIVE: The main objective during the conversion of the J-pouch to a continent ileostomy is the creation of a sufficiently sized reservoir with a high-quality valve mechanism while preserving as much small bowel as possible. CONCLUSIONS: The conversion of the J-pouch to a continent ileostomy represents a significant surgical procedure. When performed in centers of expertise, it can be a good option for patients who otherwise will require an end ileostomy. Indications for conversion include most cases of J-pouch failure, with a few important exceptions. See video from symposium .

An Expedient Approach to Access Phenalenones via Unconventional [1,2]-Phospha-Brook Rearrangement/Carbonyl Migration.

An efficient protocol for the synthesis of 2,3-disubstituted phenalenones from para-quinone methides (p-QMs) and acenaphthoquinone is described. The reaction involves P(NMe2)3-mediated [1,2]-phospha-Brook rearrangement followed by Lewis acid-assisted 1,2-carbonyl migration to afford the 2,3-disubstituted phenalenones. The developed protocol tolerates a broad range of substrates to form a variety of phenalenones in good to excellent yields. Moreover, the utility of the synthesized phenalenones is also demonstrated by performing its transformations to other adducts.

Photoinduced metal-free trifluoro/perfluoroalkylation of heteroarenes.

A practical and straightforward protocol to access trifluoromethylated/perfluoroalkylated heteroarenes via radical-type nucleophilic substitution rather than typical radical-type electrophilic substitution is described here. The substrate scope was observed to be broad and diverse-covering arenes, heteroarenes (containing N, O, S), bioactive cores, and allylic cores. Mechanistic studies confirmed a radical-mediated reaction pathway.

A comprehensive study on the identification and characterization of degradation products of lipoglycopeptide Dalbavancin using LC and LC-HRMS/MS.

Dalbavancin is the second-generation approved semisynthetic lipoglycopeptide by the United States Food and Drug Administration (USFDA) for the treatment of acute bacterial skin and skin-structure infections. Unlike other lipoglycopeptides, the stability behavior of Dalbavancin was least explored, which is a prerequisite. The current study endeavors to elucidate the oxidative and hydrolytic stability behavior of Dalbavancin by exposing the drug to oxidative, acidic, and basic stress conditions. A simple liquid chromatography (LC) method was developed, where significant resolution between Dalbavancin, its homologs, and the generated degradation products was achieved. Seven degradation products were identified under acidic, basic, and oxidative stress conditions. Using liquid chromatography and high-resolution mass spectrometry (LC-HRMS), MS/MS studies, the generated degradation products were identified and characterized. Formation of isomeric degradation products was identified especially upon exposure to basic stress conditions. The mechanistic fragmentation pathway for the seven degradation products was established, and the chemical structure for the identified degradation products was elucidated. The results strongly suggest that Dalbavancin is highly susceptible to degradation under oxidative and hydrolytic stress conditions. This study provides insights into the hydrolytic and oxidative stability of Dalbavancin, which can be employed during drug development and discovery in synthesizing relatively stable analogs.

Goal-directed fluid therapy guided by plethysmographic variability index versus conventional liberal fluid therapy in neonates undergoing abdominal surgery: A prospective randomized controlled trial.

BACKGROUND: Intraoperative fluid therapy maintains normovolemia, normal tissue perfusion, normal metabolic function, normal electrolytes, and acid-base status. Plethysmographic variability index has been shown to predict fluid responsiveness but its role in guiding intraoperative fluid therapy is still elusive. AIMS: The aim of the present study was to compare intraoperative goal-directed fluid therapy based on plethysmographic variability index with liberal fluid therapy in term neonates undergoing abdominal surgeries. METHODS: A prospective randomized controlled study was conducted in a tertiary care centre, over a period of 18 months. A total of 30 neonates completed the study out of 132 neonates screened. Neonates with tracheoesophageal fistula, congenital diaphragmatic hernia, congenital heart disease, respiratory disorders, creatinine clearance <90 mL/min and who were hemodynamically unstable were excluded. Neonates were randomized to goal-directed fluid therapy group where the plethysmographic variability index was targeted at <18 or liberal fluid therapy group. Primary outcome was comparison of total amount of fluid infused intraoperatively in both the groups. Secondary outcomes included intraoperative and postoperative arterial blood gas parameters, biochemical parameters, use of vasopressors, number of fluid boluses, complications and duration of hospital stay. RESULTS: There was no significant difference in total intraoperative fluid infused [90 (84-117.5 mL) in goal-directed fluid therapy and 105 (85.5-144.5 mL) in liberal fluid therapy group (p = .406)], median difference (95% CI) -15 (-49.1 to 19.1). There was a decrease in serum lactate levels in both groups from preoperative to postoperative 24 h. The amount of fluid infused before dopamine administration was significantly higher in liberal fluid therapy group (58 [50.25-65 mL]) compared to goal-directed fluid therapy group (36 [22-44 mL], p = .008), median difference (95% CI) -22 (-46 to 2). In postoperative period, the total amount of fluid intake over 24 h was comparable in two groups (222 [204-253 mL] in goal-directed fluid therapy group and 224 [179.5-289.5 mL] in liberal fluid therapy group, p = .917) median difference (95% CI) cutoff -2 (-65.3 to 61.2). CONCLUSION: Intraoperative plethysmographic variability index-guided goal-directed fluid therapy was comparable to liberal fluid therapy in terms of total volume of fluid infused in neonates during perioperative period. More randomized controlled trials with higher sample size are required. TRIAL REGISTRATION: Central Trial Registry of India (CTRI/2020/02/023561).

Molecular insights into the maturation of phosphodiesterase 6 by the specialized chaperone complex of HSP90 with AIPL1.

Phosphodiesterase 6 (PDE6) is a key effector enzyme in vertebrate phototransduction, and its maturation and function are known to critically depend on a specialized chaperone, aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1). Defects in PDE6 and AIPL1 underlie several severe retinal diseases, including retinitis pigmentosa and Leber congenital amaurosis. Here, we characterize the complex of AIPL1 with HSP90 and demonstrate its essential role in promoting the functional conformation of nascent PDE6. Our analysis suggests that AIPL1 preferentially binds to HSP90 in the closed state with a stoichiometry of 1:2, with the tetratricopeptide repeat domain and the tetratricopeptide repeat helix 7 extension of AIPL1 being the main contributors to the AIPL1/HSP90 interface. We demonstrate that mutations of these determinants markedly diminished both the affinity of AIPL1 for HSP90 and the ability of AIPL1 to cochaperone the maturation of PDE6 in a heterologous expression system. In addition, the FK506-binding protein (FKBP) domain of AIPL1 encloses a unique prenyl-binding site that anchors AIPL1 to posttranslational lipid modifications of PDE6. A mouse model with rod PDE6 lacking farnesylation of its PDE6A subunit revealed normal expression, trafficking, and signaling of the enzyme. Furthermore, AIPL1 was unexpectedly capable of inducing the maturation of unprenylated cone PDE6C, whereas mutant AIPL1 deficient in prenyl binding competently cochaperoned prenylated PDE6C. Thus, we conclude neither sequestration of the prenyl modifications is required for PDE6 maturation to proceed, nor is the FKBP-lipid interaction involved in the conformational switch of the enzyme into the functional state.

Genetic analysis of stripe rust resistance in the common wheat line Kfa/2*Kachu under a Chinese rust environment.

KEY MESSAGE: We mapped a new race-specific seedling stripe rust resistance gene on wheat chromosome 5BL and a new APR locus QYr.hazu-2BS from CIMMYT wheat line Kfa/2*Kachu. Breeding resistant wheat (Triticum aestivum) varieties is the most economical and efficient way to manage wheat stripe rust, but requires the prior identification of new resistance genes and development of associated molecular markers for marker-assisted selection. To map stripe rust resistance loci in wheat, we used a recombinant inbred line population generated by crossing the stripe rust-resistant parent 'Kfa/2*Kachu' and the susceptible parent 'Apav#1'. We employed genotyping-by-sequencing and bulked segregant RNA sequencing to map a new race-specific seedling stripe rust resistance gene, which we designated YrK, to wheat chromosome arm 5BL. TraesCS5B02G330700 encodes a receptor-like kinase and is a high-confidence candidate gene for YrK based on virus-induced gene silencing results and the significant induction of its expression 24 h after inoculation with wheat stripe rust. To assist breeding, we developed functional molecular markers based on the polymorphic single nucleotide polymorphisms in the coding sequence region of YrK. We also mapped four adult plant resistance (APR) loci to wheat chromosome arms 1BL, 2AS, 2BS and 4AL. Among these APR loci, we determined that QYr.hazu-1BL and QYr.hazu-2AS are allelic to the known pleiotropic resistance gene Lr46/Yr29/Pm39 and the race-specific gene Yr17, respectively. However, QYr.hazu-2BS is likely a new APR locus, for which we converted closely linked SNP polymorphisms into breeder-friendly Kompetitive allele-specific PCR (KASP) markers. In the present study, we provided new stripe rust resistance locus/gene and molecular markers for wheat breeder to develop rust-resistant wheat variety.

High density mapping of wheat stripe rust resistance gene QYrXN3517-1BL using QTL mapping, BSE-Seq and candidate gene analysis.

KEY MESSAGE: Fine mapping of a major stripe rust resistance locus QYrXN3517-1BL to a 336 kb region that includes 12 candidate genes. Utilization of genetic resistance is an effective strategy to control stripe rust disease in wheat. Cultivar XINONG-3517 (XN3517) has remained highly resistant to stripe rust since its release in 2008. To understand the genetic architecture of stripe rust resistance, Avocet S (AvS) × XN3517 F6 RIL population was assessed for stripe rust severity in five field environments. The parents and RILs were genotyped by using the GenoBaits Wheat 16 K Panel. Four stable QTL from XINONG-3517 were detected on chromosome arms 1BL, 2AL, 2BL, and 6BS, named as QYrXN3517-1BL, QYrXN3517-2AL, QYrXN3517-2BL, and QYrXN3517-6BS, respectively. Based on the Wheat 660 K array and bulked segregant exome sequencing (BSE-Seq), the most effective QTL on chromosome 1BL is most likely different from the known adult plant resistance gene Yr29 and was mapped to a 1.7 cM region [336 kb, including twelve candidate genes in International Wheat Genome Sequencing Consortium (IWGSC) RefSeq version 1.0]. The 6BS QTL was identified as Yr78, and the 2AL QTL was probably same as QYr.caas-2AL or QYrqin.nwafu-2AL. The novel QTL on 2BL was effective in seedling stage against the races used in phenotyping. In addition, allele-specifc quantitative PCR (AQP) marker nwafu.a5 was developed for QYrXN3517-1BL to assist marker-assisted breeding.

Ultrastructural study confirms the formation of single and heterotypic syncytial cells in bronchoalveolar fluids of COVID-19 patients.

BACKGROUND: SARS-CoV-2 was reported to induce cell fusions to form multinuclear syncytia that might facilitate viral replication, dissemination, immune evasion, and inflammatory responses. In this study, we have reported the types of cells involved in syncytia formation at different stages of COVID-19 disease through electron microscopy. METHODS: Bronchoalveolar fluids from the mild (n = 8, SpO2 > 95%, no hypoxia, within 2-8 days of infection), moderate (n = 8, SpO2 90% to ≤ 93% on room air, respiratory rate ≥ 24/min, breathlessness, within 9-16 days of infection), and severe (n = 8, SpO2 < 90%, respiratory rate > 30/min, external oxygen support, after 17th days of infection) COVID-19 patients were examined by PAP (cell type identification), immunofluorescence (for the level of viral infection), scanning (SEM), and transmission (TEM) electron microscopy to identify the syncytia. RESULTS: Immunofluorescence studies (S protein-specific antibodies) from each syncytium indicate a very high infection level. We could not find any syncytial cells in mildly infected patients. However, identical (neutrophils or type 2 pneumocytes) and heterotypic (neutrophils-monocytes) plasma membrane initial fusion (indicating initiation of fusion) was observed under TEM in moderately infected patients. Fully matured large-size (20-100 µm) syncytial cells were found in severe acute respiratory distress syndrome (ARDS-like) patients of neutrophils, monocytes, and macrophage origin under SEM. CONCLUSIONS: This ultrastructural study on the syncytial cells from COVID-19 patients sheds light on the disease's stages and types of cells involved in the syncytia formations. Syncytia formation was first induced in type II pneumocytes by homotypic fusion and later with haematopoetic cells (monocyte and neutrophils) by heterotypic fusion in the moderate stage (9-16 days) of the disease. Matured syncytia were reported in the late phase of the disease and formed large giant cells of 20 to 100 µm.

Stereoselective Reductive Coupling Reactions Utilizing [1,2]-Phospha-Brook Rearrangement: A Powerful Umpolung Approach.

[1,2]-Phospha-Brook rearrangement entails the generation of α-oxygenated carbanions via the umpolung process. Recently, these anionic species have been widely utilized for several C-C bond forming strategies, providing various useful frameworks that are difficult to access through conventional approaches. However, the application of this powerful methodology in the development of chiral strategies is still at the nascent stage due to challenges involved in controlling chemoselectivity and enantioselectivity. This synopsis provides a detailed summary of diastereo- and/or enantioselective chemical transformations using [1,2]-phospha-Brook rearrangement.

Enantioselective Distal Functionalization of 3-Cyano-4-methylcoumarins through Direct Vinylogous Conjugate Addition to Maleimides.

An unprecedented organocatalyzed asymmetric vinylogous Michael reaction between 3-cyano-4-methylcoumarins and maleimides with an excellent enantiomeric ratio (up to 99.5:0.5) and yield (up to 95%) is reported. This remarkable selectivity is attributed to the hydrogen bonding ability of l-tert-leucine-derived amine thiourea catalyst. The versatility, practical applicability, and scalability are demonstrated by the generation of γ-functionalized coumarin derivatives.

9-Demethoxy-medicarpin: A potential bone health supplement for the management of protein deficiency-induced bone loss in growing rats.

Human skeleton requires an adequate supply of many different nutritional factors for optimal growth and development. The role of nutrition in bone growth has piqued interest in recent years, especially in relation to maximizing peak bone mass and reducing the risk of osteoporosis. Protein deficiency-induced bone loss was induced in female growing rats. All experimental rodent diets were prepared as per recommendations for growing animals. 9-Demethoxy-medicarpin (DMM) treatment was given to growing Sprague Dawley (SD) rats at 1 mg and 10 mg dose orally for 30 days. Bones were collected for bone mineral density (BMD). Bone marrow cells were isolated from femur for calcium nodule formation. Serum samples were collected for biochemical parameters. We found that DMM treatment speeds up the recovery of musculoskeletal weakness by replenishing nutrients in proven rodent model. DMM supplementation for four weeks showed significantly increased vertebral, femur and tibial BMD compared with the untreated PD group. Albumin levels were significantly enhanced in treatment groups, in which 10 mg dose imparted a better effect. We conclude that DMM treatment led to increased BMD and biochemical parameters in protein deficient condition in growing rats and has potential as a bone growth supplement.

The evolution of the British Journal of Anaesthesia: the first 100 years.

At this centenary of the British Journal of Anaesthesia (BJA) in 2023, six of its 12 editors/editors-in-chief detail developments over the decades that have led to the BJA becoming a high-impact international scientific journal. As a charity, the BJA supports academic research and training in anaesthesia, critical care, and pain medicine including funding of research grants and postgraduate education. Building on this foundation, the BJA continues to innovate as it aims to become fully electronic, expand into open access publishing, and increase the diversity of its editorial board.

Quorum sensing inhibitors as Therapeutics: Bacterial biofilm inhibition.

The overuse and inappropriate use of antibiotics to treat bacterial infections has led to the development of multiple drug resistant strains. Biofilm is a complex microorganism aggregation defined by the presence of a dynamic, sticky, and protective extracellular matrix made of polysaccharides, proteins, and nucleic acids. The infectious diseases are caused by bacteria that flourish within quorum sensing (QS) mediated biofilms. Efforts to disrupt biofilms have enabled the identification of bioactive molecules produced by prokaryotes and eukaryotes. The QS system is quenched predominantly by these molecules. The phenomenon is also termed as quorum sensing (QS). Both synthetic and natural substances have been discovered to be useful in QS. This review describes natural and synthetic quorum sensing inhibitors (QSIs) with the potential to treat bacterial infections. It includes the discussion on quorum sensing, mechanism of quorum sensing, effect of substituents on the activity. These discoveries could result in effective therapies using far lower dosages of medications, particularly antibiotics, are currently needed.