Mechanism of Action of Dihydroquercetin in the Prevention and Therapy of Experimental Liver Injury.

Liver disease is a global health problem that affects the well-being of tens of thousands of people. Dihydroquercetin (DHQ) is a flavonoid compound derived from various plants. Furthermore, DHQ has shown excellent activity in the prevention and treatment of liver injury, such as the inhibition of hepatocellular carcinoma cell proliferation after administration, the normalization of oxidative indices (like SOD, GSH) in this tissue, and the down-regulation of pro-inflammatory molecules (such as IL-6 and TNF-α). DHQ also exerts its therapeutic effects by affecting molecular pathways such as NF-κB and Nrf2. This paper discusses the latest research progress of DHQ in the treatment of various liver diseases (including viral liver injury, drug liver injury, alcoholic liver injury, non-alcoholic liver injury, fatty liver injury, and immune liver injury). It explores how to optimize the application of DHQ to improve its effectiveness in treating liver diseases, which is valuable for preparing potential therapeutic drugs for human liver diseases in conjunction with DHQ.

The ASB@HNTs-PVA nanofiber membrane, possessing both anti-inflammatory and hemostatic activities, promotes the healing of T2D skin wounds.

The healing of diabetic wounds has long been a significant challenge in the field of medicine. The elevated sugar levels surrounding diabetic wounds create a conducive environment for harmful bacterial growth, resulting in purulent infections that impede the healing process. Thus, the development of a biomaterial that can enhance the healing of diabetic wounds holds great importance. This study developed electrospun dressings for wound healing by combining traditional Chinese medicine and clay. The study utilized electrospinning technology to prepare polyvinyl alcohol (PVA) nanofiber membranes containing ASB and HNTs. These ASB@HNTs-PVA nanofiber membranes demonstrated rapid hemostasis, along with antibacterial and anti-inflammatory properties, facilitating the recovery of type 2 diabetic (T2D) wounds. Various analyses were conducted to assess the performance of the composite nanofiber membrane, including investigations into its biocompatibility and hemostatic abilities through antibacterial experiments, cell experiments, and mouse liver tail bleeding experiments. Western blot analysis confirmed that the composite nanofiber membrane could decrease the levels of inflammatory factors IL-1ß and TNF-α. A type 2 diabetic mouse model was utilized, with wounds artificially induced on the backs of mice. Application of the nanofiber membrane to the wounds further confirmed its anti-inflammatory effects and ability to enhance wound healing in vivo.

Integrating UHPLC-Q-TOF-MS/MS, network pharmacology, bioinformatics and experimental validation to uncover the anti-cancer mechanisms of TiaoPi AnChang decoction in colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: The TiaoPi AnChang Decoction (TPACD), a Traditional Chinese Medicine (TCM) prescription based on Xiangsha Liujunzi Decoction, has demonstrated clinical efficacy as an adjuvant therapy for colorectal cancer (CRC) patients. However, its specific ingredients and potential mechanisms of action remain unclear. AIM OF THE STUDY: To identify the primary active ingredients of TPACD, their molecular targets, and potential mechanisms underlying the efficacy of TPACD in CRC treatment. MATERIALS AND METHODS: This study investigated the clinically validated TCM formula TPACD. In vitro and in vivo experiments were used to demonstrate TPACD's regulatory effects on various malignant phenotypes of tumors, providing basic research support for its anti-cancer activity. To understand its pharmacodynamic basis, we utilized ultra-high performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry/mass spectrometry (UHPLC-Q-TOF-MS/MS) to analyze TPACD constituents present in the bloodstream. Network pharmacology and bioinformatics analyses were used to identify potential active components and their molecular targets for TPACD's therapeutic effects in CRC. Subsequent experiments further elucidated its pharmacological mechanism. RESULTS: TPACD inhibits various malignant cellular processes, such as cell proliferation, apoptosis, migration, and invasion, and has shown potential anti-CRC activities both in vitro and in vivo. Following the identification of 109 constituents absorbed into the blood from TPACD, network pharmacology analysis predicted 42 potential anti-CRC targets. Clinical analyses highlighted three genes as prognostic key genes of TPACD's therapeutic action: C-X-C motif chemokine ligand 8 (CXCL8), fatty acid binding protein 4 (FABP4), and matrix metallopeptidase 3 (MMP3). Drug sensitivity analyses, molecular docking simulations and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) identified MMP3 as the most promising target for TPACD's anti-CRC action. Enzyme activity assays confirmed that TPACD inhibits MMP3 enzyme activity. Surface plasmon resonance (SPR) characterized the binding affinity between MMP3 and effective active components of TPACD, including luteolin, quercetin, kaempferol, and liensinine. CONCLUSIONS: TPACD exhibits anti-CRC activity in vitro and in vivo, with MMP3 identified as a critical target. The active compounds, including luteolin, quercetin, kaempferol, and liensinine, absorbed into the bloodstream, contribute to TPACD's efficacy by targeting MMP3.

Growth hormone improves insulin resistance in visceral adipose tissue after duodenal-jejunal bypass by regulating adiponectin secretion.

BACKGROUND: The mechanism of improvement of type 2 diabetes after duodenal-jejunal bypass (DJB) surgery is not clear. AIM: To study the morphological and functional changes in adipose tissue after DJB and explore the potential mechanisms contributing to postoperative insulin sensitivity improvement of adipose tissue in a diabetic male rat model. METHODS: DJB and sham surgery was performed in a-high-fat-diet/streptozotocin-induced diabetic rat model. All adipose tissue was weighed and observed under microscope. Use inguinal fat to represent subcutaneous adipose tissue (SAT) and mesangial fat to represent visceral adipose tissue. RNA-sequencing was utilized to evaluate gene expression alterations adipocytes. The hematoxylin and eosin staining, reverse transcription-quantitative polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay were used to study the changes. Insulin resistance was evaluated by immunofluorescence. RESULTS: After DJB, whole body blood glucose metabolism and insulin sensitivity in adipose tissue improved. Fat cell volume in both visceral adipose tissue (VAT) and SAT increased. Compared to SAT, VAT showed more significantly functional alterations after DJB and KEGG analysis indicated growth hormone (GH) pathway and downstream adiponectin secretion were involved in metabolic regulation. The circulating GH and adiponectin levels and GH receptor and adiponectin levels in VAT increased. Cytological experiment showed that GH stimulated adiponectin secretion and improve insulin sensitivity. CONCLUSION: GH improves insulin resistance in VAT in male diabetic rats after receiving DJB, possibly by increasing adiponectin secretion.

Changes in the rumen development, rumen fermentation, and rumen microbiota community in weaned calves during steviol glycosides treatment.

Early weaning leads to weaning stress in calves, which hinders healthy growth and development. As an excellent sweetener applied in food, steviol glycosides (STE) has also been shown to exhibit positive biological activity in monogastric animals. Therefore, this study aimed to evaluate the impact of incorporating STE as a dietary supplement on rumen development, fermentation, and microbiota of rumen in weaned calves. This study selected 24 healthy Holstein bull calves and randomly allocated them into two groups (CON and STE). The results indicated that supplementation STE group improved rumen development in weaned calves, as demonstrated by a marked increase in the weight of the rumen, as well as the length and surface area of the rumen papilla. Compared with the CON group, the concentrations of total volatile fatty acids (TVFA), propionate, butyrate, and valerate were higher in the STE group. Moreover, STE treatment increased the relative abundance of Firmicutes and Actinobacteria at the phylum level. At the genus level, the STE group showed a significantly increased relative abundance of Succiniclasticum, Lachnospiraceae_NK3A20_group, and Olsenella, and a decreased relative abundance of Acinetobacter compared to the CON group. Pusillimonas, Lachnospiraceae_NK3A20_group, Olsenella, and Succiniclasticum were significantly enriched in rumen chyme after supplementation with STE, as demonstrated by LEfSe analysis. Overall, our findings revealed that rumen bacterial communities altered in response to the dietary supplementation with STE, and some bacterial taxa in these communities may have positive effects on rumen development during this period.

A distinct subset of urothelial cells with enhanced EMT features promotes chemotherapy resistance and cancer recurrence by increasing COL4A1-ITGB1 mediated angiogenesis.

Drug resistance and tumor recurrence remain clinical challenges in the treatment of urothelial carcinoma (UC). However, the underlying mechanism is not fully understood. Here, we performed single-cell RNA sequencing and identified a subset of urothelial cells with epithelial-mesenchymal transition (EMT) features (EMT-UC), which is significantly correlated with chemotherapy resistance and cancer recurrence. To validate the clinical significance of EMT-UC, we constructed EMT-UC like cells by introducing overexpression of two markers, Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and Desmin (DES), and examined their histological distribution characteristics and malignant phenotypes. EMT-UC like cells were mainly enriched in UC tissues from patients with adverse prognosis and exhibited significantly elevated EMT, migration and gemcitabine tolerance in vitro. However, EMT-UC was not specifically identified from tumorous tissues, certain proportion of them were also identified in adjacent normal tissues. Tumorous EMT-UC highly expressed genes involved in malignant behaviors and exhibited adverse prognosis. Additionally, tumorous EMT-UC was associated with remodeled tumor microenvironment (TME), which exhibited high angiogenic and immunosuppressive potentials compared with the normal counterparts. Furthermore, a specific interaction of COL4A1 and ITGB1 was identified to be highly enriched in tumorous EMT-UC, and in the endothelial component. Targeting the interaction of COL4A1 and ITGB1 with specific antibodies significantly suppressed tumorous angiogenesis and alleviated gemcitabine resistance of UC. Overall, our findings demonstrated that the driven force of chemotherapy resistance and recurrence of UC was EMT-UC mediated COL4A1-ITGB1 interaction, providing a potential target for future UC treatment.

The polycaprolactone and silk fibroin nanofibers with Janus-structured sheaths for antibacterial and antioxidant by loading Taxifolin.

Electrospinning is a widely recognized method for producing Janus or core-shell nanofibers. In this study, nanofibrous membranes were fabricated through co-axial electrospinning utilizing polycaprolactone (PCL) and silk fibroin (SF) as the Janus shell, and taxifolin (TAX) and SF as the core. The resulting nanofibers had diameters of 816 ± 161 nm and core diameters of 73 ± 5 nm. The morphology and properties of the PCL-SF@SF/TAX nanofibers were subsequently analyzed. The results demonstrated that the nanofibrous membranes achieved physical and chemical characteristics potential for tissue engineering and drug delivery. Specifically, the membranes exhibited a Young's modulus of 9.64 ± 0.29 MPa, a water contact angle of 79.1 ± 1.3°, and a weight loss of 17.3 ± 1.0 % over a period of 28 days. The incorporation of TAX endowed the membranes with antibacterial properties, effectively combating Escherichia coli and Staphylococcus aureus. Furthermore, the membranes demonstrated antioxidant capabilities, with a DPPH radical scavenging efficiency of 38.5 ± 5.6 % and a Trolox-equivalent antioxidant capacity of 0.24 ± 0.01 mM. The release of the antioxidant was sustained over 28 days, following first-order release kinetics. The nanofibrous membranes, referred to as PSST, exhibit promising potential for use as biomaterials, characterized by their antibacterial activity, antioxidant and cytocompatibility.

Preparation and evaluation of gastrodin microsphere-loaded Gastrodia elata polysaccharides composite hydrogel on UVB-induced skin damage in vitro and in vivo.

Skin damage from sun exposure is a common issue among outdoor workers and is primarily caused by ultraviolet rays. Upon absorption of these rays, the skin will experience inflammation and cell apoptosis. This study explored the concept of 'Combination of medicine and adjuvant' by utilizing Gastrodia elata polysaccharide, a key component of Gastrodia elata Bl.|, to develop a new hydrogel material. Oxidized Gastrodia elata polysaccharide (OGEP) and carboxymethyl chitosan (CMCS) was use to prepare a biocompatible, biodegradable and self-healing hydrogel OGEP/CMCS (OC). And this hydrogel was further loaded with Gastrodin-containing microspheres (GAS/GEL) to create GAS/GEL/OGEP/CMCS (GGOC) hydrogel. Characterization studies revealed that OC and GGOC hydrogels exhibited favorable mechanical properties, antioxidant activity and biocompatibility. The experiments showed that OC and GGOC hydrogels could regulate mitochondrial membrane potential, prevent mitochondrial breakage, inhibit proinflammatory factors, prevent NF-κB protein activation and regulate apoptosis-related pathways. This study highlighted the application potential of Gastrodia elata polysaccharide as a 'Combination of medicine and adjuvant' and the anti-UVB damage effect of the prepared hydrogel.

Age structure and body size of two Tibetan toad (Bufo tibetanus) populations from different elevations in China.

Understanding how age and body size vary across elevations can provide insights into the evolution of life-history traits in animals. In the present study, we compared the demographic (using skeletochronology) and morphological traits of the Tibetan toad (Bufo tibetanus) between two populations from different elevational habitats (2650 vs. 3930 m). We found that (1) the mean age and body size of females were significantly greater than those of males in both populations; (2) both sexes of toads from the higher elevation tended to be significantly older in age and larger in body size; (3) there was a significant positive relationship between age and body size within each sex of the toad at both elevations; and (4) growth rates varied between the two populations, with the higher rate observed in the lower-elevation population. Our results suggested that factors other than age, such as elevation-associated temperature, influence the observed differences in body size between the two populations. Future research at a broader range of elevations should focus on these factors and evaluate their influence on animal growth patterns.

Multifunctional bilayer nanofibrous membrane enhances periodontal regeneration via mesenchymal stem cell recruitment and macrophage polarization.

The continuous stimulation of periodontitis leads to a decrease in the number of stem cells within the lesion area and significantly impairing their regenerative capacity. Therefore, it is crucial to promote stem cell homing and regulate the local immune microenvironment to suppress inflammation for the regeneration of periodontitis-related tissue defects. Here, we fabricated a novel multifunctional bilayer nanofibrous membrane using electrospinning technology. The dense poly(caprolactone) (PCL) nanofibers served as the barrier layer to resist epithelial invasion, while the polyvinyl alcohol/chitooligosaccharides (PVA/COS) composite nanofiber membrane loaded with calcium beta-hydroxy-beta-methylbutyrate (HMB-Ca) acted as the functional layer. Material characterization tests revealed that the bilayer nanofibrous membrane presented desirable mechanical strength, stability, and excellent cytocompatibility. In vitro, PCL@PVA/COS/HMB-Ca (P@PCH) can not only directly promote rBMSCs migration and differentiation, but also induce macrophage toward pro-healing (M2) phenotype-polarization with increasing the secretion of anti-inflammatory and pro-healing cytokines, thus providing a favorable osteoimmune environment for stem cells recruitment and osteogenic differentiation. In vivo, the P@PCH membrane effectively recruited host MSCs to the defect area, alleviated inflammatory infiltration, and accelerated bone defects repair. Collectively, our data indicated that the P@PCH nanocomposite membrane might be a promising biomaterial candidate for guided tissue regeneration in periodontal applications.

Ankylosing spondylitis prediction using fuzzy K-nearest neighbor classifier assisted by modified JAYA optimizer.

The diagnosis of ankylosing spondylitis (AS) can be complex, necessitating a comprehensive assessment of medical history, clinical symptoms, and radiological evidence. This multidimensional approach can exacerbate the clinical burden and increase the likelihood of diagnostic inaccuracies, which may result in delayed or overlooked cases. Consequently, supplementary diagnostic techniques for AS have become a focal point in clinical research. This study introduces an enhanced optimization algorithm, SCJAYA, which incorporates salp swarm foraging behavior with cooperative predation strategies into the JAYA algorithm framework, noted for its robust optimization capabilities that emulate the evolutionary dynamics of biological organisms. The integration of salp swarm behavior is aimed at accelerating the convergence speed and enhancing the quality of solutions of the classical JAYA algorithm while the cooperative predation strategy is incorporated to mitigate the risk of convergence on local optima. SCJAYA has been evaluated across 30 benchmark functions from the CEC2014 suite against 9 conventional meta-heuristic algorithms as well as 9 state-of-the-art meta-heuristic counterparts. The comparative analyses indicate that SCJAYA surpasses these algorithms in terms of convergence speed and solution precision. Furthermore, we proposed the bSCJAYA-FKNN classifier: an advanced model applying the binary version of SCJAYA for feature selection, with the aim of improving the accuracy in diagnosing and prognosticating AS. The efficacy of the bSCJAYA-FKNN model was substantiated through validation on 11 UCI public datasets in addition to an AS-specific dataset. The model exhibited superior performance metrics-achieving an accuracy rate, specificity, Matthews correlation coefficient (MCC), F-measure, and computational time of 99.23 %, 99.52 %, 0.9906, 99.41 %, and 7.2800 s, respectively. These results not only underscore its profound capability in classification but also its substantial promise for the efficient diagnosis and prognosis of AS.

Control and surveillance of redox potential for 233Pa dissolution in 2LiF-BeF2 molten salt.

233Pa, the precursor nuclide of 233U in the thorium-uranium conversion is prone to reductive deposition in 2LiF-BeF2 (66 : 34 mol%, FLiBe) molten salt. We explored the adjustment and control of the redox potential of the FLiBe melt to avoid the 233Pa reduction deposition. The experimental data indicated that the deposited 233Pa can be completely dissolved and reentered into the molten salt with the addition of oxidant NiF2, and the distribution and behaviour of uranium, thorium, neptunium, and most fission products did not have any significant change in the NiF2-oxidised FLiBe molten salt, showing the feasibility of this manner to make 233Pa exist stably in the melt. The effects of NiF2-addition on the behaviour of the fission products 95Nb and 131I in the FLiBe molten salt were also investigated. It was found that 131I could be used as a redox indicator to monitor the redox potential of the oxidation-enhanced FLiBe molten salt. All the information drawn from this study could provide significant support for the control and surveillance of the redox potential of the FLiBe molten salt in the upcoming thorium molten salt reactor (TMSR).

Sotorasib as first-line therapy in patients with advanced non-small cell lung cancer with KRAS gene mutations combined with brain metastases: a case report.

Background: Non-small cell lung cancer (NSCLC) has a high incidence of lung cancer, with a 30% incidence of KRAS mutations and a low 5-year survival rate. Until the Food and Drug Administration (FDA) approved sotorasib in May 2021, no therapies targeted mutated KRAS in cancer. Sotorasib, a new KRAS inhibitor, is currently recognized as the newest clinically targeted agent with apparent clinical efficacy in NSCLC patients with KRAS G12C mutations. FDA approval is required for patients with advanced or metastatic NSCLC undergoing at least one chemotherapy regimen. Case Description: In our study, we report a patient with advanced NSCLC combined with brain metastases, clinical stage IV (c.T3N0M1b), KRAS G12C (+) detected by next-generation sequencing (NGS) technology, direct use of sotorasib, an inhibitor of KRAS G12C, as first-line therapy. The patient was treated with 4 months of oral therapy, had significant partial remission (PR), and remained in stable disease (SD) for nearly 9 months of follow-up, with no other side effects. Further extension of the follow-up period is needed to assess the impact of sotorasib as first-line therapy on patient survival. A series of clinical trials in phase 3 is ongoing, covering the first-line usage widespread. Conclusions: Based on the literature review, this is the first domestic report in China where sotorasib was used directly as first-line treatment in patients with advanced combined brain metastasis from NSCLC. It needs a longer follow-up to evaluate the efficacy of sotorasib further as a first-line.

Redistribution of defective mitochondria-mediated dihydroorotate dehydrogenase imparts 5-fluorouracil resistance in colorectal cancer.

Although 5-fluorouracil (5-FU) is the primary chemotherapy treatment for colorectal cancer (CRC), its efficacy is limited by drug resistance. Ferroptosis activation is a promising treatment for 5-FU-resistant cancer cells; however, potential therapeutic targets remain elusive. This study investigated ferroptosis vulnerability and dihydroorotate dehydrogenase (DHODH) activity using stable, 5-FU-resistant CRC cell lines and xenograft models. Ferroptosis was characterized by measuring malondialdehyde levels, assessing lipid metabolism and peroxidation, and using mitochondrial imaging and assays. DHODH function is investigated through gene knockdown experiments, tumor behavior assays, mitochondrial import reactions, intramitochondrial localization, enzymatic activity analyses, and metabolomics assessments. Intracellular lipid accumulation and mitochondrial DHODH deficiency led to lipid peroxidation overload, weakening the defense system of 5-FU-resistant CRC cells against ferroptosis. DHODH, primarily located within the inner mitochondrial membrane, played a crucial role in driving intracellular pyrimidine biosynthesis and was redistributed to the cytosol in 5-FU-resistant CRC cells. Cytosolic DHODH, like its mitochondrial counterpart, exhibited dihydroorotate catalytic activity and participated in pyrimidine biosynthesis. This amplified intracellular pyrimidine pools, thereby impeding the efficacy of 5-FU treatment through molecular competition. These findings contribute to the understanding of 5-FU resistance mechanisms and suggest that ferroptosis and DHODH are promising therapeutic targets for patients with CRC exhibiting resistance to 5-FU.

Optimizing fluconazole-embedded transfersomal gel for enhanced antifungal activity and compatibility studies.

Fungal infections are of major concern all over the globe, and fluconazole is the most prevalently used drug to treat it. The goal of this research work was to formulate a fluconazole-embedded transfersomal gel for the treatment of fungal infections. A compatibility study between fluconazole and soya lecithin was performed by differential scanning calorimetry (DSC). Transfersomes were formulated by a thin-film hydration technique using soya lecithin and Span 80. A central composite design was adopted to prepare different formulations. Soya lecithin and Span 80 were chosen as independent variables, and the effect of these variables was studied on in vitro drug diffusion. Formulations were evaluated for entrapment efficiency and in vitro drug diffusion. The results of in vitro drug diffusion were analyzed using the analysis of variance (ANOVA) test. Optimized formulation was prepared based on the overlay plot and evaluated by scanning electron microscopy, DSC, vesicle size, polydispersity index (PDI), zeta potential, and in vitro drug diffusion studies. An optimized formulation was loaded into xanthan gum gel base and evaluated for pH, viscosity, in vitro and ex vivo drug diffusion, and antifungal activity. DSC studies revealed compatibility between fluconazole and soya lecithin. Entrapment efficiency and in vitro drug diffusion of various formulations ranged between 89.92% ± 0.20% to 97.28% ± 0.42% and 64% ± 1.56% to 85% ± 2.05%, respectively. A positive correlation was observed between in vitro drug diffusion and Span 80; conversely, a negative correlation was noted with soya lecithin. Entrapment efficiency, particle size, zeta potential, PDI, and drug diffusion of optimized formulation were 95.0% ± 2.2%, 397 ± 2 nm, -38 ± 5 mV, 0.43%, and 81 % ± 2%, respectively. SEM images showed well-distributed spherical-shaped transfersomes. In vitro, ex vivo drug diffusion and antifungal studies were conclusive of better diffusion and enhanced antifungal potential fluconazole in transfersomal formulation.

Is cryoablation still suitable for advanced non-small cell lung cancer after failure of first-line chemotherapy? A multicenter, prospective, randomized-controlled trial of eighty-seven patients.

The aim of this study was to investigate the therapeutic effect of cryoablation treatment in advanced NSCLC patients who had failed first-line chemotherapy. Eighty-seven patients from ten hospitals in China were enrolled into the study, forty-four patients received cryoablation treatment plus basic treatment (experimental group), and forty-three patients had basic treatment alone (control group). Follow-up was performed once every three months until the end of the study or the death of the patient. The primary endpoints were overall and post-intervention survival; secondary endpoints included tumor markers, solid tumor efficacy, and symptom changes before and after treatment. There was no significant difference in median OS between the two groups of patients (9.0 months vs 11.2 months, P = 0.583). The disease control rate (DCR) and living quality of the experimental group was higher than that of the control group. In terms of OS, indiscriminate use of cryoablation for such patients was not beneficial, though it could improve symptoms of patients. Cryoablation had a significant effect on selected advanced NSCLC patients after the failure of first-line chemotherapy.

Small vs. Large Library Docking for Positive Allosteric Modulators of the Calcium Sensing Receptor.

Drugs acting as positive allosteric modulators (PAMs) to enhance the activation of the calcium sensing receptor (CaSR) and to suppress parathyroid hormone (PTH) secretion can treat hyperparathyroidism but suffer from side effects including hypocalcemia and arrhythmias. Seeking new CaSR modulators, we docked libraries of 2.7 million and 1.2 billion molecules against transforming pockets in the active-state receptor dimer structure. Consistent with simulations suggesting that docking improves with library size, billion-molecule docking found new PAMs with a hit rate that was 2.7-fold higher than the million-molecule library and with hits up to 37-fold more potent. Structure-based optimization of ligands from both campaigns led to nanomolar leads, one of which was advanced to animal testing. This PAM displays 100-fold the potency of the standard of care, cinacalcet, in ex vivo organ assays, and reduces serum PTH levels in mice by up to 80% without the hypocalcemia typical of CaSR drugs. Cryo-EM structures with the new PAMs show that they induce residue rearrangements in the binding pockets and promote CaSR dimer conformations that are closer to the G-protein coupled state compared to established drugs. These findings highlight the promise of large library docking for therapeutic leads, especially when combined with experimental structure determination and mechanism.

Modified Approach for Extraperitoneal Colostomy Creation in Laparoscopic Abdominoperineal Resection.

BACKGROUND: Parastomal hernia is a major long-term complication after abdominoperineal resection. Extraperitoneal colostomy has been proposed as an effective step for parastomal hernia prevention, but it has not been widely used as it is technically demanding and time-consuming. We proposed a modified approach for extraperitoneal colostomy creation by entering the extraperitoneal space through the arcuate line of the posterior rectus sheath. OBJECTIVE: To evaluate the safety, difficulty, and efficacy of long-term parastomal hernia prevention of the modified approach for extraperitoneal colostomy creation compared with the conventional transperitoneal colostomy approach. DESIGN: This was a retrospective evaluation of a surgical and video database. SETTINGS: This was a single-institution retrospective study. PATIENTS: Clinical data of 74 patients who underwent laparoscopic abdominoperineal resection surgery from January 2019 to January 2020 in the Department of General Surgery, Qilu Hospital of Shandong University, were retrospectively reviewed. MAIN OUTCOME MEASURES: Baseline characteristics, time required for colostomy creation (from skin incision to colostomy maturation), perioperative complications, and long-term colostomy-related complications were compared. RESULTS: Baseline characteristics did not differ between the 2 approaches. The BMI level ranged from 19.5 to 29.4 for patients undergoing extraperitoneal approach. Time required for colostomy creation median [interquartile range], (22 [21-25] minutes for extraperitoneal vs 23 [21-25] minutes for transperitoneal, p = 0.861) were comparable between the 2 approaches. The cumulative incidence of parastomal hernia was significantly greater with transperitoneal colostomy than extraperitoneal colostomy at 2 and 3 years postoperatively (16.2% vs 0%, p = 0.025, and 21.6% vs 0%, p = 0.005). The remaining perioperative complications and long-term colostomy-related complications did not differ between the 2 approaches. LIMITATIONS: This study is limited by its retrospective design and small sample size. CONCLUSIONS: The modified approach for extraperitoneal colostomy creation is safe, technically simple, and effective for long-term parastomal hernia prevention in patients with a BMI of 19.5 to 29.4.

Multifunctional electrospun polycaprolactone/chitosan/hEGF/lidocaine nanofibers for the treatment of 2 stage pressure ulcers.

In this study, a multifunctional nanofiber dressing that can promote antibacterial, analgesic and healing was prepared by electrospinning technology. Hydrophobic polycaprolactone (PCL)/chitosan (CS)/lidocaine hydrochloride (LID) and epidermal growth factor (EGF) were used as scaffold materials and dissolved in trifluoroacetic acid to prepare spinning solution. The morphology of PCEL dressing was observed by scanning electron microscopy. The fiber structure was dense and the average diameter was 297.0 nm. The water absorption capacity test and water contact angle measurement showed that the fiber had good water absorption and hydrophilicity (1302 %, 139.258°). Drug release was 84 % within 60 h. In the results of antibacterial experiment, the dressing showed certain antibacterial properties. The results of cell experiments show that the dressing can promote cell proliferation. In addition, coagulation experiments showed that the dressing could quickly coagulate the blood within 4 min. In addition, PCEL dressing promoted collagen deposition and vascularization through animal models of pressure sores. Therefore, multifunctional dressing can be used as an ideal auxiliary means for the treatment of pressure sores, and it is a promising alternative to chronic wound healing.

Multi-threshold Image Segmentation based on an improved Salp Swarm Algorithm: Case study of breast cancer pathology images.

Breast cancer poses a significant risk to women's health, and it is essential to provide proper diagnostic support. Medical image processing technology is a key component of all supporting diagnostic techniques, with Image Segmentation (IS) being one of its primary steps. Among various methods, Multilevel Image Segmentation (MIS) is considered one of the most effective and straightforward approaches. Many researchers have attempted to improve the quality of image segmentation by combining different metaheuristic algorithms with MIS. However, these methods often suffer from issues such as low convergence accuracy and a proclivity for converging towards Local Optima (LO). To overcome these challenges, this study introduces an integrated approach that combines the Salp Swarm Algorithm (SSA), Slime Mould Algorithm (SMA) and Differential Evolution (DE) algorithm. In this manuscript, we introduce an innovative hybrid MIS model termed SDSSA, which leverages elements from the SSA, SMA and DE algorithms. The SDSSA model fundamentally relies on non-local means 2D histogram and 2D Kapur's entropy. To evaluate the proposed method effectively, we compare it initially with similar algorithms using the IEEE CEC2014 benchmark functions. The SDSSA showcases enhanced convergence velocity and precision relative to similar algorithms. Furthermore, this paper proposes an excellent MIS method. Subsequently, IS experiments were conducted separately at both low and high threshold levels. The test results demonstrate that the segmentation outcomes of MIS, at both low and high threshold levels, outperform other methods. This validates SDSSA as a superior segmentation technique that provides practical assistance for future research in breast cancer pathology image processing.