predicTTE: An accessible and optimal tool for time-to-event prediction in neurological diseases.

Time-to-event prediction is a key task for biological discovery, experimental medicine, and clinical care. This is particularly true for neurological diseases where development of reliable biomarkers is often limited by difficulty visualising and sampling relevant cell and molecular pathobiology. To date, much work has relied on Cox regression because of ease-of-use, despite evidence that this model includes incorrect assumptions. We have implemented a set of deep learning and spline models for time-to-event modelling within a fully customizable 'app' and accompanying online portal, both of which can be used for any time-to-event analysis in any disease by a non-expert user. Our online portal includes capacity for end-users including patients, Neurology clinicians, and researchers, to access and perform predictions using a trained model, and to contribute new data for model improvement, all within a data-secure environment. We demonstrate a pipeline for use of our app with three use-cases including imputation of missing data, hyperparameter tuning, model training and independent validation. We show that predictions are optimal for use in downstream applications such as genetic discovery, biomarker interpretation, and personalised choice of medication. We demonstrate the efficiency of an ensemble configuration, including focused training of a deep learning model. We have optimised a pipeline for imputation of missing data in combination with time-to-event prediction models. Overall, we provide a powerful and accessible tool to develop, access and share time-to-event prediction models; all software and tutorials are available at www.predictte.org.

Discovery of novel pyrazolo[1,5-a]pyrimidine derivatives as potent reversal agents against ABCB1-mediated multidrug resistance.

The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 µM (IC50 = 27.00 nM, RF = 247.40) and 10 µM (IC50 = 10.07 nM, RF = 663.44). Compound 16q could effectively bind and stabilize ABCB1, and does not affect the expression and subcellular localization of ABCB1 in MCF-7/ADR cells. Compound 16q inhibited the function of ABCB1, thereby increasing PTX accumulation, and interrupting the accumulation and efflux of the ABCB1-mediated Rh123, thus resulting in exhibiting good reversal effects. In addition, due to the potent reversal effects of compound 16q, the abilities of PTX to inhibit tubulin depolymerization, and induce cell cycle arrest and apoptosis in MCF-7/ADR cells under low-dose conditions were restored. These results indicate that compound 16q might be a promising potent reversal agent capable of revising ABCB1-mediated MDR, and pyrazolo [1,5-a]pyrimidine might represent a novel scaffold for the discovery of new ABCB1-mediated MDR reversal agents.

Novel analgesic peptide derived from Cinobufacini injection suppressing inflammation and pain via ERK1/2/COX-2 pathway.

Inflammatory pain is a chronic pain caused by peripheral tissue inflammation, seriously impacting the patient's life quality. Cinobufacini injection, as a traditional Chinese medicine injection preparation, shows excellent efficacy in anti-inflammatory and analgesic treatment in patients with advanced tumors. In this study, a novel analgesic peptide CI5 with anti-inflammatory and analgesic bio-functions that naturally presents in Cinobufacini injection and its regulatory mechanism are reported. Our results showed that the administration of CI5 significantly relieved the pain of mice in the acetic acid twisting analgesic model and formalin inflammatory pain model. Furthermore, CI5 effectively reduced the inflammatory cytokines (IL-6, TNF-α and IL-1ß) and inflammatory mediator (PGE2) expressions, and prevented the carrageenan-induced paw edema in mice. Further LC-MS/MS results showed the anti-inflammatory and analgesic bio-functions of CI5 depended on its interaction with the Rac-2 protein upstream of ERK1/2 and the inflammatory signaling pathway (ERK1/2/COX-2 axis). In summary, CI5, as a novel natural candidate identified from Cinobufacini injection, showed substantial clinical promise for inflammatory pain treatments.

Heterometallic Eu/Zn-MOF-based ratiometric sensing platform: Highly sensitive fluorescence / second-order scattering identification of tetracycline analogs and its molecular informatization applications.

The traditional preparation method of ratiometric probes faces challenges such as cumbersome preparation and low sensitivity. Thus, there is an urgent need to provide a simple method of preparing a highly sensitive ratiometric probe. Here, Eu3+-doped zinc-based organic framework (Eu/Zn-MOF) was prepared through hydrothermal method for the detection of tetracycline analogs (TCs). Under the same excitation conditions, the probe can simultaneously display valuable fluorescence and second-order scattering signals. The developed probe enabled specific identification and fast detection (1 min) of TCs, including tetracycline, oxytetracycline, doxycycline, and chlortetracycline. The linear detection ranges of tetracycline, oxytetracycline, doxycycline and chlortetracycline were respectively 100 nM - 200 µM, 100 nM - 200 µM, 98 nM - 195 µM, and 97 nM - 291 µM, and the corresponding detection limits were respectively 15.79 nM, 20.83 nM, 15.31 nM, and 28.30 nM. The developed sensor was successfully applied to detect TCs in real samples, and the recovery rate was from 92.54 % to 109.69 % and the relative standard deviation was from 0.04 % to 2.97 %. Moreover, the heterometallic Eu/Zn-MOF was designed as a ratiometric neuron for Boolean logic computing and information encryption based on the specific identification of TCs. As a proof of concept, molecular steganography was successfully employed to encode, store, and conceal information by transforming the specific identification patterns of Eu/Zn-MOF into binary strings. This study is anticipated to advance the application of metal-organic frameworks in logic detection and information security, and bridging the gap between molecular sensors and the realm of information.

Alendronate sodium induces G1 phase arrest and apoptosis in human umbilical vein endothelial cells by inhibiting ROS-mediated ERK1/2 signaling.

Bisphosphonates are potent bone resorption inhibitors, among which alendronate sodium (ALN) is commonly prescribed for most osteoporosis patients, but long-term application of ALN can cause bisphosphonate-related osteonecrosis of jaw (BRONJ), the pathogenesis of which remains unclear. Previous studies have suggested that bisphosphonates cause jaw ischemia by affecting the biological behavior of vascular endothelial cells, leading to BRONJ. However, the impacts of ALN on vascular endothelial cells and its mechanism remain unclear. The purpose of this work is to assess the influence of ALN on human umbilical vein endothelial cells (HUVECs) and clarify the molecular pathways involved. We found that high concentration of ALN induced G1 phase arrest in HUVECs, demonstrated by downregulation of Cyclin D1 and Cyclin D3. Moreover, high concentration of ALN treatment showed pro-apoptotic effect on HUVECs, demonstrated by increased levels of the cleaved caspase-3, the cleaved PARP and Bax, along with decreased levels of anti-apoptotic protein Bcl-2. Further experiments showed that ERK1/2 phosphorylation was decreased. Additionally, ALN provoked the build-up of reactive oxygen species (ROS) in HUVECs, leading to ERK1/2 pathway suppression. N-acetyl-L-cysteine (NAC), a ROS scavenger, efficiently promoted the ERK1/2 phosphorylation and mitigated the G1 phase arrest and apoptosis triggered by ALN in HUVECs. PD0325901, an inhibitor of ERK1/2 that diminishes the ERK1/2 phosphorylation enhanced the ALN-induced G1 phase arrest and apoptosis in HUVECs. These findings show that ALN induces G1 phase arrest and apoptosis through ROS-mediated ERK1/2 pathway inhibition in HUVECs, providing novel insights into the pathogenic process, prevention and treatment of BRONJ in individuals receiving extended use of ALN.

Electrosynthesis of Ammonia from Nitrate Using a Self-Activated Carbon Fiber Paper.

While electrochemically upcycling nitrate wastes to valuable ammonia is considered a very promising pathway for tackling the environmental and energy challenges underlying the nitrogen cycle, the effective catalysts involved are mainly limited to metal-based materials. Here, we report that commercial carbon fiber paper, which is a classical current collector and is typically assumed to be electrochemically inert, can be significantly activated during the reaction. As a result, it shows a high NH3 Faradaic efficiency of 87.39% at an industrial-level current density of 300 mA cm-2 for over 90 h of continuous operation, with a NH3 production rate of as high as 1.22 mmol cm-2 h-1. Through experimental and theoretical analysis, the in situ-formed oxygen functional groups are demonstrated to be responsible for the NO3RR performance. Among them, the C-O-C group is finally identified as the active center, which lowers the thermodynamic energy barrier and simultaneously improves the hydrogenation kinetics. Moreover, high-purity NH4Cl and NH3·H2O were obtained by coupling the NO3RR with an air-stripping approach, providing an effective way for converting nitrate waste into high-value-added NH3 products.

Targeting focal adhesion kinase (FAK) in cancer therapy: A recent update on inhibitors and PROTAC degraders.

Focal adhesion kinase (FAK) is considered as a pivotal intracellular non-receptor tyrosine kinase, and has garnered significant attention as a promising target for anticancer drug development. As of early 2024, a total of 12 drugs targeting FAK have been approved for clinical or preclinical studies worldwide, including three PROTAC degraders. In recent three years (2021-2023), significant progress has been made in designing targeted FAK anticancer agents, including the development of a novel benzenesulfofurazan type NO-releasing FAK inhibitor and the first-in-class dual-target inhibitors simultaneously targeting FAK and HDACs. Given the pivotal role of FAK in the discovery of anticancer drugs, as well as the notable advancements achieved in FAK inhibitors and PROTAC degraders in recent years, this review is underbaked to present a comprehensive overview of the function and structure of FAK. Additionally, the latest findings on the inhibitors and PROTAC degraders of FAK from the past three years, along with their optimization strategies and anticancer activities, were summarized, which might help to provide novel insights for the development of novel targeted FAK agents with promising anticancer potential and favorable pharmacological profiles.

Strategies that regulate Hippo signaling pathway for novel anticancer therapeutics.

As a highly conserved signaling network across different species, the Hippo pathway is involved in various biological processes. Dysregulation of the Hippo pathway could lead to a wide range of diseases, particularly cancers. Extensive researches have demonstrated the close association between dysregulated Hippo signaling and tumorigenesis as well as tumor progression. Consequently, targeting the Hippo pathway has emerged as a promising strategy for cancer treatment. In fact, there has been an increasing number of reports on small molecules that target the Hippo pathway, exhibiting therapeutic potential as anticancer agents. Importantly, some of Hippo signaling pathway inhibitors have been approved for the clinical trials. In this work, we try to provide an overview of the core components and signal transduction mechanisms of the Hippo signaling pathway. Furthermore, we also analyze the relationship between Hippo signaling pathway and cancers, as well as summarize the small molecules with proven anti-tumor effects in clinical trials or reported in literatures. Additionally, we discuss the anti-tumor potency and structure-activity relationship of the small molecule compounds, providing a valuable insight for further development of anticancer agents against this pathway.

Circadian rhythm disruption upregulating Per1 in mandibular condylar chondrocytes mediating temporomandibular joint osteoarthritis via GSK3ß/ß-CATENIN pathway.

BACKGROUND: Temporomandibular joint osteoarthritis (TMJOA) has a high incidence rate, but its pathogenesis remains unclear. Circadian rhythm is an important oscillation in the human body and influences various biological activities. However, it is still unclear whether circadian rhythm affects the onset and development of TMJOA. METHODS: We disrupted the normal rhythm of rats and examined the expression of core clock genes in the mandibular condylar cartilage of the jaw and histological changes in condyles. After isolating rat mandibular condylar chondrocytes, we upregulated or downregulated the clock gene Per1, examined the expression of cartilage matrix-degrading enzymes, tested the activation of the GSK3ß/ß-CATENIN pathway and verified it using agonists and inhibitors. Finally, after downregulating the expression of Per1 in the mandibular condylar cartilage of rats with jet lag, we examined the expression of cartilage matrix-degrading enzymes and histological changes in condyles. RESULTS: Jet lag led to TMJOA-like lesions in the rat mandibular condyles, and the expression of the clock gene Per1 and cartilage matrix-degrading enzymes increased in the condylar cartilage of rats. When Per1 was downregulated or upregulated in mandibular condylar chondrocytes, the GSK3ß/ß-CATENIN pathway was inhibited or activated, and the expression of cartilage matrix-degrading enzymes decreased or increased, which can be rescued by activator and inhibitor of the GSK3ß/ß-CATENIN pathway. Moreover, after down-regulation of Per1 in mandibular condylar cartilage in vivo, significant alleviation of cartilage degradation, cartilage loss, subchondral bone loss induced by jet lag, and inhibition of the GSK3ß/ß-CATENIN signaling pathway were observed. Circadian rhythm disruption can lead to TMJOA. The clock gene Per1 can promote the occurrence of TMJOA by activating the GSK3ß/ß-CATENIN pathway and promoting the expression of cartilage matrix-degrading enzymes. The clock gene Per1 is a target for the prevention and treatment of TMJOA.

Emamectin benzoate-induced toxicity affects intestinal epithelial integrity involving apoptosis.

The frequency presence of emamectin benzoate in agricultural production highlights the need for studying their toxicity against human intestinal epithelial barrier (IEB). Herein, we combined a Caco-2 cell model with transcriptome analysis to assess the intestinal toxicity of emamectin benzoate and its disease-causing potential. Results showed that the half maximal inhibitory concentration (IC50) of emamectin benzoate on Caco-2 cell viability after 24, 48, and 72 h of exposure were 18.1, 9.9, and 8.3 µM, respectively. Emamectin benzoate exposure enhanced the Caco-2 monolayer paracellular permeability, damaged the IEB, and increased cellular apoptosis. Key driver gene analysis of 42 apoptosis - related DEGs, identified 10 genes (XIAP, KRAS, MCL1, NRAS, PIK3CA, CYCS, MAPK8, CASP3, FADD, and TNFRSF10B) with the strongest correlation with emamectin benzoate - induced apoptosis. Transcriptomics identified 326 differentially expressed genes (DEGs, 204 upregulated and 122 downregulated). The functional terms of neurodegeneration - multiple diseases was enriched with the most number of DEGs, and the Parkinson disease pathway had the highest enrichment degree. Our findings provided support for environmental toxicology studies and the health risk assessment of emamectin benzoate.

Clinical study of the prognostic value of the Essen score for acute cerebral infarction.

OBJECTIVE: A few clinical studies have been conducted on the prognostic value of the Essen score in acute cerebral infarction (ACI), and this study explores whether the Essen score can assess the prognosis of ACI. METHODS: Data were collected from 1176 patients with ACI. The patients were divided into three groups on the basis of the Essen score, with groups 1, 2 and 3 having scores of 0-2, 3-6 and 7-9, respectively. Logistic multivariate analysis was performed to analyse the predictors of poor prognosis in patients with ACI. The X2 trend test was used to compare the poor-prognosis groups on the basis of the Essen score. The receiver operating characteristic (ROC) curve of patient prognosis was plotted using MedCalc software, and the area under the ROC curve (AUC) was calculated. P < 0.05 was considered statistically significant. RESULTS: Multivariate analysis of the good- and poor-prognosis groups of ACI showed that the Essen score and the male gender were predictors of poor prognosis. The X2 trend test was used to compare the poor-prognosis groups on the basis of the Essen score, and results suggested that the higher the Essen score was, the worse the prognosis was. The Essen score assessed the prognosis of ACI with an AUC of 0.787 and P < 0.001. CONCLUSION: The Essen score is a valuable scoring system for predicting the prognosis of patients with ACI.

Corrosion Behavior and Mechanical Property of 5182 Aluminum/DP780 Steel Resistance Spot Welding Joints.

Corrosion behavior is critical to the application of lightweight aluminum/steel joints using new resistance spot welding (RSW) technology. The study investigated the corrosion mechanism and the shear strength of RSW joints comprising 1.2 mm 5182 aluminum and 1.5 mm DP780 galvanized steel. Electrochemical corrosion tests were conducted on the base materials and various positions of the welds in a 3.5% NaCl solution. This result revealed that the corrosion susceptibility of the interfacial intermetallic compound (IMC) layer was not accelerated by the aluminum nugget because of the noble corrosion potential. Subsequently, the spray acceleration test was employed to investigate the corrosion mechanism. It is noteworthy that microcracks, as well as regions enriched with silicon and oxygen at the interface front, are preferential to corrosion during salt spray exposure, instead of the IMC layer. Moreover, the shear strength of the joints decreases with the reduction in the effective joint area after the salt spray exposure of the weld joints. This research systematically explored the corrosion behavior and its relationship with the mechanical properties of Al alloy/steel RSW joints.

Electrospun radially oriented berberine-PHBV nanofiber dressing patches for accelerating diabetic wound healing.

A dressing patch made of radially oriented poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanofibers was successfully manufactured with a modified electrospinning strategy. The as-electrospun PHBV radially oriented nanofiber dressing patch exhibited uniform and bead-free nanofibrous morphology and innovative radially oriented arrangement, which was demonstrated to possess obviously improved mechanical property, increased surface hydrophilicity and enhanced biological properties compared to the PHBV nanofiber dressing patch control with traditionally randomly oriented pattern. Interestingly, it was found that the radially oriented pattern could induce the cell migration from the periphery to the center along the radially oriented nanofibers in a rapid manner. To further improve the biofunction of PHBV radially oriented nanofiber dressing patch, berberine (Beri, an isoquinoline alkaloid) with two different concentrations were encapsulated into PHBV nanofibers during electrospinning, which were found to present a sustained drug release behavior for nearly one month. Importantly, the addition of Beri could impart the dressing patch with excellent anti-inflammatory property by significantly inhibiting the secretion of pro-inflammatory factors of M1 macrophages, and also showed an additive influence on promoting the proliferation of human dermal fibroblasts (HDFs), as well as inhibiting the growth of E. coli, S. aureus and C. albicans, compared with the Beri-free dressing patch. In the animal studies, the electrospun PHBV radially oriented nanofiber dressing patch loading with high Beri content was found to obviously accelerate the healing process of diabetic mouse full-thickness skin wound with shortened healing time (100% wound closure rate after 18 days' treatment) and improved healing quality (improved collagen deposition, enhanced re-epithelialization and neovascularization and increased hair follicles). In all, this study reported an innovative therapeutic strategy integrating the excellent physical cues of electrospun PHBV radially oriented nanofiber dressing patch with the multiple biological cues of Beri for the effective treatment of hard-to-heal diabetic wounds.

Remediation effect of walnut shell biochar on Cu and Pb co-contaminated soils in different utilization types.

Biochar, with its dual roles of soil remediation and carbon sequestration, is gradually demonstrating great potential for sustainability in agricultural and ecological aspects. In this study, a porous biochar derived from walnut shell wastes was prepared via a facile pyrolysis coupling with in-situ alkali etching method. An incubation study was conducted to investigate its performance in stabilizing copper (Cu) and lead (Pb) co-contaminated soils under different utilization types. The biochar effectively decreased the bioavailable Cu (8.5-91.68%) and Pb (5.03-88.54%), while increasing the pH, CEC, and SOM contents in both soils. Additionally, the results of sequential extraction confirmed that biochar promoted the transformation of the labile fraction of Cu and Pb to stable fractions. The mechanisms of Cu and Pb stabilization were found to be greatly dependent on the soil types. For tea plantation yellow soil, the main approach for stabilization was the complexation of heavy metals with abundant organic functional groups and deprotonation structure. Surface electrostatic adsorption and cation exchange contributed to the immobilization of Cu and Pb in vegetable-cultivated purple soil. This research provides valuable information for the stabilization of Cu and Pb co-contaminated soils for different utilization types using environmentally-friendly biochar.

G protein subunit Gγ13-mediated signaling pathway is critical to the inflammation resolution and functional recovery of severely injured lungs.

Tuft cells are a group of rare epithelial cells that can detect pathogenic microbes and parasites. Many of these cells express signaling proteins initially found in taste buds. It is, however, not well understood how these taste signaling proteins contribute to the response to the invading pathogens or to the recovery of injured tissues. In this study, we conditionally nullified the signaling G protein subunit Gγ13 and found that the number of ectopic tuft cells in the injured lung was reduced following the infection of the influenza virus H1N1. Furthermore, the infected mutant mice exhibited significantly larger areas of lung injury, increased macrophage infiltration, severer pulmonary epithelial leakage, augmented pyroptosis and cell death, greater bodyweight loss, slower recovery, worsened fibrosis and increased fatality. Our data demonstrate that the Gγ13-mediated signal transduction pathway is critical to tuft cells-mediated inflammation resolution and functional repair of the damaged lungs.To our best knowledge, it is the first report indicating subtype-specific contributions of tuft cells to the resolution and recovery.

Diagnostic value of carbohydrate antigen 50 in biliary tract cancer: A large-scale multicenter study.

BACKGROUND: To date, carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) have been widely used for the screening, diagnosis and prediction of biliary tract cancer (BTC) patients. However, few studies with large sample sizes of carbohydrate antigen 50 (CA50) were reported in BTC patients. METHODS: A total of 1121 patients from the Liver Cancer Clin-Bio Databank of Anhui Hepatobiliary Surgery Union between January 2017 and December 2022 were included in this study (673 in the training cohort and 448 in the validation cohort): among them, 458 with BTC, 178 with hepatocellular carcinoma (HCC), 23 with combined hepatocellular-cholangiocarcinoma, and 462 with nontumor patients. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the diagnostic efficacy and clinical usefulness. RESULTS: ROC curves obtained by combining CA50, CA19-9, and AFP showed that the AUC value of the diagnostic MODEL 1 was 0.885 (95% CI 0.856-0.885, specificity 70.3%, and sensitivity 84.0%) in the training cohort and 0.879 (0.841-0.917, 76.7%, and 84.3%) in the validation cohort. In addition, comparing iCCA and HCC (235 in the training cohort, 157 in the validation cohort), the AUC values of the diagnostic MODEL 2 were 0.893 (95% CI 0.853-0.933, specificity 96%, and sensitivity 68.6%) in the training cohort and 0.872 (95% CI 0.818-0.927, 94.2%, and 64.6%) in the validation cohort. CONCLUSION: The model combining CA50, CA19-9, and AFP not only has good diagnostic value for BTC but also has good diagnostic value for distinguishing iCCA and HCC.

Machine learning is an effective method to predict the 3-month prognosis of patients with acute ischemic stroke.

Background and objectives: Upwards of 50% of acute ischemic stroke (AIS) survivors endure varying degrees of disability, with a recurrence rate of 17.7%. Thus, the prediction of outcomes in AIS may be useful for treatment decisions. This study aimed to determine the applicability of a machine learning approach for forecasting early outcomes in AIS patients. Methods: A total of 659 patients with new-onset AIS admitted to the Department of Neurology of both the First and Second Affiliated Hospitals of Bengbu Medical University from January 2020 to October 2022 included in the study. The patient' demographic information, medical history, Trial of Org 10,172 in Acute Stroke Treatment (TOAST), National Institute of Health Stroke Scale (NIHSS) and laboratory indicators at 24 h of admission data were collected. The Modified Rankine Scale (mRS) was used to assess the 3-mouth outcome of participants' prognosis. We constructed nine machine learning models based on 18 parameters and compared their accuracies for outcome variables. Results: Feature selection through the Least Absolute Shrinkage and Selection Operator cross-validation (Lasso CV) method identified the most critical predictors for early prognosis in AIS patients as white blood cell (WBC), homocysteine (HCY), D-Dimer, baseline NIHSS, fibrinogen degradation product (FDP), and glucose (GLU). Among the nine machine learning models evaluated, the Random Forest model exhibited superior performance in the test set, achieving an Area Under the Curve (AUC) of 0.852, an accuracy rate of 0.818, a sensitivity of 0.654, a specificity of 0.945, and a recall rate of 0.900. Conclusion: These findings indicate that RF models utilizing general clinical and laboratory data from the initial 24 h of admission can effectively predict the early prognosis of AIS patients.

Effects of improved amino acid balance diet on lysine mammary utilization, whole body protein turnover and muscle protein breakdown on lactating sows.

BACKGROUND: The study objective was to test the hypothesis that low crude protein (CP) diet with crystalline amino acids (CAA) supplementation improves Lys utilization efficiency for milk production and reduces protein turnover and muscle protein breakdown. Eighteen lactating multiparous Yorkshire sows were allotted to 1 of 2 isocaloric diets (10.80 MJ/kg net energy): control (CON; 19.24% CP) and reduced CP with "optimal" AA profile (OPT; 14.00% CP). Sow body weight and backfat were recorded on d 1 and 21 of lactation and piglets were weighed on d 1, 14, 18, and 21 of lactation. Between d 14 and 18, a subset of 9 sows (CON = 4, OPT = 5) was infused with a mixed solution of 3-[methyl-2H3]histidine (bolus injection) and [13C]bicarbonate (priming dose) first, then a constant 2-h [13C]bicarbonate infusion followed by a 6-h primed constant [1-13C]lysine infusion. Serial blood and milk sampling were performed to determine plasma and milk Lys enrichment, Lys oxidation rate, whole body protein turnover, and muscle protein breakdown. RESULTS: Over the 21-d lactation period, compared to CON, sows fed OPT had greater litter growth rate (P < 0.05). Compared to CON, sows fed OPT had greater efficiency of Lys (P < 0.05), Lys mammary flux (P < 0.01) and whole-body protein turnover efficiency (P < 0.05). Compared to CON, sows fed OPT tended to have lower whole body protein breakdown rate (P = 0.069). Muscle protein breakdown rate did not differ between OPT and CON (P = 0.197). CONCLUSION: Feeding an improved AA balance diet increased efficiency of Lys and reduced whole-body protein turnover and protein breakdown. These results imply that the lower maternal N retention observed in lactating sows fed improved AA balance diets in previous studies may be a result of greater partitioning of AA towards milk rather than greater body protein breakdown.

C(sp)-C(sp) Lever-Based Targets of Orientational Chirality: Design and Asymmetric Synthesis.

In this study, the design and asymmetric synthesis of a series of chiral targets of orientational chirality were conducted by taking advantage of N-sulfinylimine-assisted nucleophilic addition and modified Sonogashira catalytic coupling systems. Orientational isomers were controlled completely using alkynyl/alkynyl levers [C(sp)-C(sp) axis] with absolute configuration assignment determined by X-ray structural analysis. The key structural element of the resulting orientational chirality is uniquely characterized by remote through-space blocking. Forty examples of multi-step synthesis were performed, with modest to good yields and excellent orientational selectivity. Several chiral orientational amino targets are attached with scaffolds of natural and medicinal products, showing potential pharmaceutical and medical applications in the future.

Optimization Design of CMUT Sensors with Broadband and High Sensitivity Characteristics Based on the Genetic Algorithm.

In this study, we propose a method for optimizing the design of CMUT sensors using genetic algorithms. Existing CMUT sensors face frequency response and sensitivity limitations, necessitating optimization to enhance their sensing performance. Traditional optimization methods are often intricate and time-consuming and may fail to yield the optimal solution. Genetic algorithms, which simulate the biological evolution process, offer advantages in global optimization and efficiency, making them widely utilized in the optimization design of Microelectromechanical Systems (MEMS) devices. Based on the theoretical framework and finite element model of CMUT sensors, we propose a CMUT array element optimization design method based on genetic algorithms. The optimization and validation results demonstrate that we have successfully designed a broadband CMUT array element consisting of four microelements with a 1-2 MHz frequency range. Compared with a randomly arranged array element, the optimized array shows a 63.9% increase in bandwidth and a 7.5% increase in average sensitivity within the passband. Moreover, the sensitivity variance within the passband is reduced by 50.2%. Our proposed method effectively optimizes the design of high sensitivity CMUT sensors with the desired bandwidth, thereby offering significant reference value for the optimization design of CMUT sensors.