Megalin-targeted acetylcysteine polymeric prodrug ameliorates ischemia-reperfusion-induced acute kidney injury.

Acute kidney injury (AKI), a condition associated with reactive oxygen species (ROS), causes high mortality in clinics annually. Active targeted antioxidative therapy is emerging as a novel strategy for AKI treatment. In this study, we developed a polymeric prodrug that targets the highly expressed Megalin receptor on proximal tubule cells, enabling direct delivery of N-Acetylcysteine (NAC) for the treatment of ischemia reperfusion injury (IRI)-induced AKI. We conjugated NAC with low molecular weight chitosan (LMWC), a biocompatible and biodegradable polymer consisting of glucosamine and N-acetylglucosamine, to enhance its internalization by tubular epithelial cells. Moreover, we further conjugated triphenylphosphonium (TPP), a lipophilic cation with a delocalized positive charge, to low molecular weight chitosan-NAC in order to enhance the distribution of NAC in mitochondria. Our study confirmed that triphenylphosphonium-low molecular weight chitosan-NAC (TLN) exhibits remarkable therapeutic effects on IRI-AKI mice. This was evidenced by improvements in renal function, reduction in oxidative stress, mitigation of pathological progress, and decreased levels of kidney injury molecule-1. These findings suggested that the polymeric prodrug TLN holds promising potential for IRI-AKI treatment.

CDK12-inactivation-induced MYC signaling causes dependency on the splicing kinase SRPK1.

Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes an aggressive sub-group of castration-resistant prostate cancer (CRPC). Hyper-activation of MYC transcription factor is sufficient to confer the CRPC phenotype. Here, we show that loss of CDK12 promotes MYC activity, which renders the cells dependent on the otherwise non-essential splicing regulatory kinase SRSF protein kinase 1 (SRPK1). High MYC expression is associated with increased levels of SRPK1 in patient samples, and overexpression of MYC sensitizes prostate cancer cells to SRPK1 inhibition using pharmacological and genetic strategies. We show that Endovion (SCO-101), a compound currently in clinical trials against pancreatic cancer, phenocopies the effects of the well-characterized SRPK1 inhibitor SRPIN340 on nascent transcription. This is the first study to show that Endovion is an SRPK1 inhibitor. Inhibition of SRPK1 with either of the compounds promotes transcription elongation, and transcriptionally activates the unfolded protein response. In brief, here we discover that CDK12 inactivation promotes MYC signaling in an SRPK1-dependent manner, and show that the clinical grade compound Endovion selectively targets the cells with CDK12 inactivation.

Production of cleavage-resistant phytase transgenic pigs by handmade cloning.

With the rapid development of intensive animal husbandry in the livestock industry, large quantities of manure waste containing phytate phosphorus are being generated. Phytase can effectively solve the problem of high phosphorus pollution in the feces of monogastric animals. Enviropig, which produces phytase in the salivary glands and secretes the enzyme in the saliva, were first generated in 1999. However, phytase is easily inactivated during digestion. To address this problem, cleavage-resistant phytase transgenic pigs were generated using handmade cloning in this study. Transgene construction was improved and three cell lines carrying Cafp were obtained. In total, 810 blastocysts were generated and 712 good-quality were transferred into six recipients. Fourteen piglets were born, of which six survived after weaning. Polymerase chain reaction and sequencing results showed that seven (three live and four dead) of the fourteen piglets carried Cafp. Phytase activity in the saliva of the six live cloned pigs was tested at four months of age, and only one pig had 0.155 FTU/mL enzyme activity. The other five pigs may not have been activated in the transgenic parotid gland. Among all the transgenic pigs, the highest phosphorus digestion rate was 59.2% of intake, representing a 25.4% decrease in fecal emission compared to the average of controls. Immunohistochemical results on the three Cafp-positive pigs that died after six months of age showed that the transgene was only expressed in parotid glands, confirming tissue-specific gene expression. In conclusion, cleavage-resistant phytase transgenic pigs were successfully produced through handmade cloning. The cloned pigs offer a unique biological approach to managing phosphorus nutrition and environmental pollution in animal husbandry.

Expression of 10 circulating cytokines/chemokines in HBV-related liver disease.

BACKGROUND: Cytokines/chemokines play essential roles in the occurrence and progression of hepatitis B virus (HBV) infection. This study aimed to observe the expression patterns of 10 related cytokines/chemokines in the serum of healthy individuals, self-limited patients and HBV-infected patients at different stages of disease (chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular dysplastic nodules (DNs) and hepatocellular carcinoma (HCC)) and to analyze the relationships of these cytokines/chemokines with disease progression. METHODS: The levels of six cytokines (FGF-2, IFN-α2, IL-4, IL-6, IL-10 and VEGF-A) and four chemokines (GRO-α, IL-8, IP-10 and MCP-1) were quantified using Luminex multiplex technology. RESULTS: There were no significant differences in the expression of the 10 cytokines/chemokines between healthy individuals and self-limited patients. The levels of IL-4, IL-6, and IL-8 increased significantly in the CHB and LC groups. IL-10 was highly expressed in the HCC group. The level of IP-10 was significantly greater in all liver disease groups (CHB, LC, DN and HCC) than in the HI and SL-HBV groups, while the level of GRO was significantly lower in all liver disease groups than in the HI and SL-HBV groups. The levels of the 10 cytokines/chemokines were not significantly different between the preoperative group and the two-day postoperative group. Significant increases in the levels of IL-4, VEGF-A and IL-8 and significant decreases in those of IL-10 and GRO-α were observed 3 months after surgery. Correlation analysis revealed that most of the cytokines/chemokines with significant correlation differences were positively correlated before and after HCC surgery. CONCLUSION: Our results highlight the fluctuating status of specific cytokines in HBV infection-related disease progression. It is speculated that these cytokines may be used as serum markers to monitor dynamic changes during the progression of HBV-related liver disease and to predict patient prognosis.

Surface-phonon-polariton-enhanced photoinduced dipole force for nanoscale infrared imaging.

The photoinduced dipole force (PiDF) is an attractive force arising from the Coulombic interaction between the light-induced dipoles on the illuminated tip and the sample. It shows extreme sample-tip distance and refractive index dependence, which is promising for nanoscale infrared (IR) imaging of ultrathin samples. However, the existence of PiDF in the mid-IR region has not been experimentally demonstrated due to the coexistence of photoinduced thermal force (PiTF), typically one to two orders of magnitude higher than PiDF. In this study, we demonstrate that, with the assistance of surface phonon polaritons, the PiDF of c-quartz can be enhanced to surpass its PiTF, enabling a clear observation of PiDF spectra reflecting the properties of the real part of permittivity. Leveraging the detection of the PiDF of phonon polaritonic substrate, we propose a strategy to enhance the sensitivity and contrast of photoinduced force responses in transmission images, facilitating the precise differentiation of the heterogeneous distribution of ultrathin samples.

The Regulation of Selenoproteins in Diabetes: A New Way to Treat Diabetes.

Selenium is an essential micronutrient required for the synthesis and function of selenoproteins, most of which are enzymes involved in maintaining oxidative balance in the body. Diabetes is a group of metabolic disorders characterized by high blood glucose levels over a prolonged period of time. There are three main types of diabetes: type 1, type 2, and gestational diabetes. This review summarizes recent advances in the field of diabetes research with an emphasis on the roles of selenoproteins on metabolic disturbance in diabetes. We also discuss the interaction between selenoproteins and glucose and lipid metabolism to provide new insights into the prevention and treatment of diabetes.

A filtering reconfigurable intelligent surface for interference-free wireless communications.

The powerful capability of reconfigurable intelligent surfaces (RISs) in tailoring electromagnetic waves and fields has put them under the spotlight in wireless communications. However, the current designs are criticized due to their poor frequency selectivity, which hinders their applications in real-world scenarios where the spectrum is becoming increasingly congested. Here we propose a filtering RIS to feature sharp frequency-selecting and 2-bit phase-shifting properties. It permits the signals in a narrow bandwidth to transmit but rejects the out-of-band ones; meanwhile, the phase of the transmitted signals can be digitally controlled, enabling flexible manipulations of signal propagations. A prototype is designed, fabricated, and measured, and its high quality factor and phase-shifting characteristics are validated by scattering parameters and beam-steering phenomena. Further, we conduct a wireless communication experiment to illustrate the intriguing functions of the RIS. The filtering behavior enables the RIS to perform wireless signal manipulations with anti-interference ability, thus showing big potential to advance the development of next-generation wireless communications.

Is Chinese Medicine Facing a Potential Workforce Crisis in Australia? Demographic Changes in the Profession over the Last Decade.

Background: As a prominent part of complementary and alternative medicine, Chinese Medicine (CM) has proved its strengths in treating a diverse range of acute and chronic medical conditions and is at present recognized in 196 countries and territories worldwide. In 2012, Australia regulated the CM profession under the National Regulation and Accreditation Scheme (NRAS) by legislation and reports quarterly demographic information about individual CM practitioners so to ensure public interest, although research examining the change of CM workforce in Australia has been scarce. Objective: This study aims to investigate the construction of the CM workforce in Australia and more importantly, evaluated its development in the last decade to capture the trajectory and trend in the present period and future potential changes. Methods: Data were sourced from the Australian Health Practitioner Regulation Agency (AHPRA) annual reports and the Chinese Medicine Board of Australia (CMBA) registration statistics from 2012 to 2023. A descriptive analysis was conducted with demographic variables, including profession, age, and gender, and chi-square tests and linear regression modeling were carried out to assess the variations between regions and across years. Results: The population of CM practitioners in 2022/2023 stagnated with slight decrease to 4,823, in contrast to the increase rate of 2.9% in the whole health care community. The number of young CM registrants (<35 y) shrank by 37.5% from 691 in 2012 to 432 in 2023. In comparison with other health care professions, CM comprises the smallest proportion of the population aged younger than 25 (0.2%) and the largest proportion aged older than 65 years (16.2%), advancing into an aging era. Conclusions: This study indicates a worrying potential decline in CM workforce in Australia, which is likely to be further exacerbated by the lack of new graduates and rise of median age among practitioners. Meanwhile, continued advancement in Western medicine technology and standards requires substantial efforts to increase both a better understanding of CM and demonstration of its efficacy. Furthermore, greater effort is needed to recruit and educate new young CM practitioners in Australia and to broaden the international training pipeline for a sustainable development of CM practice.

Development of natural perfume as potential fungicide candidates: construction and biological evaluation of vanillin analogs bearing the 1,3,4-oxadiazole/1,3-thiazolidin-4-one fragments.

Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 µg/ml) and 7a (38.15 µg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani. The inhibitory activity of compound 7d (10.53 µg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 µg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k, 7a, and 7d showed good selectivity and less toxicity to normal mammalian cells.

Enhanced biodegradation of phenol under Cr(VI) stress by microbial collaboration and potential application of machine learning for phenol biodegradation.

Cr(VI) and phenol commonly coexist in wastewater, posing a great threat to the environment and human health. However, it is still a challenge for microorganisms to degrade phenol under high Cr(VI) stress. In this study, the phenol-degrading strain Bacillus cereus ZWB3 was co-cultured with the Cr(VI)-reducing strain Bacillus licheniformis MZ-1 to enhance phenol biodegradation under Cr(Ⅵ) stress. Compared with phenol-degrading strain ZWB3, which has weak tolerance to Cr(Ⅵ), and Cr(Ⅵ)-reducing strain MZ-1, which has no phenol-degrading ability, the co-culture of two strains could significantly increase the degraded rate and capacity of phenol. In addition, the co-cultured strains exhibited phenol degradation ability over a wide pH range (7-10). The reduced content of intracellular proteins and polysaccharides produced by the co-cultured strains contributed to the enhancement of phenol degradation and Cr(Ⅵ) tolerance. The determination coefficients R2, RMSE, and MAPE showed that the BP-ANN model could predict the degradation of phenol under various conditions, which saved time and economic cost. The metabolic pathway of microbial degradation of phenol was deduced by metabolic analysis. This study provides a valuable strategy for wastewater treatment containing Cr(Ⅵ) and phenol.

Optical design of low-location illumination based on asymmetric double freeform surfaces.

The development of optical optics for low-location road lighting is a challenging problem in providing high luminance and uniformity of illumination and meeting many other specific requirements. This study proposes an optical design method of low-location illumination based on an asymmetric double freeform surface lens. The ray emitted from the light source is refracted and reflected through the different surface types to the corresponding area of the receiving surface. In the design example, the road has dual-side mounted luminaires and a width of 6 m, and a height of 0.8 m. Simulation results indicate that, compared with conventional high-pole streetlights, the luminance uniformity had increased from 0.60 to 0.66, the illuminance uniformity had improved from 0.75 to 0.86, and the glare had been reduced.

Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer's mouse model.

Physical exercise represents a primary defense against age-related cognitive decline and neurodegenerative disorders like Alzheimer's disease (AD). To impartially investigate the underlying mechanisms, we conducted single-nucleus transcriptomic and chromatin accessibility analyses (snRNA-seq and ATAC-seq) on the hippocampus of mice carrying AD-linked NL-G-F mutations in the amyloid precursor protein gene (APPNL-G-F) following prolonged voluntary wheel-running exercise. Our study reveals that exercise mitigates amyloid-induced changes in both transcriptomic expression and chromatin accessibility through cell type-specific transcriptional regulatory networks. These networks converge on the activation of growth factor signaling pathways, particularly the epidermal growth factor receptor (EGFR) and insulin signaling, correlating with an increased proportion of immature dentate granule cells and oligodendrocytes. Notably, the beneficial effects of exercise on neurocognitive functions can be blocked by pharmacological inhibition of EGFR and the downstream phosphoinositide 3-kinases (PI3K). Furthermore, exercise leads to elevated levels of heparin-binding EGF (HB-EGF) in the blood, and intranasal administration of HB-EGF enhances memory function in sedentary APPNL-G-F mice. These findings offer a panoramic delineation of cell type-specific hippocampal transcriptional networks activated by exercise and suggest EGF-related growth factor signaling as a druggable contributor to exercise-induced memory enhancement, thereby suggesting therapeutic avenues for combatting AD-related cognitive decline.

Skip connection information enhancement network for retinal vessel segmentation.

Many major diseases of the retina often show symptoms of lesions in the fundus of the eye. The extraction of blood vessels from retinal fundus images is essential to assist doctors. Some of the existing methods do not fully extract the detailed features of retinal images or lose some information, making it difficult to accurately segment capillaries located at the edges of the images. In this paper, we propose a multi-scale retinal vessel segmentation network (SCIE_Net) based on skip connection information enhancement. Firstly, the network processes retinal images at multiple scales to achieve network capture of features at different scales. Secondly, the feature aggregation module is proposed to aggregate the rich information of the shallow network. Further, the skip connection information enhancement module is proposed to take into account the detailed features of the shallow layer and the advanced features of the deeper network to avoid the problem of incomplete information interaction between the layers of the network. Finally, SCIE_Net achieves better vessel segmentation performance and results on the publicly available retinal image standard datasets DRIVE, CHASE_DB1, and STARE.

miR-423-5p Regulates Skeletal Muscle Growth and Development by Negatively Inhibiting Target Gene SRF.

The process of muscle growth directly affects the yield and quality of pork food products. Muscle fibers are created during the embryonic stage, grow following birth, and regenerate during adulthood; these are all considered to be phases of muscle development. A multilevel network of transcriptional, post-transcriptional, and pathway levels controls this process. An integrated toolbox of genetics and genomics as well as the use of genomics techniques has been used in the past to attempt to understand the molecular processes behind skeletal muscle growth and development in pigs under divergent selection processes. A class of endogenous noncoding RNAs have a major regulatory function in myogenesis. But the precise function of miRNA-423-5p in muscle development and the related molecular pathways remain largely unknown. Using target prediction software, initially, the potential target genes of miR-423-5p in the Guangxi Bama miniature pig line were identified using various selection criteria for skeletal muscle growth and development. The serum response factor (SRF) was found to be one of the potential target genes, and the two are negatively correlated, suggesting that there may be targeted interactions. In addition to being strongly expressed in swine skeletal muscle, miR-423-5p was also up-regulated during C2C12 cell development. Furthermore, real-time PCR analysis showed that the overexpression of miR-423-5p significantly reduced the expression of myogenin and the myogenic differentiation antigen (p < 0.05). Moreover, the results of the enzyme-linked immunosorbent assay (ELISA) demonstrated that the overexpression of miR-423-5p led to a significant reduction in SRF expression (p < 0.05). Furthermore, miR-423-5p down-regulated the luciferase activities of report vectors carrying the 3' UTR of porcine SRF, confirming that SRF is a target gene of miR-423-5p. Taken together, miR-423-5p's involvement in skeletal muscle differentiation may be through the regulation of SRF.

PPARγ Antagonists Exhibit Antitumor Effects by Regulating Ferroptosis and Disulfidptosis.

Oral squamous cell carcinoma (OSCC) stands as a prevalent subtype of head and neck squamous cell carcinoma, leading to disease recurrence and low survival rates. PPARγ, a ligand-dependent nuclear transcription factor, holds significance in tumor development. However, the role of PPARγ in the development of OSCC has not been fully elucidated. Through transcriptome sequencing analysis, we discovered a notable enrichment of ferroptosis-related molecules upon treatment with PPARγ antagonist. We subsequently confirmed the occurrence of ferroptosis through transmission electron microscopy, iron detection, etc. Notably, ferroptosis inhibitors could not completely rescue the cell death caused by PPARγ inhibitors, and the rescue effect was the greatest when disulfidptosis and ferroptosis inhibitors coexisted. We confirmed that the disulfidptosis phenotype indeed existed. Mechanistically, through qPCR and Western blotting, we observed that the inhibition of PPARγ resulted in the upregulation of heme oxygenase 1 (HMOX1), thereby promoting ferroptosis, while solute carrier family 7 member 11 (SLC7A11) was also upregulated to promote disulfidptosis in OSCC. Finally, a flow cytometry analysis of flight and multiplex immunohistochemical staining was used to characterize the immune status of PPARγ antagonist-treated OSCC tissues in a mouse tongue orthotopic transplantation tumor model, and the results showed that the inhibition of PPARγ led to ferroptosis and disulfidptosis, promoted the aggregation of cDCs and CD8+ T cells, and inhibited the progression of OSCC. Overall, our findings reveal that PPARγ plays a key role in regulating cell death in OSCC and that targeting PPARγ may be a potential therapeutic approach for OSCC.

Efficient photodegradation of antibiotics by g-C3N4 and 3D flower-like Bi2WO6 perovskite structure: Insights into the preparation, evaluation, and potential mechanism.

Antibiotics are emerging organic pollutants that have attracted huge attention owing to their abundant use and associated ecological threats. The aim of this study is to develop and use photocatalysts to degrade antibiotics, including tetracycline (TC), ciprofloxacin (CIP), and amoxicillin (AMOX). Therefore, a novel Z-scheme heterojunction composite of g-C3N4 (gCN) and 3D flower-like Bi2WO6 (BW) perovskite structure was designed and developed, namely Bi2WO6/g-C3N4 (BW/gCN), which can degrade low-concentration of antibiotics in aquatic environments under visible light. According to the Density Functional Theory (DFT) calculation and the characterization results of X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FITR), Scanning electron microscopy - energy spectroscopy (SEM-EDS) and X-ray photoelectron spectroscopy (XPS), this heterojunction was formed in the recombination process. Furthermore, the results of 15 wt%-BW/gCN photocatalytic experiments showed that the photodegradation rates (Rp) of TC, CIP, and AMOX were 92.4%, 90.1% and 82.3%, respectively, with good stability in three-cycle photocatalytic experiments. Finally, the quenching experiment of free radicals showed that the holes (h+) and superoxide radicals (·O2-) play a more important role than the hydroxyl radicals (·OH) in photocatalysis. In addition, a possible antibiotic degradation pathway was hypothesized on the basis of High performance liquid chromatography (HPLC) analysis. In general, we have developed an effective catalyst for photocatalytic degradation of antibiotic pollutants and analyzed its photocatalytic degradation mechanism, which provides new ideas for follow-up research and expands its application in the field of antibiotic composite pollution prevention and control.

Compare the Quadriceps Activity between Mini-Midvastus and Mini-Medial Parapatellar Approach in Total Knee Arthroplasty with Electromyography.

Background: The comparison between the mini-midvastus (mini-MV) and mini-parapatellar (mini-MPP) approach in total knee arthroplasty (TKA) remains a subject of debate. The present study compared quadriceps activation, pain levels, and clinical outcomes between the two approaches; quadricep activation was assessed using surface electromyography (sEMG). Methods: This retrospective cross-sectional study comprised a total of 78 patients aged between 50 and 85 years with primary osteoarthritis. Patients were divided into a mini-MV (n = 38) group and a mini-MPP (n = 40) group according to the surgical approach. Results: The two groups exhibited no significant differences in sEMG for the vastus medialis (VM) or rectus femoris (RF) at the follow-up time points, with the exception that the mini-MV group exhibited superior strength of RF during extensions at the 2-week follow-up. However, the mini-MPP group had superior Western Ontario and McMaster Universities Index (WOMAC) total and function scores at the 2- and 6-week follow-ups. The mini-MPP group also had superior WOMAC stiffness scores at the 2-week follow-up. The two groups did not differ significantly in terms of pain levels or morphine consumption. Conclusions: The sEMG data of quadriceps muscle would not differ significantly between the mini-MV and mini-MPP approaches for TKA. Moreover, the mini-MPP approach may yield superior WOMAC scores when compared with the mini-MV approach.

Association between NUDT17 polymorphisms and breast cancer risk.

BACKGROUND: Breast cancer (BC) is the leading cause of cancer death among women worldwide. The nudix hydrolase 17 (NUDT17) may play notable roles in cancer growth and metastasis. In this study, we explored the importance of NUDT17 gene polymorphism in patients with BC. METHODS: In our study, 563 BC patients and 552 healthy controls participated. We used logistic regression analysis to calculate odds ratios (OR) and 95% confidence intervals (CI), and multifactor dimension reduction (MDR) analysis of SNP-SNP interactions. Finally, UALCAN and THPA databases were used for bioinformatics analysis. RESULTS: The rs9286836 G allele was associated with a decreased the BC risk (p = 0.022), and the carriers of rs2004659 G allele had a 32% decreased risk of BC than individuals with allele A (p = 0.004). In the four genetic models, rs9286836 and rs2004659 reduced the risk of BC. Additionally, we found that the NUDT17 SNPs were associated with BC risk under age, tumor size, and clinical stage stratification. The MDR analysis showed that the five-locus interaction model was the best in the multi-locus model. CONCLUSION: Our study found that NUDT17 single nucleotide polymorphisms are associated with BC susceptibility in Chinese Han population.

Causal relationships between gut microbiota and lymphoma: a bidirectional Mendelian randomization study.

Background: Multiple studies have suggested a possible connection between the gut microbiota and the development of lymphoma, though the exact nature of this relationship remains unclear. This study aimed to explore whether a causal association exists between gut microbiota and lymphoma. Methods: A bidirectional two-sample Mendelian randomization (MR) approach was conducted to investigate potential causal effects between gut microbiota and various lymphoma subtypes. The primary method employed for MR analysis was inverse variance weighted (IVW), supplemented by additional methods including MR-Egger, weighted median, and weighted mode approaches. The Cochrane Q test, MR-PRESSO global test and MR-Egger intercept test were performed to assess pleiotropy and heterogeneity. Furthermore, a reverse MR analysis was performed to explore potential reverse causal effect. Results: The primary MR analysis identified 36 causal relationships between genetic liabilities in gut microbiota and different lymphoma subtypes. Neither the MR-PRESSO test nor the MR-Egger regression detected any pleiotropy, and Cochran's Q test indicated no significant heterogeneity. Conclusions: Our MR analysis revealed substantial causal associations between gut microbiota and lymphoma, offering new insights into lymphoma prevention and management microbiota.