Human-induced pluripotent stem cell-derived neural stem cell exosomes improve blood-brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis.

JOURNAL/nrgr/04.03/01300535-202502000-00029/figure1/v/2024-05-28T214302Z/r/image-tiff Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis. Human-induced pluripotent stem cell-derived neural stem cell exosomes (hiPSC-NSC-Exos) have shown potential for brain injury repair in central nervous system diseases. In this study, we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism. Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits, enhanced blood-brain barrier integrity, and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage. Additionally, hiPSC-NSC-Exos decreased immune cell infiltration, activated astrocytes, and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α post-intracerebral hemorrhage, thereby improving the inflammatory microenvironment. RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion, thereby improving blood-brain barrier integrity. Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects. In summary, our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity, in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

Improving the Selectivity and Stability of Supported Cobalt Catalysts via Static Bi-Doping and Dynamic Trace CO2 Co-feeding during Propane Dehydrogenation.

Simultaneously enhancing selectivity and stability on supported propane dehydrogenation (PDH) catalysts remains a formidable challenge. Here, we report a combined static and dynamic strategy to address these issues synergistically. Firstly, we demonstrate a feasible sol-gel method for preparing atomically-dispersed Bi-decorated metal nanoparticle catalysts (MBi/Al2O3, M= Fe, Co, Ni, and Zn). In PDH testing, the total selectivity of by-products (CH4 and C2H6) significantly decreases to 4% for CoBi catalysts due to the static Bi-doping, compared with 16% for Co-supported catalysts. Secondly, to enhance catalytic stability, we introduce a dynamic trace CO2 co-feeding route. 10CoBi/Al2O3 catalysts exhibit superior durability against coke formation for 330 hours in PDH under a 40% C3H8 atmosphere followed by pure C3H8 conditions at 600 °C while maintaining propylene selectivity at 96%. Notably, introducing trace CO2 leads to a remarkable 6-fold decrease in the deactivation rate constant (kd). Multiple characterizations and density functional theory calculations reveal that charge transfer from atomically-distributed Bi to Co nanoparticles benefits lowering the energy of C3H6 adsorption thereby suppressing by-products. Furthermore, the dynamic co-feeding of trace CO2 facilitates coke removal, suppressing catalyst deactivation. The static Bi-doping and dynamic trace CO2 co-feeding strategy contributes simultaneously to increased selectivity and stability on supported PDH catalysts.

Research on the aerodynamic characteristics of dragonfly leading edge.

Dragonflies are some of the most stable and maneuverable flying organisms. To explore the mechanism of how dragonfly leading edges enhance flight lift, this article conducts a detailed study on the leading edge veins and the microstructures on them of dragonfly wings. Observations have discovered the special leading edge vein and the regularly distributed microstructures on the leading edge vein. A biomimetic model has been established, and computational fluid dynamics (CFD) simulation analysis has been conducted on the biomimetic model. The analysis explores the effects of microstructure characteristics, distribution patterns, and positions on the aerodynamic characteristics of dragonfly gliding. The analysis shows that the leading edge structure influences the incoming flow, simultaneously promotes the formation of the leading edge vortex (LEV), and increases the lift-to-drag ratio by up to 4%. A wing prototype featuring biomimetic microstructures is subsequently fabricated and tested in wind tunnel experiments. Compared with a control group without leading edge structures, the airflow passing through the biomimetic structures is influenced by the shape and arrangement of these structures. The smoother transition of the leading edge vein's shape facilitates the flow of air. The microstructures primarily filter and accelerate the airflow. The spacing of the microstructures affects the stability of the airflow, thereby influencing aerodynamic performance. Additionally, the middle-row arrangement of microstructures is more beneficial for gliding conditions, while the upper-row arrangement is more advantageous for flapping conditions. These findings enhance our understanding of insect wings and advance micro aerial vehicle applications. RESEARCH HIGHLIGHTS: This study observed the leading-edge veins and microstructures of dragonfly wings in detail. Using a biomimetic model and computational fluid dynamics (CFD) simulations, it was found that these leading-edge structures promote the formation of leading-edge vortices (LEV), increasing the lift-to-drag ratio by up to 4%. Wind tunnel experiments demonstrated that wings with biomimetic microstructures significantly improved airflow smoothness and lift compared with control wings. Additionally, the arrangement of microstructures greatly affects airflow stability and aerodynamic performance, with middle-row arrangements being more beneficial for gliding and upper-row arrangements for flapping conditions. These findings enhance our understanding of insect wings and provide innovative guidance for designing efficient micro aerial vehicles.

Radical Replacement Process for Ligated Boryl Radical-Mediated Activation of Unactivated Alkyl Chlorides for C(sp3)-C(sp3) Bond Formation.

The ligated boryl radical (LBR) has emerged as a potent tool for activating alkyl halides in radical transformations through halogen-atom transfer (XAT). However, unactivated alkyl chlorides still present an open challenge for this strategy. We herein describe a new activation mode of the LBR for the activation of unactivated alkyl chlorides to construct a C(sp3)-C(sp3) bond. Mechanistic studies reveal that the success of the protocol relies on a radical replacement process between the LBR and unactivated alkyl chloride, forming an alkyl borane intermediate as the alkyl radical precursor. Aided with the additive K3PO4, the alkyl borane then undergoes one-electron oxidation, generating an alkyl radical. The incorporation of the radical replacement activation model to activate unactivated alkyl chlorides significantly enriches LBR chemistry, which has been applied to activate alkyl iodides, alkyl bromides, and activated alkyl chlorides via XAT.

Response of food waste anaerobic digestion to the dimensions of micron-biochar under 30 g VS/L organic loading rate: Focus on gas production and microbial community structure.

Biochar modification is an effective approach to enhance its ability to promote anaerobic digestion (AD). Focusing on the physical properties of biochar, the impact of different particle sizes of biochar on AD of food waste (FW) at high organic loading rate (OLR) was investigated. Four biochar with different sizes (40-200 mesh) were prepared and used in AD systems at OLR 30 g VS/L. The research results found that biochar with a volume particle size of 102 µm (RBC-P140) had top-performance in promoting cumulative methane production, increasing by 13.20% compared to the control group. The analysis results of the variety in volatile acids and alkalinity in the system did not show a correlation with the size of biochar, but small size has the potential to improve the environmental tolerance of the system to high acidity. Microbial community analysis showed that the abundance of aceticlastic methanogen and the composition of zoogloea were optimized through relatively small-sized biochar. Through revealing the effect of biochar particle size on AD system at high OLR, this work provided theoretical guidance for regulating fermentation systems using biochar.

Clinical value of peripheral blood miR-21 and miR-486 combined with CT forearly cancer diagnosis in pulmonary nodulessmoking.

PURPOSE: This study aimed to investigate the clinical significance of combining peripheral blood miR-21 and miR-486 with CT for the early cancer diagnosis in pulmonary nodules. METHODS: A total of 215 patients diagnosed with isolated pulmonary nodules with a history of smoking were selected as researchsubjects. 30 healthy volunteers with a history of smoking were recruitedas the control group.The selection of subjectswas based on the presence of isolated pulmonary nodules detected on chest CT scans. The training set consisted of 65 patients with lung nodules and 30 healthy smokers, while the verification setincluded 150 patients with lung nodules. RESULTS: Compared with the control group, the plasma expression level of miR-210 was significantly higher in the group of patients with benign pulmonary nodules (P < 0.05). The level of miR-486-5p was lower in patients with malignant pulmonary nodules compared to those with benign pulmonary nodules (P < 0.05). Moreover, the plasma level of miR-210was higher in patients with malignant pulmonary nodules compared to those with benign pulmonary nodules and healthy smokers (P < 0.05). The combination of miR-21 and miR-486 yielded an AUC of 0.865, which was significantly higher than any other gene combination (95%CI: 0.653-0.764, P < 0.05). CONCLUSIONS: This study offered preliminary evidence supporting the use of peripheral blood miR-21 and miR-486, combined with CT scans, as potential biomarkers for the early cancer diagnosis in lung nodules.

GLT-1 downregulation in hippocampal astrocytes induced by type 2 diabetes contributes to postoperative cognitive dysfunction in adult mice.

AIMS: Type 2 diabetes mellitus (T2DM) is related to an increased risk of postoperative cognitive dysfunction (POCD), which may be caused by neuronal hyperexcitability. Astrocyte glutamate transporter 1 (GLT-1) plays a crucial role in regulating neuron excitability. We investigated if T2DM would magnify the increased neuronal excitability induced by anesthesia/surgery (A/S) and lead to POCD in young adult mice, and if so, determined whether these effects were associated with GLT-1 expression. METHODS: T2DM model was induced by high fat diet (HFD) and injecting STZ. Then, we evaluated the spatial learning and memory of T2DM mice after A/S with the novel object recognition test (NORT) and object location test (OLT). Western blotting and immunofluorescence were used to analyze the expression levels of GLT-1 and neuronal excitability. Oxidative stress reaction and neuronal apoptosis were detected with SOD2 expression, MMP level, and Tunel staining. Hippocampal functional synaptic plasticity was assessed with long-term potentiation (LTP). In the intervention study, we overexpressed hippocampal astrocyte GLT-1 in GFAP-Cre mice. Besides, AAV-Camkllα-hM4Di-mCherry was injected to inhibit neuronal hyperexcitability in CA1 region. RESULTS: Our study found T2DM but not A/S reduced GLT-1 expression in hippocampal astrocytes. Interestingly, GLT-1 deficiency alone couldn't lead to cognitive decline, but the downregulation of GLT-1 in T2DM mice obviously enhanced increased hippocampal glutamatergic neuron excitability induced by A/S. The hyperexcitability caused neuronal apoptosis and cognitive impairment. Overexpression of GLT-1 rescued postoperative cognitive dysfunction, glutamatergic neuron hyperexcitability, oxidative stress reaction, and apoptosis in hippocampus. Moreover, chemogenetic inhibition of hippocampal glutamatergic neurons reduced oxidative stress and apoptosis and alleviated postoperative cognitive dysfunction. CONCLUSIONS: These findings suggest that the adult mice with type 2 diabetes are at an increased risk of developing POCD, perhaps due to the downregulation of GLT-1 in hippocampal astrocytes, which enhances increased glutamatergic neuron excitability induced by A/S and leads to oxidative stress reaction, and neuronal apoptosis.

Influence of presentation duration on filtering of irrelevant stimuli in visual working memory.

In environments teeming with distractions, the ability to selectively focus on relevant information is crucial for advanced cognitive processing. Existing research using event-related potential (ERP) technology has shown active suppression of irrelevant stimuli during the consolidation phase of visual working memory (VWM). In previous studies, participants have always been given sufficient time to consolidate VWM, while suppressing distracting information. However, it remains unclear whether the suppression of irrelevant distractors requires continuous effort throughout their presence or whether this suppression is only necessary after the consolidation of task-relevant information. To address this question, our study examines whether distractor suppression is necessary in scenarios where consolidation time is limited. This research investigates the effect of varying presentation durations on the filtering of distractors in VWM. We tasked participants with memorizing two color stimuli and ignoring four distractors, presented for either 50 ms or 200 ms. Using ERP technology, we discovered that the distractor-induced distractor positivity (PD) amplitude is larger during longer presentation durations compared to shorter ones. These findings underscore the significant impact of presentation duration on the efficacy of distractor suppression in VWM, as prolonged exposure results in a stronger suppression effect on distractors. This study sheds light on the temporal dynamics of attention and memory, emphasizing the critical role of stimulus timing in cognitive tasks. These findings provide valuable insights into the mechanisms underlying VWM and have significant implications for models of attention and memory.

An amygdalar oscillator coordinates cellular and behavioral rhythms.

Circadian rhythms are generated by the master pacemaker suprachiasmatic nucleus (SCN) in concert with local clocks throughout the body. Although many brain regions exhibit cycling clock gene expression, the identity of a discrete extra-SCN brain oscillator that produces rhythmic behavior has remained elusive. Here, we show that an extra-SCN oscillator in the lateral amygdala (LA) is defined by expression of the clock-output molecule mWAKE/ANKFN1. mWAKE is enriched in the anterior/dorsal LA (adLA), and, strikingly, selective disruption of clock function or excitatory signaling in adLAmWAKE neurons abolishes Period2 (PER2) rhythms throughout the LA. mWAKE levels rise at night and promote rhythmic excitability of adLAmWAKE neurons by upregulating Ca2+-activated K+ channel activity specifically at night. adLAmWAKE neurons coordinate rhythmic sensory perception and anxiety in a clock-dependent and WAKE-dependent manner. Together, these data reveal the cellular identity of an extra-SCN brain oscillator and suggest a multi-level hierarchical system organizing molecular and behavioral rhythms.

Advancing anaerobic digestion with MnO2-modified biochar: Insights into performance and mechanisms.

The use of bio-based composites to enhance the methane production in anaerobic digestion has attracted considerable attention. Nevertheless, the study of electron transfer mechanisms and the applications of biochar/MnO2 (MBC) in complex systems remains largely unexplored. Biochar composited with MnO2 at 10:1 mass ratio (MBC10) increased the content of volatile fatty acids by 9.09 % during acidogenic phase. During the methanogenic experiments using acetate, cumulative methane production (CMP) rose by 5.83 %, and in the methanogenic experiments using food waste, CMP increased by 24.32 %. Microbial community analysis indicated an enrichment of Syntrophomonas, Bacilli, and Methanosaetaceae in the MBC10 group. This enrichment occurred mainly due to the redox capability of MnO2 enhancing MBC capacitance, thereby facilitating microbial electron transfer processes. Additionally, under 2 g/L ammonia nitrogen concentration and 30 g/L organic load, the CMP of MBC10 increased by 12.74 % and 9.44 %, respectively, compared to the BC600 group. This study illuminates MBC's electron transfer mechanisms and applications, facilitating its wider practical adoption and fostering future innovations.

Decoding the pathogenesis of spermatogenic failure in cryptorchidism through single-cell transcriptomic profiling.

Cryptorchidism, commonly known as undescended testis, affects 1%-9% of male newborns, posing infertility and testis tumor risks. Despite its prevalence, the detailed pathophysiology underlying male infertility within cryptorchidism remains unclear. Here, we profile and analyze 46,644 single-cell transcriptomes from individual testicular cells obtained from adult males diagnosed with cryptorchidism and healthy controls. Spermatogenesis compromise in cryptorchidism links primarily to spermatogonium self-renewal and differentiation dysfunctions. We illuminate the involvement of testicular somatic cells, including immune cells, thereby unveiling the activation and degranulation of mast cells in cryptorchidism. Mast cells are identified as contributors to interstitial fibrosis via transforming growth factor ß1 (TGF-ß1) and cathepsin G secretion. Furthermore, significantly increased levels of secretory proteins indicate mast cell activation and testicular fibrosis in the seminal plasma of individuals with cryptorchidism compared to controls. These insights serve as valuable translational references, enriching our comprehension of testicular pathogenesis and informing more precise diagnosis and targeted therapeutic strategies for cryptorchidism.

Buckling behaviour of rectangular and skew plates with elastically restrained edges under non-uniform mechanical edge loading.

In this paper, the buckling behaviour of rectangular and skew plates with elastically restrained edges subjected to non-uniform mechanical edge loading is investigated. An analysis method is developed for calculating the critical buckling load of plates using the Ritz method under non-uniform mechanical edge loading, in which the shape function is expressed as Legendre polynomials. The in-plane stress distribution under non-uniform mechanical edge loading is defined by the pre-buckling analysis. Contributions of elastic boundary conditions are taken into accounted by giving different edge spring stiffnesses. The proposed method for buckling analysis of plates is validated by the comparison of exiting results in literature. Finally, the effects of the edge restrained stiffness, non-uniform edge loading, skew angle, aspect ratio and combined compression-shear load are discussed by parametric analysis.

Discovery and validation of colorectal cancer tissue-specific methylation markers: a dual-center retrospective cohort study.

BACKGROUND AND PURPOSE: Early detection, diagnosis, and treatment of colorectal cancer and its precancerous lesions can significantly improve patients' survival rates. The purpose of this research is to identify methylation markers specific to colorectal cancer tissues and validate their diagnostic capability in colorectal cancer and precancerous changes by measuring the level of DNA methylation in stool samples. METHOD: We analyzed samples from six cancer tissues and adjacent normal tissues and fecal samples from 758 participants, including 62 patients with interfering diseases. Bioinformatics databases were used to screen for candidate biomarkers for CRC, and quantitative methylation-specific PCR methods were applied for identification. The methylation levels of the candidate biomarkers in fecal and tissue samples were measured. Logistic regression and random forest models were built and validated using fecal sample data from one of the centers, and the independent or combined diagnostic value of the candidate biomarkers in fecal samples for CRC and precancerous lesions was analyzed. Finally, the diagnostic capability and stability of the model were validated at another medical center. RESULTS: This study identified two colorectal cancer CpG sites with tissue specificity. These two biomarkers have certain diagnostic power when used individually, but their diagnostic value for colorectal cancer and colorectal adenoma is more significant when they are used in combination. CONCLUSION: The results indicate that a DNA methylation biomarker combined diagnostic model based on two CpG sites, cg13096260 and cg12587766, has the potential for screening and diagnosing precancerous lesions and colorectal cancer. Additionally, compared to traditional diagnostic models, machine learning algorithms perform better but may yield more false-positive results, necessitating further investigation.

Carrier-free cryptotanshinone-peptide conjugates self-assembled nanoparticles: An efficient and low-risk strategy for acne vulgaris.

Acne vulgaris ranks as the second most prevalent dermatological condition worldwide, and there are still insufficient safe and reliable drugs to treat it. Cryptotanshinone (CTS), a bioactive compound derived from traditional Chinese medicine Salvia miltiorrhiza, has shown promise for treating acne vulgaris due to its broad-spectrum antimicrobial and significant anti-inflammatory properties. Nevertheless, its local application is hindered by its low solubility and poor skin permeability. To overcome these challenges, a carrier-free pure drug self-assembled nanosystem is employed, which can specifically modify drug molecules based on the disease type and microenvironment, offering a potential for more effective treatment. We designed and synthesized three distinct structures of cationic CTS-peptide conjugates, creating self-assembled nanoparticles. This study has explored their self-assembly behavior, skin permeation, cellular uptake, and both in vitro and in vivo anti-acne effects. Molecular dynamics simulations revealed these nanoparticles form through intermolecular hydrogen bonding and π-π stacking interactions. Notably, self-assembled nanoparticles demonstrated enhanced bioavailability with higher skin permeation and cellular uptake rates. Furthermore, the nanoparticles exhibited superior anti-acne effects compared to the parent drug, attributed to heightened antimicrobial activity and significant downregulation of the MAPK/NF-κB pathway, leading to reduced expression of pro-inflammatory factors including TNF-α, IL-1ß and IL-8. In summary, the carrier-free self-assembled nanoparticles based on CTS-peptide conjugate effectively address the issue of poor skin bioavailability, offering a promising new approach for acne treatment.

Autophagy Modulation in Therapeutic Strategy of Breast Cancer Drug Resistance.

Breast cancer (BC) is a prevalent malignancy globally. Autophagy plays a pivotal role in all stages of this disease, including development, metastasis, and onset. Therefore, it is envisaged that targeting cell autophagy through appropriate tactics would evolve into a novel breast cancer prevention and therapy strategy. A multitude of chemotherapeutic medications can stimulate autophagy in tumor cells. It has led to divergent opinions on the function of autophagy in cancer treatment, as both stimulating and blocking autophagy can improve the effectiveness of anticancer medications. Consequently, the decision of whether to stimulate or inhibit autophagy during breast cancer treatment has become crucial. Understanding the distinctive mechanisms of autophagy in BC and its significance in medication therapy might facilitate the creation of targeted treatment plans based on the roles particular to autophagy. This review summarizes recent studies on the autophagy mechanism in breast cancer and provides insights into autophagy-based BC therapeutic techniques, giving fresh avenues for future BC treatment.

SPECT/CT imaging of poor sleep quality in people with epilepsy.

PURPOSE: To analyze the characteristics of cerebral blood flow changes of poor sleep quality in people with epilepsy(PWE). METHODS: 90 PWE treated in The General Hospital of Ningxia Medical University from December 2021 to September 2023 were divided into poor sleep quality group (PSQG) and good sleep quality group (GSQG) according to the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI), to compare the differences in cerebral perfusion between the two groups of patients, so as to summarize the characteristics of cerebral blood flow changes of poor sleep quality in PWE. RESULTS: The positive rate of interictal single-photon emission computed tomography/computed tomography (SPECT/CT) was 76.7 %(69/90), which showed localized cerebral hypoperfusion. There was no statistical difference between the two groups of PSQG (N=29) and GSQG (N=61) in terms of the positive rate of SPECT/CT, the number of hypoperfusion foci, and the range of hypoperfusion foci. In PSQG and GSQG, 9 patients(31.0 %) and 6 patients(9.8 %) showed hypoperfusion in the right parietal lobe, respectively, and the difference between the two groups was statistically significant (P=0.017). There was no statistical difference the rate of the interictal epileptiform discharges (IEDs) and the brain area of IEDs in electroencephalography(EEG) between the two groups. CONCLUSION: SPECT/CT of poor sleep quality in PWE demonstrated hypoperfusion in the right parietal lobe.

Chemosensory protein 22 in Riptortus pedestris is involved in the recognition of three soybean volatiles.

Riptortus pedestris (Hemiptera: Alydidae), a common agricultural pest, is the major causative agent of "soybean staygreen." However, the interactions between chemosensory proteins (CSPs) in R. pedestris and host plant volatiles have yet to be comprehensively studied. In this study, we performed real-time fluorescence quantitative polymerase chain reaction (PCR) to analyze the antennal expression of RpedCSP22 and subsequently analyzed the interactions between 21 soybean volatiles, five aggregation pheromones, and RpedCSP22 protein in vitro using a protein expression system, molecular docking, site-directed mutagenesis, and fluorescence competitive binding experiments. The RpedCSP22 protein showed binding affinity to three soybean volatiles (benzaldehyde, 4-ethylbenzaldehyde, and 1-octene-3-ol), with optimal binding observed under neutral pH conditions, and lost binding ability after site-directed mutagenesis. In subsequent RNA interference (RNAi) studies, gene silencing was more than 90 %, and in silenced insects, electroantennographic responses were reduced by more than 75 % compared to non-silenced insects. Moreover, Y-tube olfactory behavioral assessments revealed that the attraction of R. pedestris to the three soybean volatiles was significantly attenuated. These findings suggest that RpedCSP22 plays an important role in the recognition of host plant volatiles by R. pedestris andprovides a theoretical basis for the development of novel inhibitors targeting pest behavior.

Programmed death receptor (PD-)1/PD-ligand (L)1 in urological cancers : the "all-around warrior" in immunotherapy.

Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy.

Influences of lauric acid addition on performance, nutrient digestibility and proteins related to mammary gland development in dairy cows.

Lauric acid (LA) has the possibility to improve milk production in dairy cows by improving mammary gland development, however, the mechanism by which it might regulate mammary gland development is unclear. The influence of LA on milk production, nutrient digestibility and the expression of proteins related to mammary gland development in dairy cows were evaluated. Forty primiparous Holstein dairy cows were divided into 4 groups in a randomized block design. Four treatments included the control (0 g/d LA per cow), low-LA (100 g/d LA per cow), medium-LA (200 g/d LA per cow), and high-LA (300 g/d LA per cow). Yields of milk, fat-corrected milk, and energy-corrected milk quadratically increased (P < 0.05), and yield and content of milk fat linearly increased (P < 0.05) with LA supplementation. Percentages of C12:0, C18:1 and C20:1 fatty acids in milk fat linearly increased (P < 0.05), but that of C16:0 fatty acid linearly decreased (P = 0.046). Supplementation of LA led to a linear and quadratical increase (P < 0.05) in digestibility of dry matter, organic matter, neutral detergent fibre and acid detergent fibre, and ruminal total volatile fatty acid concentration but a linear reduction (P = 0.018) in the ratio of acetate to propionate. The enzymatic activities of ruminal pectinase, xylanase, and α-amylase, and populations of total bacteria and anaerobic fungi increased linearly (P < 0.05), while populations of total protozoa and methanogens decreased linearly (P < 0.05) with increased LA addition. Following LA addition, blood glucose, triglyceride, estradiol, prolactin, and insulin-like growth factor 1 concentrations increased linearly (P < 0.05) and albumin and total protein concentrations increased quadratically (P < 0.05). Moreover, addition of 200 g/d LA promoted (P < 0.05) the expression of protein involved in mammary gland development and fatty acids synthesis. These results suggested that LA addition enhanced milk production and fatty acids synthesis by stimulating nutrient digestion, the expression of proteins associated with milk fat synthesis and mammary gland development.