Phospholipid Phosphatase 3 (PLPP3) Induces Oxidative Stress to Accelerate Ovarian Aging in Pigs.

Ovarian aging results in reproductive disorders and infertility in mammals. Previous studies have reported that the ferroptosis and autophagy caused by oxidative stress may lead to ovarian aging, but the mechanisms remain unclear. In this study, we compared the morphological characteristics between the aged and young ovaries of pigs and found that the aged ovaries were larger in size and showed more corpora lutea. TUNEL assay further showed that the apoptosis level of granulosa cells (GCs) was relatively higher in the aged ovaries than those in young ovaries, as well as the expressions of autophagy-associated genes, e.g., p62, ATG7, ATG5, and BECN1, but that the expressions of oxidative stress and aging-associated genes, e.g., SOD1, SIRT1, and SIRT6, were significantly lower. Furthermore, the RNA-seq, Western blotting, and immunofluorescence suggested that phospholipid phosphatase 3 (PLPP3) protein was significantly upregulated in the aged ovaries. PLPP3 was likely to decrease the expressions of SIRT1 and SIRT6 to accelerate cellular senescence of porcine GCs, inhibit the expressions of SOD1, CAT, FSP1, FTH1, and SLC7A11 to exacerbate oxidative stress and ferroptosis, and arouse autophagy to retard the follicular development. In addition, two SNPs of PLPP3 promoter were significantly associated with the age at puberty. g.155798586 (T/T) and g.155798718 (C/C) notably facilitated the mRNA and protein level of PLPP3. In conclusion, PLPP3 might aggravate the oxidative stress of GCs to accelerate ovarian aging, and two molecular markers of PLPP3 were identified for ovarian aging in pigs. This work not only contributes to investigations on mechanisms for ovarian aging but also provides valuable molecular markers to postpone ovarian aging in populations.

The value of shear wave elastography combined with red blood cell distribution width in evaluating arterial erectile dysfunction.

PURPOSE: A retrospective study was conducted to determine the value of shear wave elastography (SWE) and red blood cell distribution width (RDW) in the diagnosis of various forms of erectile dysfunction (ED). METHODS: With the method of Nocturnal Penile Tumescence and Rigidity (NPTR) and the screening method of Color Duplex Doppler Ultrasound (CDDU), hematological data were collected from 131 individuals, among whom 24 are with psychogenic ED, 48 are with non-arterial ED(NAED) and 59 are with arterial ED(AED) with erectile dysfunction. SWE value of penile corpus cavernosum(CCP) and cavernous arterial flow velocity were measured before (flaccid state) and after (erect state) intracavernous injection (ICI) in all patients. RESULTS: Among the AED patients and other types of ED patients, there were statistically significant differences in the abridged five-item International Index of Erectile Function (IIEF-5), red blood cell distribution width-coefficient of variation (RDW-CV), red blood cell distribution width-standard deviation (RDW-SD), and SWE values (all P < 0.01). In the AED patients, the IIEF-5 scores had a significant negative relationship with RDW-CV, RDW-SD, and SWE values, with SWE values having the strongest correlation. (p < 0.001, r=-0.638). CONCLUSION: The combination of RDW level and SWE value demonstrated the greatest performance in diagnosing AED, according to the receiver-operator characteristic(ROC) curve analysis (AUC = 0.870, p < 0.0001, cut-off value of 0.75, sensitivity of 74.6%, specificity of 91.7%).RDW and SWE value may develop into an incredibly simple, practical tool for predicting and diagnosing AED. TRIAL REGISTRATION: retrospectively registered.

Effects of yeast culture supplementation on milk yield, rumen fermentation, metabolism, and bacterial composition in dairy goats.

The effects of yeast culture (YC) on dairy goat milk yield and potential effects of rumen microbial population changes on rumen fermentation are poorly understood. This study aimed to evaluate the effects of YC on milk yield and rumen fermentation in dairy goats and explore the potential microbial mechanisms. Forty Laoshan dairy goats with a weight of 51.23 ± 2.23 kg and daily milk yield of 1.41 ± 0.26 kg were randomly divided into 4 groups: control (no YC), YC1 (10 g/day per goat), YC2 (25 g/day per goat), and YC3 (40 g/day per goat). The pre-feeding period was 15 days, and the official period was 60 days. Laoshan dairy goats were milked twice daily, and the individual milk yield was recorded. On the last day of the official period, rumen fluid was collected to measure rumen fermentation, perform quantitative polymerase chain reaction (PCR), and detect metabolites. Compared to the control group, the YC group had greater milk yield; higher acetic acid, butyric acid, and total volatile fatty acid contents; and lower ammonia-N (NH3-N) content in the rumen (p < 0.05). YC increased the abundance of Clostridia_UCG-014 and Paraprevotella (p < 0.05). Differential metabolites L-leucine and aspartic acid were screened. This study revealed the microbial mechanisms linking the relative abundance of Paraprevotella and Clostridia_UCG-014 to L-leucine and aspartic acid utilization. These results describe the potential benefits of supplementing 10 g/day per goat YC in the diets of Laoshan dairy goats for improving the rumen environment and milk yield.

The effects of baicalin in depression: preclinical evidence construction based on meta-analysis.

Background: Depression manifests as a mental disorder characterized by a low mood, suicidal tendencies, disturbances in sleep-wake cycles, psychomotor agitation, and pronounced feelings of hopelessness and anhedonia. Baicalin, a natural flavonoid compound, shows significant promise in alleviating depressive symptoms in animals. This study aims to assess the impact of baicalin on experimental models of depression. Methods: A systematic search of electronic databases was conducted using the search terms "baicalin" AND "depression" OR "depressed" OR "anti-depression". Preclinical animal models representing experimental depression were included in the analysis. The risk of bias in the included studies was evaluated using the CAMARADES tools. Results: Baicalin significantly increased sucrose preference test (SPT) [SMD= 21.31, 95%CI (16.32, 26.31), P < 0.00001]. mThe tail suspension test (TST) duration significantly decreased in the baicalin group compared to the model group [SMD = -39.3, 95%CI (-49.71, -28.89), P < 0.0001]. Furthermore, baicalin reduced immobility time in rats subjected to the forced swim test (FST) [SMD = -39.73, 95%CI (-48.77, -30.69) P < 0.0001]. Compared to the model group, baicalin treatment also significantly increased the frequency of crossings in the open field test (OFT) [SMD = 32.44, 95%CI (17.74, 47.13), P < 0.00001]. Conclusion: Baicalin significantly improves the manifestations of depressive symptoms. The effect of baicalin against depression is exerted through its anti-inflammatory actions, inhibition of oxidative stress, regulation of the HPA axis, and restoration of neuroplasticity. Future studies will be needed to further explore how these promising preclinical findings can be translated into clinical treatment for depression. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023472181.

Effects of Ginger Straw Silage with Enzymes on Growth Performance, Digestion and Metabolism, Meat Quality and Rumen Microflora Diversity of Laiwu Black Goat.

Laiwu black goats comprise an excellent local germplasm resource; however, a shortage of feed resources has led to the application of unconventional feed. Ginger straw feed has good physiological effects, but research on this feed source for ruminant animals is lacking. The aim of this study was to determine the effects of enzymatic silage ginger straw on Laiwu black goat performance. The experiment used an independent sample t-test analysis method; 24 healthy Laiwu black goats with a body weight of 20.05 ± 1.15 kg and age of 5.67 ± 0.25 months were randomly divided into two groups with three replicates (bars) per group and four goats per replicate. The experimental diet was composed of mixed concentrate, silage, and garlic peel at a 2:7:1 ratio. The silage used in the two groups was whole corn silage (CON group) and 60% whole corn silage plus 40% enzymatic silage ginger straw (SG group), and the other components were identical. Daily feed intake/daily gain (F/G) was significantly higher in the SG group than in the CON group (p < 0.05), but there were no significant differences in dry matter (DM), crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF) digestibility between the groups. The shear force, cooking loss, centrifugal loss, and pressure loss of the longissimus dorsi muscle group were significantly lower in the SG than in the CON group (p < 0.05). Compared with those in the CON group, the serum and liver total antioxidant capacity was significantly increased in the SG group, and in the liver, the O2·-, malondialdehyde, and OH· contents were significantly decreased. Collectively, the rumen fluid microbial diversity was changed in the SG group. It was concluded that enzymatic silage ginger straw usage instead of 40% whole silage corn as feed for Laiwu black goats can significantly improve the muscle quality, antioxidant capacity, and intestinal flora, with no adverse effects on production performance. In conclusion, our study provides a basis for ginger straw processing and storage and its rational application in the Laiwu black goat diet.

Hua-Feng-Dan alleviates LPS-induced neuroinflammation by inhibiting the TLR4/Myd88/NF-κB pathway: Through Integrating Network Pharmacology and Experimental Validation.

BACKGROUND: Neuroinflammation is the pathological basis of many neurological diseases, including neurodegenerative diseases and stroke. Hua-Feng-Dan (HFD) is a well-established traditional Chinese medicine that has been used for centuries to treat stroke and various other brain-related ailments. OBJECTIVE: Our study aims to elucidate the molecular mechanism by which HFD mitigates neuroinflammation by combining network pharmacology and in vitro experiments. METHODS: TCMSP and SymMap databases were used to extract active compounds and their related targets. The neuroinflammation-related targets were obtained from the GeneCards database. The common targets of HFD and neuroinflammation were used to construct a protein-protein interaction (PPI) network. MCODE plug-in was used to find the hub module genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to dissect the hub module genes. The lipopolysaccharide (LPS)-induced BV2 microglial neuroinflammation model was utilized to assess the therapeutic effects of HFD on neuroin- flammation. Western blotting analysis was performed to examine the core target proteins in the TLR4/My- D88/NF-κB signaling pathway, potentially implicated in HFD's therapeutic effects on neuroinflammation. Hoechst 33342 staining and JC-1 staining were employed to evaluate neuronal apoptosis. RESULTS: Through network pharmacology, 73 active compounds were identified, with quercetin, beta-sitos- terol, luteolin, and (-)-Epigallocatechin-3-Gallate recognized as important compounds. Meanwhile, 115 com- mon targets of HFD and neuroinflammation were identified, and 61 targets were selected as the hub targets uti- lizing the MCODE algorithm. The results of in vitro experiments demonstrated that HFD significantly inhibit- ed microglial-mediated neuronal inflammation induced by LPS. Integrating the predictions from network phar- macology with the in vitro experiment results, it was determined that the mechanism of HFD in mitigating neu- roinflammation is closely related to the TLR4/MyD88/NF-κB pathway. Furthermore, HFD demonstrated the capacity to shield neurons from apoptosis by curbing the secretion of pro-inflammatory factors subsequent to microglial activation. CONCLUSION: The findings demonstrated that HFD had an inhibitory effect on LPS-induced neuroinflammation in microglia and elucidated its underlying mechanism. These findings will offer a theoretical foundation for the clinical utilization of HFD in treating neurodegenerative diseases associated with neuroinflammation.

Effect of Steel Fibers on Tensile Properties of Ultra-High-Performance Concrete: A Review.

Ultra-high-performance concrete (UHPC) is an advanced cement-based material with excellent mechanical properties and durability. However, with the improvement of UHPC's compressive properties, its insufficient tensile properties have gradually attracted attention. This paper reviews the tensile properties of steel fibers in UHPC. The purpose is to summarize the existing research and to provide guidance for future research. The relevant papers were retrieved through three commonly used experimental methods for UHPC tensile properties (the direct tensile test, flexural test, and splitting test), and classified according to the content, length, type, and combination of the steel fibers. The results show that the direct tensile test can better reflect the true tensile strength of UHPC materials. The tensile properties of UHPC are not only related to the content, shape, length, and hybrids of the steel fibers, but also to the composition of the UHPC matrix, the orientation of the fibers, and the geometric dimensions of the specimen. The improvement of the tensile properties of the steel fiber combinations depends on the effectiveness of the synergy between the fibers. Additionally, digital image correlation (DIC) technology is mainly used for crack propagation in UHPC. The analysis of the post-crack phase of UHPC is facilitated. Theoretical models and empirical formulas for tensile properties can further deepen the understanding of UHPC tensile properties and provide suggestions for future research.

Surrogacy of one-year survival for overall survival in advanced hepatocellular carcinoma.

BACKGROUND: The increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials. METHODS: We systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival. RESULTS: Thirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75). CONCLUSIONS: One-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials.

Analysis of Age-Related Changes in Lower Facial Fat Compartments and of the Course of Blood Vessels Using Computed Tomography.

BACKGROUND: According to the volume restoration theory, lower facial fat compartments tend to selectively atrophy or hypertrophy with age. The aim of this study was to demonstrate age-related changes in lower facial fat compartments using computed tomography, with strict control of the body mass index and underlying diseases. METHODS: This study included 60 adult women in three age-based categories. The thicknesses of the jowl, labiomandibular, and chin fat compartments were measured using computed tomographic images. The distribution and arrangement of facial blood vessels were further analyzed to provide evidence of the safety of rejuvenation strategies based on the facial volumetric theory. RESULTS: The inferior part of the superficial jowl fat compartment and deep jowl fat compartment thickened with age. The deep layer of the labiomandibular fat compartment thinned with age, and the superficial layer thickened with age. The deep and superficial layers of the chin compartments thickened with age. The facial vein passes through the lower mandibular border at the anterior edge of the masseter muscle and moves upward, perpendicular to the lower mandibular border. The high-risk area of the facial artery had an angle of approximately 45 degrees to the lower mandibular border. CONCLUSIONS: This study suggests that with age, selective thickening or thinning occurs in different lower facial fat compartments. The mandible and masseter muscle were used as reference markers to analyze the courses of the facial artery and facial vein, which can help clinicians to reduce vascular injury.

Response of Neuropeptides to Hunger Signals in Teleost.

INTRODUCTION: The perception of hunger is a complex physiological process that requires precise coordination between the central and peripheral tissues. METHODS: In this study, tilapia fasted for 24 h was chosen to establish a hunger model to study the mechanism of homeostasis recovery under the joint regulation of the central nervous system (CNS) and peripheral tissues. RESULTS: The gastric and intestinal contents of tilapia were predominantly depleted after a fasting period of 9 h and 24 h, respectively. The serum glucose level significantly decreased at the 9-h and 24-h fasting, respectively, and the glucokinase-dependent glucosensing mechanism in the liver was identified as well as the significant activation of phospho-AMPK. However, fasting for 24 h did not activate glucosensing mechanisms and AMPK signaling pathways in the hypothalamus. On the other hand, significant reductions were observed in the mRNA levels of the lipid synthesis-related genes fas and accα, and the serum triglyceride levels as well. The mRNA levels of npy, agrp, pomc, and cart in the hypothalamus fluctuated during the fasting period without significant differences. With in situ hybridization npy signals upregulated in the ventral zone of posterior periventricular nucleus after 24-h fasting, pomc signals enhanced in the lateral tuberal nucleus. Based on the serum metabolomic analysis, the levels of branched-chain amino acids, butyrate, and short-chain acylcarnitine decreased, while those of medium- and long-chain acylcarnitine increased. CONCLUSION: Fasting for 24 h resulted in changes in npy and pomc signals within the hypothalamus and triggered the glucosensing mechanism in the liver of tilapia. This study is beneficial for elucidating the response of neuropeptides in the CNS to the changes of nutritional factors when hungry.

Artesunate attenuates serum amyloid A-induced M1 macrophage differentiation through the promotion of PHGDH.

Clinical studies indicated that Serum Amyloid A (SAA) might be a promising biomarker for forecasting the activity, severity, and adverse prognosis of systemic lupus erythematosus (SLE). Simultaneously, a positive correlation has been observed between macrophages, Th17 cells, and SLE disease activity, with both these immune cells being affected by SAA. Presently, the relationship between SAA and the aforementioned immune cell types in SLE remains to be elucidated. To discern the immune cell type most closely associated with SAA, we undertook a single-cell RNA sequencing data analysis via the GEO database. Subsequent results revealed a strong association between macrophages and SAA, a relationship further validated through flow cytometry of spleen macrophages in the MRL/lpr model. We discovered that SAA stimulate M1 macrophage differentiation along with the upregulation of pro-inflammatory cytokines such as IL-6 and IL-1ß. Our findings suggest that SAA may promote M1 macrophage differentiation via the downregulation of phosphoglycerate dehydrogenase (PHGDH). Artesunate (ART), primarily utilized for malaria treatment, was shown to inhibit M1 macrophage differentiation and pro-inflammatory cytokine levels via upregulating the PHGDH expression, thereby attenuating the disease activity in SLE.

Gas Chromatography-Mass Spectrometry Reveals Stage-Specific Metabolic Signatures of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a type of chronic rheumatic immune disease, and the crucial point of AS treatment is identifying the correct stage of the disease. However, there is a lack of effective diagnostic methods for AS staging. The primary objective of this study was to perform an untargeted metabolomic approach in AS patients in an effort to reveal metabolic differences between patients in remission and acute stages. Serum samples from 40 controls and 57 AS patients were analyzed via gas chromatography-mass spectrometry (GC-MS). Twenty-four kinds of differential metabolites were identified between the healthy controls and AS patients, mainly involving valine/leucine/isoleucine biosynthesis and degradation, phenylalanine/tyrosine/tryptophan biosynthesis, glutathione metabolism, etc. Furthermore, the levels of fatty acids (linoleate, dodecanoate, hexadecanoate, and octadecanoate), amino acids (serine and pyroglutamate), 2-hydroxybutanoate, glucose, etc., were lower in patients in the acute stage than those in the remission stage, which may be associated with the aggravated inflammatory response and elevated oxidative stress in the acute stage. Multiple stage-specific metabolites were significantly correlated with inflammatory indicators (CRP and ESR). In addition, the combination of serum 2-hydroxybutanoate and hexadecanoate plays a significant role in the diagnosis of AS stages. These metabolomics-based findings provide new perspectives for AS staging, treatment, and pathogenesis studies.

Transparent nanopaper for ultrashort pulse generation in the near-infrared region.

Transparent nanopaper (T-paper) can be applied in the field of electromagnetic shielding materials, antistatic materials, composite conductive materials, electric pool materials, super capacitors, and thermal management systems. However, this kind of T-paper has not been employed in ultrafast photonics yet. For the first time, to our knowledge, transparent electrical nanopaper is used in fiber lasers, different from the conventional pulsed fiber laser, which operates in the Q-switched regime under low pump power and then in the mode-locked regime under high pump power. Mode-locking is achieved first with a pulse duration of 550 fs under low pump power (166 mW). When further increasing the pump power up to 198 mW, the proposed fiber laser can be converted from a mode-locked to Q-switched state, which is a result of the two-photon absorption effect. The proposed fiber laser based on T-paper can be potentially applied in optical tomography, metrology, spectroscopy, micro-machining technology, and biomedical diagnostics.

Graphdiyne-polymer composites for a hybrid bound-state pulsed fiber laser.

In this paper, the graphdiyne (GDY)-polymethyl methacrylate (PMMA) films are prepared by a spin-coating method. The PMMA films have the function of isolating GDY from air and protecting the GDY from mechanical damage. The nonlinear optical properties of GDY-PMMA films are probed experimentally. The nonlinear optical responses of GDY-PMMA films with a modulation depth of ∼4.94% and saturated magnetization of ∼0.3M W/c m 2 are proved. When the GDY-PMMA films are applied to an erbium-doped hybrid passively mode-locked fiber laser (saturable absorber), the bound-state solitons, which are also called soliton molecules, can be obtained. The soliton molecule has a time separation of 13.31 ps, and the spectral modulation period of 0.58 nm. Along with the pump power increase, the separation of bound-state pulses becomes larger. When the pump power is fixed, stable bound solitons can be observed without any degeneration for more than 4.5 h. It is demonstrated that GDY-PMMA films have excellent nonlinear optical performance in a near-infrared regime, which we believe can be a novel type of photonics instrument and has a number of properties that are potentially promising in the ultrafast properties of laser.

Characteristics of steroid hormones in systemic lupus erythematosus revealed by GC/MS-based metabolic profiling.

Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a remarkable predominance in female, suggesting that steroid hormones may be involved in the pathogenesis. However, steroid signature of SLE patients has not been fully explored. Methods: A metabolic profiling analysis based on gas chromatography/mass spectrometry (GC/MS) with high sensitivity and reproducibility was employed to comprehensively reveal SLE-specific steroid alterations. Results: More than 70 kinds of steroids in urine were detected by gas chromatography/mass spectrometry (GC/MS) to reveal SLE-specific steroid alterations. Principle component analysis demonstrated that the steroid profile was obviously distinguished between patients with SLE and controls. A lower level of total androgens was observed in patients, and nine androgens [dehydroepiandrosterone (DHEA), testosterone, Etio, androsterone, ßαß-Diol, Epi-An, Epi-DHT, 16α-OH-DHEA, and A-Diol] underwent significant decrease. Moreover, patients with SLE exhibited a slightly higher level of total estrogens than controls, and three estrogens (17-Epi-E3, 17α-E2, and E3) were remarkably increased. Furthermore, we identified the elevation of two sterols (Lan and Chol), and the reduction of one corticoid (11-DeoxyF) and two progestins (5α-DHP and 11ß-OH-Prog) in patients. Discussion: In this study, metabolic signature of urinary steroids associated with SLE was comprehensively defined by GC/MS for the first time, and steroid metabolism disorders were found in patients with SLE, especially the conversion of androgens to estrogens. Our findings will provide new insights for a deeper understanding of the mechanism of steroid hormones in the pathogenesis of SLE and will help to unravel the reason of sexual disparity in SLE.

An overview of pim kinase as a target in multiple myeloma.

Multiple myeloma (MM) is the second common hematologic malignancy manifesting as a clonal proliferation of plasma cells in the bone marrow. In recent years, high expression and activity of pim kinase have been found to be associated with both the progression and prognosis of a significant proportion of malignant diseases. Therefore, pim kinase has become a potential therapeutic target in the treatment of MM and some pim kinase inhibitors have demonstrated good efficacy in clinical trials. Based on nearly the entire literature searched from PubMed in the field of pim kinase in MM, the paper concluded how pim kinase got involved in the proliferation of myeloma cells, the progression of bone disease infiltration, and even in the regulation of the immune microenvironment. Next as a very promising drug, the effectiveness of pim kinase inhibitors as single agents or in combination with other drugs in the treatment of MM was also summarized. Our analysis will guide the clinical use of pim kinase inhibitors for managing tumor load and bone disease in MM patients.

Induction of Tumor Ferroptosis-Dependent Immunity via an Injectable Attractive Pickering Emulsion Gel.

The combination of ferroptosis inducers and immune checkpoint blockade can enhance antitumor effects. However, the efficacy in tumors with low immunogenicity requires further investigation. In this work, a water-in-oil Pickering emulsion gel is developed to deliver (1S, 3R)-RSL-3 (RSL-3), a ferroptosis inducer dissolved in iodized oil, and programmed death-1 (PD-1) antibody, the most commonly used immune checkpoint inhibitor dissolved in water, with optimal characteristics (RSL-3 + PD-1@gel). Tumor lipase degrades the continuous oil phase, which results in the slow release of RSL-3 and PD-1 antibody and a notable antitumor effect against low-immunogenic hepatocellular carcinoma and pancreatic cancer. Intriguingly, the RSL-3 + PD-1@gel induces ferroptosis of tumor cells, resulting in antitumor immune response via accumulation of helper T lymphocyte cells and cytotoxic T cells. Additionally, the single-cell sequence profiling analysis during tumor treatment reveals the induction of ferroptosis in tumor cells together with strong antitumor immune response in ascites.

Effects of nonantibiotic growth promoter combinations on growth performance, nutrient utilization, digestive enzymes, intestinal morphology, and cecal microflora of broilers.

Given the ban on antibiotic growth promoters, the effects of nonantibiotic alternative growth promoter combinations (NAGPCs) on the growth performance, nutrient utilization, digestive enzyme activity, intestinal morphology, and cecal microflora of broilers were evaluated. All birds were fed pellets of two basal diets-starter (0-21 d) and grower (22-42 d)-with either enramycin (ENR) or NAGPC supplemented. 1) control + ENR; 2) control diet (CON, basal diet); 3) control + mannose oligosaccharide (MOS) + mannanase (MAN) + sodium butyrate (SB) (MMS); 4) control + MOS + MAN + Bacillus subtilis (BS) (MMB); 5) control + MOS + fruit oligosaccharide (FOS) + SB (MFS); 6) control + FOS + BS (MFB); 7) control + MOS + FOS + MAN (MFM); 8) control + MOS + BS + phytase (PT) (MBP). ENR, MOS, FOS, SB, MAN, PT, and BS were added at 100, 2,000, 9,000, 1,500, 300, 37, and 500 mg/kg, respectively. The experiment used a completely random block design with six replicates per group: 2400 Ross 308 broilers in the starter phase and 768 in the grower phase. All NAGPCs significantly improved body weight gain (P < 0.01), utilization of dry matter, organic matter, and crude protein (P < 0.05), villus height and villus height/crypt depth in the jejunum and ileum (P < 0.01), and decreased the feed conversion ratio (P < 0.01) at d 21 and 42. MMS, MMB, MFB, and MFM duodenum trypsin, lipase, and amylase activities increased significantly (P < 0.05) at d 21 and 42. On d 21 and 42, MMS, MMB, and MBP increased the abundance of Firmicutes and Bacteroides whereas MMB, MFB, and MBP decreased the abundance of Proteobacteria, compared to ENR and CON. Overall, the NAGPCs were found to have some beneficial effects and may be used as effective antibiotic replacements in broilers.

Effects of KMT2D mutation and its exon 39 mutation on the immune microenvironment and drug sensitivity in colorectal adenocarcinoma.

Background: KMT2D mutation (KMT2DMT) was found to play an important role in cancer immunity and response to immune checkpoint inhibitors (ICIs). The present study aims to investigate the association between KMT2D exon 39 mutation (K-ex39MT) and molecular and clinical characteristics in colorectal adenocarcinoma (CRAD). Methods: We performed profiling of KMT2DMT and K-ex39MT via Kaplan-Meier analysis, cBioportal, Immune-related functional analysis and correlation analysis with TCGA and MSK cohorts to explore their effects on the prognosis, immune landscape, molecular characteristics and drug sensitivity in CRAD. Panel gene sequencing of 30 in-house CRAD tissues and multiple immunofluorescences (mIF) were also used. Results: In multi-cancer, patients with KMT2DMT have a worse overall survival (OS), and CRAD with K-ex39MT exhibited a greater degree of immune cellular infiltration. For CRAD, compared with KMT2D exon39 wild type (K-ex39WT), K-ex39MT patients had higher tumor mutational burden (TMB) and lower copy number alteration (CNA), and were accompanied by more immune cell infiltration including activated T cells, NK cells, Treg cells and exhausted T cells and enrichment of immune-related genes and pathways. In drug sensitivity prediction, K-ex39MT patients have a lower CTX-S score and IC50 of 5-Fluorouracil and irinotecan, and higher Tumor Immune Dysfunction and Rejection (TIDE) dysfunction score. Conclusions: CRAD patients with K-ex39MT have more abundant immune cell infiltration and enrichment of immune-related pathways and signatures. And they may be more sensitive to some chemotherapies but less to cetuximab.