Transjugular intrahepatic portosystemic shunt (TIPS) with variceal embolization reduces rebleeding risk for patients with portal pressure gradient over 12 mmHg: A long-term follow-up study.

OBJECTIVE: The consensus on whether Transjugular intrahepatic portosystemic shunt (TIPS) should be combined with variceal embolization in the treatment of portal hypertension-induced bleeding has not yet been reached. This study aimed to compare the difference in rebleeding incidence between TIPS and TIPS combined with variceal embolization and to analyze the optimal population for variceal embolization. METHODS: Clinical data of 721 patients undergoing TIPS were retrospectively collected. Patients were divided into two groups: TIPS alone (n = 155) and TIPS with embolization (TIPS+E, n = 251). Kaplan-Meier (KM) curves were used to analyze prognostic differences between the two groups, and subgroup analysis was conducted based on post-TIPS portal pressure gradient (PPG) exceeding 12 mmHg. RESULTS: After TIPS placement, the mean PPG significantly decreased for all patients. A total of 51 patients (12.6 %) experienced rebleeding, with 24 cases (15.9 %) in the TIPS group and 27 cases (10.6 %) in the TIPS+E group. There was no significant difference in cumulative rebleeding incidence between the TIPS+E and TIPS groups. In the subgroup with post-TIPS PPG greater than 12 mmHg, the cumulative rebleeding incidence was significantly lower in the TIPS+E group compared to the TIPS group (HR = 0.47, 95 %CI = 0.24-0.93, Log rank P = 0.026). No significant difference was found in patients with a post-TIPS PPG less than 12 mmHg. CONCLUSION: For patients with post-TIPS PPG exceeding 12 mmHg, simultaneous variceal embolization with TIPS placement significantly reduces the risk of rebleeding.

Case report: Multi-antibody-positive myasthenia gravis concomitant myositis associated with thymoma.

Myasthenia gravis (MG) and idiopathic inflammatory myopathy (IIM) are autoimmune diseases of the nervous system, and their main clinical manifestation is muscle weakness. The concurrent presence of both conditions in the same patient is clinically rare and easily missed. Here, we report the case of a 74-year-old woman who went to the doctor with fluctuating weakness of the limbs and muscle pain. By analyzing the patient's history and the results of repeated frequency electrical stimulation, chest computed tomography, thigh muscle magnetic resonance imaging, serum antibody detection, lymph node biopsy, etc., she was finally diagnosed with MG-concomitant IIM with squamous cell carcinoma of the thymus. Acetylcholine receptor antibody, titin antibody, ryanodine receptor antibody, anti-JO-1 antibody, and Ro-52 antibody tests were positive. MG-concomitant IIM is often associated with thymoma. The immunopathology mechanism may be different from that of pure MG or IIM, which needs further research.

MRI T2w Radiomics-Based Machine Learning Models in Imaging Simulated Biopsy Add Diagnostic Value to PI-RADS in Predicting Prostate Cancer: A Retrospective Diagnostic Study.

BACKGROUND: Currently, prostate cancer (PCa) prebiopsy medical image diagnosis mainly relies on mpMRI and PI-RADS scores. However, PI-RADS has its limitations, such as inter- and intra-radiologist variability and the potential for imperceptible features. The primary objective of this study is to evaluate the effectiveness of a machine learning model based on radiomics analysis of MRI T2-weighted (T2w) images for predicting PCa in prebiopsy cases. METHOD: A retrospective analysis was conducted using 820 lesions (363 cases, 457 controls) from The Cancer Imaging Archive (TCIA) Database for model development and validation. An additional 83 lesions (30 cases, 53 controls) from Hong Kong Queen Mary Hospital were used for independent external validation. The MRI T2w images were preprocessed, and radiomic features were extracted. Feature selection was performed using Cross Validation Least Angle Regression (CV-LARS). Using three different machine learning algorithms, a total of 18 prediction models and 3 shape control models were developed. The performance of the models, including the area under the curve (AUC) and diagnostic values such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were compared to the PI-RADS scoring system for both internal and external validation. RESULTS: All the models showed significant differences compared to the shape control model (all p < 0.001, except SVM model PI-RADS+2 Features p = 0.004, SVM model PI-RADS+3 Features p = 0.002). In internal validation, the best model, based on the LR algorithm, incorporated 3 radiomic features (AUC = 0.838, sensitivity = 76.85%, specificity = 77.36%). In external validation, the LR (3 features) model outperformed PI-RADS in predictive value with AUC 0.870 vs. 0.658, sensitivity 56.67% vs. 46.67%, specificity 92.45% vs. 84.91%, PPV 80.95% vs. 63.64%, and NPV 79.03% vs. 73.77%. CONCLUSIONS: The machine learning model based on radiomics analysis of MRI T2w images, along with simulated biopsy, provides additional diagnostic value to the PI-RADS scoring system in predicting PCa.

Identification of Drought Stress-Responsive Genes in Rice by Random Walk with Multi-Restart Probability on MultiPlex Biological Networks.

Exploring drought stress-responsive genes in rice is essential for breeding drought-resistant varieties. Rice drought resistance is controlled by multiple genes, and mining drought stress-responsive genes solely based on single omics data lacks stability and accuracy. Multi-omics correlation analysis and biological molecular network analysis provide robust solutions. This study proposed a random walk with a multi-restart probability (RWMRP) algorithm, based on the Restarted Random Walk (RWR) algorithm, to operate on rice MultiPlex biological networks. It explores the interactions between biological molecules across various levels and ranks potential genes. RWMRP uses eigenvector centrality to evaluate node importance in the network and adjusts the restart probabilities accordingly, diverging from the uniform restart probability employed in RWR. In the random walk process, it can be better to consider the global relationships in the network. Firstly, we constructed a MultiPlex biological network by integrating the rice protein-protein interaction, gene pathway, and gene co-expression network. Then, we employed RWMRP to predict the potential genes associated with rice tolerance to drought stress. Enrichment and correlation analyses resulted in the identification of 12 drought-related genes. We further conducted quantitative real-time polymerase chain reaction (qRT-PCR) analysis on these 12 genes, ultimately identifying 10 genes responsive to drought stress.

Enhanced efficacy of combined VEGFR peptide-drug conjugate and anti-PD-1 antibody in treating hepatocellular carcinoma.

This study aimed to design a VEGFR-targeting peptide-drug conjugate with the ability to decrease tumor burden and suppress tumor angiogenesis, and to further evaluate the therapeutic effect of anti-PD-1 antibody in HCC therapy. A VEGFR-targeting peptide VEGF125 - 136 (QR) was conjugated with a lytic peptide (KLU) to form a peptide-drug conjugate QR-KLU. And the efficacy of QR-KLU in combination with anti-PD-1 antibody for HCC therapy in vivo and in vitro were evaluated. QR-KLU inhibited the proliferation and migration of mouse HCC cell line (Hepa1-6) cells under normoxic and hypoxic conditions in a dose-dependent manner. In the subcutaneous Hepa1-6 tumor model, QR-KLU combined with the anti-PD-1 antibody substantially inhibited tumor growth, promoted tumor necrosis, and prolonged the survival time of tumor-bearing mice. QR-KLU substantially inhibited hypoxia-induced expression of VEGF, promoted tumor vascular normalization, and increased cluster of differentiation 8+ (CD8+) T cell infiltration in the tumor. In addition, QR-KLU and anti-PD-1 antibody demonstrated a strong synergistic effect in promoting the activation of intratumoral CD8+ T cells, reducing the expression of immune-inhibitory factors, and increasing the expression of immune-stimulatory factors. This study proposed a novel approach for enhancing the efficacy of anti-PD-1 antibody using a VEGFR-targeting peptide-drug conjugate in HCC therapy.

Correlation between glymphatic dysfunction and cranial defect in severe traumatic brain injury: a retrospective case-control study based on a diffusion tensor image analysis along the perivascular space (DTI-ALPS) investigation.

Background: To date, limited research has been conducted on the functionality of the glymphatic system during the recovery phase of severe traumatic brain injury (sTBI). This study aimed to use a diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate glymphatic system function in patients recovering from sTBI who underwent unilateral decompressive craniectomy, and to examine the correlation between the ALPS index and the size of the cranial defect. We hypothesized that assessments would reveal ongoing impairments in glymphatic system function among sTBI patients during the recovery phase. Methods: A total of 23 patients with a history of sTBI who had previously undergone unilateral decompressive craniectomy at Xiangya Hospital of Central South University from January 2020 to December 2020 were enrolled in the study, along with 33 healthy control (HC) subjects. All the subjects underwent magnetic resonance imaging (MRI) with DTI scans, and the ALPS index was subsequently calculated to assess glymphatic system functionality. Additionally, the circumference and sectional area of the cranial defect were measured for each patient. An analysis of variance (ANOVA) was used to compare the ALPS index values between the sTBI patients and HC subjects, while a Pearson correlation analysis was used to examine the correlation between the ALPS index and cranial defect characteristics. Results: The ALPS index values of both the craniectomy side (t=-9.08, P<0.001) and non-craniectomy side (t=-5.06, P<0.001) of the sTBI group were significantly lower than those of the HC group. However, no statistically significant differences were observed between the ALPS index values of the craniectomy and non-craniectomy sides. Additionally, no significant differences were observed in the ALPS index values of both the craniectomy and non-craniectomy sides among the early, intermediate, and late recovery phases. In the sTBI patients, a moderately strong negative correlation was found between the circumference of the cranial defect and the ALPS index of the craniectomy side (r=-0.62, P=0.002), and a moderately negative correlation was found between the sectional area of the cranial defect and the ALPS index of the craniectomy side (r=-0.56, P=0.005). Conclusions: The non-invasive DTI-ALPS technique revealed significantly reduced ALPS index values during the recovery phase of sTBI, indicating persistent impairment in glymphatic system function. A significant negative correlation was found between the ALPS index value of the craniectomy side and the size of the cranial defect. These findings suggest that the ALPS index may serve as a valuable prognostic factor in the recovery phase of sTBI.

Thermochromic hydrogel-based energy efficient smart windows: fabrication, mechanisms, and advancements.

Thermochromic smart windows are regarded as highly cost-effective and easily implementable strategies with zero energy input among the smart window technologies. They possess the capability to spontaneously adjust between transparent and opaque states according to the ambient temperatures, which is essential for energy-efficient buildings. Recently, thermochromic smart windows based on hydrogels with various chromic mechanisms have emerged to meet the increasing demand for energy-saving smart windows. This review provides an overview of recent advancements in hydrogel-based thermochromic smart windows, focusing on fabrication strategies, chromic mechanisms, and improvements in responsiveness, stability and energy-saving performance. Key developments include dual-responsiveness, tunable critical transition temperatures, freezing resistance, and integrations with radiative cooling/power generation technologies. Finally, we also offer a perspective on the future development of thermochromic smart windows utilizing hydrogels. We hope that this review will enhance the understanding of the chromic mechanism of thermochromic hydrogels, and bring new insights and inspirations on the further design and development of thermochromic hydrogels and derived smart windows.

Association of hepatitis B core antibody level and hepatitis B surface antigen clearance in HBeAg-negative patients with chronic hepatitis B.

Predicting hepatitis B surface antigen (HBsAg) clearance is important for chronic hepatitis B (CHB) patients receiving pegylated interferon-alfa (Peg-IFN) therapy. We aimed to determine the predictive value of serum hepatitis B core antibody (anti-HBc) for HBsAg clearance. A total of 189 HBeAg-negative CHB patients who received Peg-IFN based therapy were retrospectively included and classified into two groups: nucleos(t)ide analogues (NAs) add-on Peg-IFN group (add-on group, n = 94) and Peg-IFN combined with NAs or Peg-IFN monotherapy group (combination or monotherapy group, n = 95). After 48 weeks of treatment, 27.5% (52/189) and 15.9% (30/189) of patients achieved HBsAg clearance and seroconversion, respectively. Patients in the combination or monotherapy group tended to achieve relatively higher HBsAg clearance (31.6% vs. 23.4%, p = 0.208) and seroconversion (21.1% vs. 10.6%, p = 0.050) rates than those in the add-on group. In combination or monotherapy group, anti-HBc levels at week 12 were lower in patients with HBsAg clearance (9.0 S/CO vs. 9.9 S/CO, p < 0.001) and seroconversion (8.8 S/CO vs. 9.8 S/CO, p < 0.001) than those without. Anti-HBc level at week 12 was an independent predictor of HBsAg clearance and seroconversion. Patients with lower anti-HBc levels at week 12 showed a more significant decline in HBsAg levels during treatment. Combination of anti-HBc at week 12 and baseline HBsAg could identify over 70% of patients who achieved HBsAg clearance after 48 weeks of treatment. In addition to HBsAg, anti-HBc level could be used as a promising marker for selecting HBeAg-negative CHB patients who are more likely to respond to Peg-IFN-based therapy.

Effects of intravenous pulse methylprednisolone in neuromyelitis optica during the acute phase.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. While intravenous pulse methylprednisolone (IVMP) is the recommended initial treatment option for acute onset NMOSD, its therapeutic mechanism remains unclear. We hypothesized that IVMP would reduce the expression of pro-inflammatory factors and increase the resolution of inflammation in patients with NMOSD. METHODS: Mendelian randomization (MR) analysis was used to screen meaningful inflammatory and resolution factors for inclusion. Three MR methods with inverse variance weighting (IVW) were primarily used to identify positive results. Interleukin (IL)-10, IL-1ß, IL-6, C-X-C motif chemokine ligand 12 (CXCL12), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were screened from 41 inflammatory factors, and resolvin D1 (RvD1), maresin 1 (MaR1), and lipoxin A4 (LXA4) were screened from 6 resolution markers for inclusion. Subsequently, 12 patients with NMOSD were enrolled and treated with IVMP. Serum levels of the aforementioned inflammatory and resolution markers were measured by enzyme-linked immunosorbent assay before and after IVMP treatment. RESULTS: High levels of TRAIL, CXCL12, and IL-1ß were associated with an increased risk of NMOSD (TRAIL: odds ratio [OR], 1.582; 95% confidence interval [CI], 1.003-2.495; CXCL12: OR, 3.610; 95% CI, 1.011-12.889; IL-1ß: OR, 4.500; 95% CI, 1.129-17.927). High levels of RvD1, MaR1, and LXA4 were associated with a reduced risk of NMOSD (RvD1: OR, 0.725; 95% CI, 0.538-0.976; MaR1: OR, 0.985; 95% CI, 0.970-0.999; LXA4: OR, 0.849; 95% CI, 0.727-0.993). Among patients with NMOSD, serum levels of IL-6, CXCL12, and TRAIL significantly decreased following IVMP treatment, compared with pretreatment levels, while levels of IL-1ß, LXA4, and MaR1 significantly increased after IVMP treatment (p < 0.05). A significant positive correlation was observed between CXCL12 levels and Expanded Disability Status Scale (EDSS) scores (r = 0.451, p < 0.05). CONCLUSION: Several systemic inflammatory regulators associated with the pathogenesis of NMOSD were identified. The protective roles of LXA4 and MaR1 may be indispensable components of glucocorticoid treatment. Therefore, the use of resolution markers may be a potential strategy for improving central nervous system injury in individuals with NMOSD.

Dendrite-free zinc metal anode for long-life zinc-ion batteries enabled by an artificial hydrophobic-zincophilic coating.

Considering the desired energy density, safety and cost-effectiveness, rechargeable zinc-ion batteries (ZIBs) are regarded as one of the most promising energy storage units in next-generation energy systems. Nonetheless, the service life of the current ZIBs is significantly limited by rampant dendrite growth and severe parasitic reactions occurring on the anode side. To overcome these issues caused by poor interfacial ionic conduction and water erosion, we have developed a facile strategy to fabricate a uniform zinc borate layer at the zinc anode/electrolyte interface (ZnBO). Such protective layer integrates superhydrophobic-zincopholic properties, which can effectively eliminate the direct contact of water molecules on the anode, and homogenize the interfacial ionic transfer, thereby enhancing the cyclic stability of the zinc plating/stripping. As a result, the as-prepared ZnBO-coated anode exhibits extended lifespan of 1200 h at 1 mA cm-2 and demonstrates remarkable durability of 570 h at 20 mA cm-2 in Zn||Zn symmetric cells. Additionally, when coupled to an NH4V4O10 (NVO) cathode, it also delivers a superior cyclability (203.5 mAh/g after 2000 cycles at 5 A/g, 89.3 % capacity retention) in coin full cells and a feasible capacity of 2.5 mAh at 1 A/g after 200 cycles in pouch full cells. This work offers a unique perspective on integrating hydrophobicity and zincophilicity at the anode/electrolyte interface through an artificial layer, thereby enhancing the cycle lifespan of ZIBs.

Cellular senescence: A novel therapeutic target for central nervous system diseases.

The underlying mechanisms of diseases affecting the central nervous system (CNS) remain unclear, limiting the development of effective therapeutic strategies. Remarkably, cellular senescence, a biological phenomenon observed in cultured fibroblasts in vitro, is a crucial intrinsic mechanism that influences homeostasis of the brain microenvironment and contributes to the onset and progression of CNS diseases. Cellular senescence has been observed in disease models established in vitro and in vivo and in bodily fluids or tissue components from patients with CNS diseases. These findings highlight cellular senescence as a promising target for preventing and treating CNS diseases. Consequently, emerging novel therapies targeting senescent cells have exhibited promising therapeutic effects in preclinical and clinical studies on aging-related diseases. These innovative therapies can potentially delay brain cell loss and functional changes, improve the prognosis of CNS diseases, and provide alternative treatments for patients. In this study, we examined the relevant advancements in this field, particularly focusing on the targeting of senescent cells in the brain for the treatment of chronic neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and multiple sclerosis) and acute neurotraumatic insults (e.g., ischemic stroke, spinal cord injury, and traumatic brain injury).

Planar Deposition via In Situ Conversion Engineering for Dendrite-Free Zinc Batteries.

Owing to the considerable capacity, high safety, and abundant zinc resources, zinc-ion batteries (ZIBs) have been garnering much attention. Nonetheless, the unsatisfactory cyclic lifespan and poor reversibility originate from side reactions and dendrite obstacles to their practical applications. In addition to inhibiting the corrosion of aqueous electrolytes, regulating planar deposition is a key strategy to enhance their long-term stability. Herein, an in situ conversion strategy is reported to construct a protective "dual-layer" structure (VZSe/V@Zn) on zinc metal, consisting of the VSe2-ZnSe outer layer with low lattice mismatch to Zn (002) plane, and corrosion-resistant nanometallic V inner layer. Such design integrates superior interfacial ionic/electronic transfer, corrosion resistance, and unique planar deposition regulation capability. The as-prepared VZSe/V@Zn demonstrates remarkable durability of 238 h at 50 mA cm-2 with a high depth of discharge (68.3% DOD) in the Zn||Zn symmetric cell. Even in the anode-free system, the as-prepared protective layer can extend the cycle life up to 2000 cycles, with an outstanding capacity retention of 93.1% and ultra-high average coulombic efficiency of 99.998%. This work delineates an effective strategy for fabricating lattice-matching protective layers, with profound implications for elucidating zinc deposition mechanisms and paving the way for the development of high-performance zinc batteries.

Structural basis for linker histone H5-nucleosome binding and chromatin fiber compaction.

The hierarchical packaging of chromatin fibers plays a critical role in gene regulation. The 30-nm chromatin fibers, a central-level structure bridging nucleosomal arrays to higher-order organizations, function as the first level of transcriptional dormant chromatin. The dynamics of 30-nm chromatin fiber play a crucial role in biological processes related to DNA. Here, we report a 3.6-angstrom resolution cryogenic electron microscopy structure of H5-bound dodecanucleosome, i.e., the chromatin fiber reconstituted in the presence of linker histone H5, which shows a two-start left-handed double helical structure twisted by tetranucleosomal units. An atomic structural model of the H5-bound chromatin fiber, including an intact chromatosome, is built, which provides structural details of the full-length linker histone H5, including its N-terminal domain and an HMG-motif-like C-terminal domain. The chromatosome structure shows that H5 binds the nucleosome off-dyad through a three-contact mode in the chromatin fiber. More importantly, the H5-chromatin structure provides a fine molecular basis for the intra-tetranucleosomal and inter-tetranucleosomal interactions. In addition, we systematically validated the physiological functions and structural characteristics of the tetranucleosomal unit through a series of genetic and genomic studies in Saccharomyces cerevisiae and in vitro biophysical experiments. Furthermore, our structure reveals that multiple structural asymmetries of histone tails confer a polarity to the chromatin fiber. These findings provide structural and mechanistic insights into how a nucleosomal array folds into a higher-order chromatin fiber with a polarity in vitro and in vivo.

phi and phiD predict adverse pathological features after radical prostatectomy for prostate cancer in Chinese population.

BACKGROUND: Anticipating the postoperative pathological stage and potential for adverse features of prostate cancer (PCa) patients before radical prostatectomy (RP) is crucial for guiding perioperative treatment. METHODS: A cohort consisting of three sub-cohorts with a total of 709 patients has been enlisted from two major tertiary medical centres in China. The primary assessment parameters for adverse pathological features in this study are the pathological T stage, the AJCC prognostic stage groups and perineural invasion (PNI). Logistic regression analyses were performed to investigate the relationship between prostate specific antigen (PSA), its derivatives (incluing Prostate Health Index, phi and phi density, phiD), and the pathological outcomes after RP. RESULTS: Both phi and phiD showed a significant association with pathologic T stage of pT3 or above (phi, adjusted OR, AOR = 2.82, 95% confidence interval, 95% CI: 1.88-4.23, p < 0.001; phiD, AOR = 2.47, 95% CI: 1.76-3.48, p < 0.001) and PNI (phi, AOR = 2.15, 95% CI: 1.39-3.32, p < 0.001; phiD, AOR = 1.94, 95% CI: 1.38-2.73, p < 0.001). In a subgroup analysis with a total PSA value <10 ng/mL, phi and phiD continued to show a significant correlation with pT3 or above (phi, AOR = 4.70, 95% CI: 1.29-17.12, p = 0.019; phiD, AOR = 3.44, 95% CI: 1.51-7.85, p = 0.003), and phiD also maintained its predictive capability for PNI in this subgroup (AOR = 2.10, 95% CI: 1.17-3.80, p = 0.014). Sensitivity analysis indicated that the findings in the combined cohort are mainly influenced by one of the sub-cohorts, partially attributable to disparities in sample sizes between sub-cohorts. Combined analysis of phi(D) and multiparametric MRI (mpMRI) data yielded similar results. CONCLUSIONS: Preoperative measurement of serum phi and phiD is valuable for predicting the occurrence of adverse pathological features in Chinese PCa patients after RP.

Prediction of metastases in confusing mediastinal lymph nodes based on flourine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging using machine learning.

Background: For patient management and prognosis, accurate assessment of mediastinal lymph node (LN) status is essential. This study aimed to use machine learning approaches to assess the status of confusing LNs in the mediastinum using positron emission tomography/computed tomography (PET/CT) images; the results were then compared with the diagnostic conclusions of nuclear medicine physicians. Methods: A total of 509 confusing mediastinal LNs that had undergone pathological assessment or follow-up from 320 patients from three centres were retrospectively included in the study. LNs from centres I and II were randomised into a training cohort (N=324) and an internal validation cohort (N=81), while those from centre III patients formed an external validation cohort (N=104). Various parameters measured from PET and CT images and extracted radiomics and deep learning features were used to construct PET/CT-parameter, radiomics, and deep learning models, respectively. Model performance was compared with the diagnostic results of nuclear medicine physicians using the area under the curve (AUC), sensitivity, specificity, and decision curve analysis (DCA). Results: The coupled model of gradient boosting decision tree-logistic regression (GBDT-LR) incorporating radiomic features showed AUCs of 92.2% [95% confidence interval (CI), 0.890-0.953], 84.6% (95% CI, 0.761-0.930) and 84.6% (95% CI, 0.770-0.922) across the three cohorts. It significantly outperformed the deep learning model, the parametric PET/CT model and the physician's diagnosis. DCA demonstrated the clinical usefulness of the GBDT-LR model. Conclusions: The presented GBDT-LR model performed well in evaluating confusing mediastinal LNs in both internal and external validation sets. It not only crossed radiometric features but also avoided overfitting.

Growth, Antioxidant Capacity, and Liver Health in Largemouth Bass (Micropterus salmoides) Fed Multi-Strain Yeast-Based Paraprobiotic: A Lab-to-Pilot Scale Evaluation.

A multi-strain yeast-based paraprobiotic (MsYbP) comprising inactive cells and polysaccharides (ß-glucan, mannan oligosaccharides, and oligosaccharides) derived from Saccharomyces cerevisiae and Cyberlindnera jadinii could ensure optimal growth and health in farmed fish. This study assessed the impact of an MsYbP on the growth, immune responses, antioxidant capacities, and liver health of largemouth bass (Micropterus salmoides) through lab-scale (65 days) and pilot-scale (15 weeks) experiments. Two groups of fish were monitored: one fed a control diet without the MsYbP and another fed 0.08% and 0.1% MsYbP in the lab-scale and pilot-scale studies, respectively (referred to as YANG). In the lab-scale study, four replicates were conducted, with 20 fish per replicate (average initial body weight = 31.0 ± 0.8 g), while the pilot-scale study involved three replicates with approximately 1500 fish per replicate (average initial body weight = 80.0 ± 2.2 g). The results indicate that the MsYbP-fed fish exhibited a significant increase in growth in both studies (p < 0.05). Additionally, the dietary MsYbP led to a noteworthy reduction in the liver function parameters (p < 0.05), such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (AKP), and hepatic nuclear density, indicating improved liver health. Furthermore, the dietary MsYbP elevated the antioxidative capacity of the fish by reducing their malondialdehyde levels and increasing their levels and gene expressions related to antioxidative markers, such as total antioxidant ca-pacity (T-AOC), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), catalase (CAT), nuclear factor erythroid 2-related factor 2 (nrf2) and kelch-1ike ech-associated protein (keap1) in both studies (p < 0.05). In terms of hepatic immune responses, the lab-scale study showed an increase in inflammation-related gene expressions, such as interleukin-1ß (il-1ß) and transforming growth factor ß1 (tgf-ß1), while the pilot-scale study significantly suppressed the expressions of genes related to inflammatory responses, such as tumor necrosis factor α (tnfα) and interleukin-10 (il-10) (p < 0.05). In summary, our findings underscore the role of dietary multi-strain yeast-based paraprobiotics in enhancing the growth and liver health of largemouth bass, potentially through increased antioxidative capacity and the modulation of immune responses, emphasizing the significance of employing yeast-based paraprobiotics in commercial conditions.

Lubricin-Inspired Nanozymes Reconstruct Cartilage Lubrication System with an "In-Out" Strategy.

Lubricin, secreted primarily by chondrocytes, plays a critical role in maintaining the function of the cartilage lubrication system. However, both external factors such as friction and internal factors like oxidative stress can disrupt this system, leading to osteoarthritis. Inspired by lubricin, a lubricating nanozyme, that is, Poly-2-acrylamide-2-methylpropanesulfonic acid sodium salt-grafted aminofullerene, is developed to restore the cartilage lubrication system using an "In-Out" strategy. The "Out" aspect involves reducing friction through a combination of hydration lubrication and ball-bearing lubrication. Simultaneously, the "In" aspect aims to mitigate oxidative stress by reducing free radical, increasing autophagy, and improving the mitochondrial respiratory chain. This results in reduced chondrocyte senescence and increased lubricin production, enhancing the natural lubrication ability of cartilage. Transcriptome sequencing and Western blot results demonstrate that it enhances the functionality of mitochondrial respiratory chain complexes I, III, and V, thereby improving mitochondrial function in chondrocytes. In vitro and in vivo experiments show that the lubricating nanozymes reduce cartilage wear, improve chondrocyte senescence, and mitigate oxidative stress damage, thereby mitigating the progression of osteoarthritis. These findings provide novel insights into treating diseases associated with oxidative stress and frictional damage, such as osteoarthritis, and set the stage for future research and development of therapeutic interventions.

Atmospheric oxidation drove climate change on Noachian Mars.

Modern Mars is bipolar, cold, and oxidizing, while early Mars was characterized by icy highlands, episodic warmth and reducing atmosphere. The timing and association of the climate and redox transitions remain inadequately understood. Here we examine the spatiotemporal distribution of the low surface iron abundance in the ancient Martian terrains, revealing that iron abundance decreases with elevation in the older Noachian terrains but with latitude in the younger Noachian terrains. These observations suggest: (a) low-temperature conditions contribute to surface iron depletion, likely facilitated by anoxic leaching through freeze-thaw cycles under a reducing atmosphere, and (b) temperature distribution mode shifted from elevation-dominant to latitude-dominant during the Noachian period. Additionally, we find iron leaching intensity decreases from the Early to Late Noachian epoch, suggesting a gradual atmospheric oxidation coupled with temperature mode transition during the Noachian period. We think atmospheric oxidation led to Mars becoming cold and bipolar in its early history.

Neuronal DNA repair reveals strategies to influence CRISPR editing outcomes.

Genome editing is poised to revolutionize treatment of genetic diseases, but poor understanding and control of DNA repair outcomes hinders its therapeutic potential. DNA repair is especially understudied in nondividing cells like neurons, which must withstand decades of DNA damage without replicating. This lack of knowledge limits the efficiency and precision of genome editing in clinically relevant cells. To address this, we used induced pluripotent stem cells (iPSCs) and iPSC-derived neurons to examine how postmitotic human neurons repair Cas9-induced DNA damage. We discovered that neurons can take weeks to fully resolve this damage, compared to just days in isogenic iPSCs. Furthermore, Cas9-treated neurons upregulated unexpected DNA repair genes, including factors canonically associated with replication. Manipulating this response with chemical or genetic perturbations allowed us to direct neuronal repair toward desired editing outcomes. By studying DNA repair in postmitotic human cells, we uncovered unforeseen challenges and opportunities for precise therapeutic editing.

Blocking TGFßR synergistically enhances anti-tumor effects of anti-PD-1 antibody in a mouse model of incomplete thermal ablation.

The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy is reported to be ineffective to prevent the progression of residual tumor resulted from iMWA. Transforming growth factor-ß (TGFß) signaling pathway plays an important role in tumorigenesis and development. We assume blocking transforming growth factor-ß receptor (TGFßR) after incomplete iMWA may synergistically enhance the effect of anti-PD-1 antibody to prevent the progression of residual tumor. We construct an iMWA model with mice harboring Hepa1-6 derived xenograft. The Tgfb1 expression and phosphorylated-Smad3 protein expression is upregulated in the residual tumor after iMWA. With the application of TGFßR inhibitor SB431542, the cell proliferation potential, the tumor growth, the mRNA expression of epithelial mesenchymal transition (EMT) markers including Cdh2, and Vim, and cancer stem cell marker Epcam, and the infiltrating Treg cells are reduced in the residual tumor tissue. In addition, iMWA combined with TGFßR blocker and anti-PD-1 antibody further decreases the cell proliferation, tumor growth, expression of EMT markers and cancer stem cell marker, and the infiltrating Treg cells in the residual tumor tissue. Blocking TGFßR may alleviate the pro-tumoral effect of tumor microenvironment thereby significantly prevents the progression of residual tumor tissue. Our study indicates that blocking TGFßR may be a novel therapeutic strategy to enhance the effect of anti-PD-1 antibody to prevent residual hepatocellular carcinoma (HCC) progression after iMWA.