Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans.

Immunotherapy leads to cancer eradication despite the tumor's immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules. The craters harbor the highest density of CD8 + T cells in the tumor. In zebrafish, CD8 + T cells formed prolonged interactions with melanoma cells within craters, characteristic of antigen recognition. Following immunostimulatory treatment, the craters enlarged and became the major site of activated CD8 + T cell accumulation and tumor killing that was B2M dependent. In humans, craters predicted immune response to ICB therapy, showing response better than high T cell infiltration. This marks craters as potential new diagnostic tool for immunotherapy success and targets to enhance ICB response.

Analysis of risk factors for post-thrombotic syndrome after thrombolysis therapy for acute deep venous thrombosis of lower extremities.

Objective: The purpose of the research is to explore post-thrombotic syndrome (PTS) after catheter-directed thrombolysis (CDT) treatment for acute lower extremity deep vein thrombosis (DVT) risk factors. Methods: We retrospectively selected 171 patients with acute lower extremity DVT undergoing CDT treatment, collected clinical data of the patients, grouped them according to the follow-up results of 1 year after treatment, and included patients with PTS into the concurrent group and patients who did not develop PTS assigned to the unconcurrent group. Univariate analysis and Logistic regression were applied to analyze the risk factors of PTS after catheterization and thrombolytic therapy for acute lower extremity DVT. We applied R4.2.3 software to build three hybrid machine-learning models, including a nomogram, decision tree, and random forest with independent influencing factors as predictive variables. Results: The incidence of PTS after CDT in acute lower extremity DVT was 36.84 %. BMI >24.33 kg/m2, disease time >7 d, mixed DVT, varicose vein history, stress treatment time>6.5 months, and filter category were independent risk factors for PTS after CDT treatment for acute lower extremity DVT. The AUC value predicted by the random forest model was higher than that of the nomogram model (Z = -2.337, P = 0.019) and the decision tree model (Z = -2.995, P = 0.003). Conclusion: The occurrence of PTS after CDT treatment of acute lower extremity DVT is closely related to many factors, and the established random forest model had the best effect in predicting PTS complicated with PTS.

SREBP2 restricts osteoclast differentiation and activity by regulating IRF7 and limits inflammatory bone erosion.

Osteoclasts are multinucleated bone-resorbing cells, and their formation is tightly regulated to prevent excessive bone loss. However, the mechanisms by which osteoclast formation is restricted remain incompletely determined. Here, we found that sterol regulatory element binding protein 2 (SREBP2) functions as a negative regulator of osteoclast formation and inflammatory bone loss. Cholesterols and SREBP2, a key transcription factor for cholesterol biosynthesis, increased in the late phase of osteoclastogenesis. The ablation of SREBP2 in myeloid cells resulted in increased in vivo and in vitro osteoclastogenesis, leading to low bone mass. Moreover, deletion of SREBP2 accelerated inflammatory bone destruction in murine inflammatory osteolysis and arthritis models. SREBP2-mediated regulation of osteoclastogenesis is independent of its canonical function in cholesterol biosynthesis but is mediated, in part, by its downstream target, interferon regulatory factor 7 (IRF7). Taken together, our study highlights a previously undescribed role of the SREBP2-IRF7 regulatory circuit as a negative feedback loop in osteoclast differentiation and represents a novel mechanism to restrain pathological bone destruction.

CT anatomical study of extreme lateral interbody fusion in thoracic spine.

Extreme Lateral Interbody Fusion (XLIF) is currently used in the clinical treatment of thoracic spine disorders and has achieved desirable results. In this study, we selected CT images of the thoracic spine from 54 patients and divided the intervertebral spaces into six regions (A, I, II, III, IV, P) using the Moro method. We observed the adjacent relationships between the thoracic spine and surrounding tissues such as the scapula, esophagus, thoracic aorta, and superior vena cava. We made four main findings: firstly, when the scapulae were symmetrical on both sides, over 80% of patients had the T1-4 II-III region obstructed by the scapulae; secondly, when the esophagus was located on the left side of the vertebral body, 3.7% to 24.1% of patients had the T4-9 region located in the II-III zone; furthermore, when the thoracic aorta was on the left side of the vertebral body, over 80% of individuals in the T4-9 segment occupied the II-III region, with the values being 55.5% and 20.4% for T9/10 and T10/11, respectively; finally, the superior vena cava was located on the right side of the T4/5 vertebra, with 3.7% of individuals having it in the II-III region, while on the left side of T5-9, 3.7% to 18.5% of individuals had it in the II-III region. Based on these findings, we suggest that XLIF should not be performed on the T1-4 vertebrae due to scapular obstruction. Selecting the left-sided approach for XLIF in the T4-11 segments may risk injuring the thoracic aorta, esophagus, and superior vena cava, while the T11/12 segment is considered safe and feasible. Choosing the right-sided approach for XLIF may pose a risk of injuring the superior vena cava in the T4/5 segment, but it is safe and feasible in the T5-12 segments.

Unlocking Fast Potassium Ion Kinetics: High-Rate and Long-Life Potassium Dual-Ion Battery for Operation at -60 °C.

Energy storage devices operating at low temperatures are plagued by sluggish kinetics, reduced capacity, and notorious dendritic growth. Herein, novel potassium dual-ion batteries (PDIBs) capable of superior performance at -60 °C, and fabricated by combining MXenes and polytriphenylamine (PTPAn) as the anode and cathode, respectively, are presented. Additionally, the reason for the anomalous kinetics of K+ (faster at low temperature than at room temperature) on the Ti3C2 anode is investigated. Theoretical calculations, crossover experiments, and in situ XRD at room and low temperatures revealed that K+ tends to bind with solvent molecules rather than anions at subzero temperatures, which not only inhibits the participation of PF6 - in the formation of the solid electrolyte interphase (SEI), but also guarantees co-intercalation behavior and suppresses undesirable K+ storage. The advantageous properties at low temperatures endow the Ti3C2 anode with fast K+ kinetics to unlock the outstanding performance of PDIB at ultralow temperatures. The PDIBs exhibit superior rate capability and high capacity retention at -40 °C and -60 °C. Impressively, after charging-discharging for 20,000 cycles at -60 °C, the PDIB retained 86.7 % of its initial capacity. This study reveals the influence of temperatures on MXenes and offers a unique design for dual-ion batteries operating at ultralow temperatures.

Synergistic N/Mn Codoping Deagglomerate Carbon Coating of LiFePO4/C To Boost Electrochemical Performance.

LiFePO4 is widely used because of its high safety and cycle stability, but its inefficient electronic conductivity combined with sluggish Li+ diffusivity restricts its performance. To overcome this obstacle, applying a layer of conductive carbon onto the surface of LiFePO4 has the greatest improvement in electronic conductivity and Li+ diffusivity. However, the rate performance of carbon-coated LiFePO4 makes it difficult to meet the application requirements. Although nitrogen doping improves electrochemical performance by providing active sites and electronic conductivity, the N-doped carbon coating is prone to agglomeration, which causes a sharp decrease in capacity when the current rate increases. In this work, a synergistic N, Mn codoping strategy is implemented to overcome the aforementioned drawbacks by disrupting the large agglomeration of C-N bonds, improving the uniformity of the surface coating layer to enhance the completeness of the conductive network and increasing the number of Li+ diffusion channels, and thus accelerating the mass transfer rate under high-rate current. Consequently, this strategy effectively improves the rate capability (119 mA h g-1 at 10 C) while maintaining excellent cycling performance (88% capacity retention over 600 cycles at 5 C). This work improves the rate of ion diffusion and the rate capability of micrometer-sized LiFePO4, thus, enabling its wider application.

A memory-based spatial evolutionary game with the dynamic interaction between learners and profiteers.

Spatial evolutionary games provide a valuable framework for elucidating the emergence and maintenance of cooperative behaviors. However, most previous studies assume that individuals are profiteers and neglect to consider the effects of memory. To bridge this gap, in this paper, we propose a memory-based spatial evolutionary game with dynamic interaction between learners and profiteers. Specifically, there are two different categories of individuals in the network, including profiteers and learners with different strategy updating rules. Notably, there is a dynamic interaction between profiteers and learners, i.e., each individual has the transition probability between profiteers and learners, which is portrayed by a Markov process. Besides, the payoff of each individual is not only determined by a single round of the game but also depends on the memory mechanism of the individual. Extensive numerical simulations validate the theoretical analysis and uncover that dynamic interactions between profiteers and learners foster cooperation, memory mechanisms facilitate the emergence of cooperative behaviors among profiteers, and increasing the learning rate of learners promotes a rise in the number of cooperators. In addition, the robustness of the model is verified through simulations across various network sizes. Overall, this work contributes to a deeper understanding of the mechanisms driving the formation and evolution of cooperation.

Association of Human Whole-blood NAD + Levels with Nabothian Cyst.

Objective: Little is known about the association between whole-blood nicotinamide adenine dinucleotide (NAD +) levels and nabothian cysts. This study aimed to assess the association between NAD + levels and nabothian cysts in healthy Chinese women. Methods: Multivariate logistic regression analysis was performed to analyze the association between NAD + levels and nabothian cysts. Results: The mean age was 43.0 ± 11.5 years, and the mean level of NAD + was 31.3 ± 5.3 µmol/L. Nabothian cysts occurred in 184 (27.7%) participants, with single and multiple cysts in 100 (15.0%) and 84 (12.6%) participants, respectively. The total nabothian cyst prevalence gradually decreased from 37.4% to 21.6% from Q1 to Q4 of NAD + and the prevalence of single and multiple nabothian cysts also decreased across the NAD + quartiles. As compared with the highest NAD + quartile (≥ 34.4 µmol/L), the adjusted odds ratios with 95% confidence interval of the NAD + Q1 was 1.89 (1.14-3.14) for total nabothian cysts. The risk of total and single nabothian cysts linearly decreased with increasing NAD + levels, while the risk of multiple nabothian cysts decreased more rapidly at NAD + levels of 28.0 to 35.0 µmol/L. Conclusion: Low NAD + levels were associated with an increased risk of total and multiple nabothian cysts.

Xylarkarynone A and B: Two Bioactive Eremophilane Sesquiterpenes from Xylaria sp. HHY-2.

A new compound xylarkarynone A (1), a first reported natural product compound xylarkarynone B (2) and eight known compounds (3-10) were isolated from Xylaria sp. HHY-2. Their structures were elucidated by spectroscopic methods, DP4+ probability analyses and electronic circular dichroism (ECD) calculations. The bioactivities of isolated compounds were assayed. Compound 1 exhibited obvious activity against A549 cells with an IC50 value of 6.12±0.28 µM. Additionally, compound 1 showed moderate antifungal activities against Plectosphaerella cucumerina and Aspergillus niger with minimum inhibitory concentrations (MICs) of both 16 µg/mL, which was at the same grade with positive control nystatin. Most compounds exhibited varying degrees of inhibitory activity against P. cucumerina, indicating that Xylaria sp. has potential as inhibitors against P. cucumerina.

Hydrogen Therapy Reverses Cancer-Associated Fibroblasts Phenotypes and Remodels Stromal Microenvironment to Stimulate Systematic Anti-Tumor Immunity.

Tumor microenvironment (TME) plays an important role in the tumor progression. Among TME components, cancer-associated fibroblasts (CAFs) show multiple tumor-promoting effects and can induce tumor immune evasion and drug-resistance. Regulating CAFs can be a potential strategy to augment systemic anti-tumor immunity. Here, the study observes that hydrogen treatment can alleviate intracellular reactive oxygen species of CAFs and reshape CAFs' tumor-promoting and immune-suppressive phenotypes. Accordingly, a controllable and TME-responsive hydrogen therapy based on a CaCO3 nanoparticles-coated magnesium system (Mg-CaCO3) is developed. The hydrogen therapy by Mg-CaCO3 can not only directly kill tumor cells, but also inhibit pro-tumor and immune suppressive factors in CAFs, and thus augment immune activities of CD4+ T cells. As implanted in situ, Mg-CaCO3 can significantly suppress tumor growth, turn the "cold" primary tumor into "hot", and stimulate systematic anti-tumor immunity, which is confirmed by the bilateral tumor transplantation models of "cold tumor" (4T1 cells) and "hot tumor" (MC38 cells). This hydrogen therapy system reverses immune suppressive phenotypes of CAFs, thus providing a systematic anti-tumor immune stimulating strategy by remodeling tumor stromal microenvironment.