Cancer Cachexia in STK11/LKB1 -mutated NSCLC is Dependent on Tumor-secreted GDF15.

Cachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations in STK11/LKB1 , a regulator of the energy sensor AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are associated with cancer-related weight loss in NSCLC patients. Here we characterized the relevance of the NSCLC-associated cachexia factor growth differentiation factor 15 (GDF15) in several patient-derived and genetically engineered STK11/LKB1 -mutant NSCLC cachexia lines. Both tumor mRNA expression and serum concentrations of tumor-derived GDF15 were significantly elevated in multiple mice transplanted with patient-derived STK11/LKB1 -mutated NSCLC lines. GDF15 neutralizing antibody administered to mice transplanted with patient- or mouse-derived STK11/LKB1 -mutated NSCLC lines suppressed cachexia-associated adipose loss, muscle atrophy, and changes in body weight. The silencing of GDF15 in multiple human NSCLC lines was also sufficient to eliminate in vivo circulating GDF15 levels and abrogate cachexia induction, suggesting that tumor and not host tissues represent a key source of GDF15 production in these cancer models. Finally, reconstitution of wild-type STK11/LKB1 in a human STK11/LKB1 loss-of-function NSCLC line that normally induces cachexia in vivo correlated with the absence of tumor-secreted GDF15 and rescue from the cachexia phenotype. The current data provide evidence for tumor-secreted GDF15 as a conduit and a therapeutic target through which NSCLCs with STK11/LKB1 loss-of-function mutations promote cachexia-associated wasting.

An international relations quantitative evaluation model (IRQEM) based on an integrated method.

International relations (IR) have great uncertainty and instability. Bad IR or conflicts will bring about heavy economic losses and widespread social unrest domestically and internationally. The accurate prediction for bilateral relations can support decision making for timely responses, which will be used to find ways to maintain development in the complex international situation. An international relations quantitative evaluation model (IRQEM) is proposed by integrating a variety of research models and methods like the interpretative structural modeling method (ISM), Bayesian network (BN) model, the Bayesian search (BS), and the expectation-maximization (EM) algorithm, which is novel for IR research. Factors from several different fields are identified as BN nodes. Each node is assigned different state values. The hierarchical structure of these BN nodes is obtained by ISM. The data collection of 192 cases is used to construct the BN model by GeNIe 4.0. The IRQEM can be used to evaluate the influence of emergencies on IR. The critical factors of IR also can be explored through our proposed model. Results show that the prediction of bilateral relations under emergencies can be realized by updating the indicator set when emergencies occur. The capability to anticipate threats of IR changes is advanced by optimizing the reporting information of IR forecasting through a combination of qualitative and quantitative methods, charts, and texts. Relevant analysis results can provide support for national security decision making.

Blood-Catalyzed Polymerization Creates Conductive Polymer in Live Zebrafish.

Conducting polymers are of great interest in bioimaging, bio-interfaces, and bioelectronics for their biocompatibility and the unique combination of optical, electrical, and mechanical properties. They are typically prepared outside through traditional organic synthesis and delivered into the biological systems. The ability to call for the polymerization ingredients available inside the living systems to generate conducting polymers in vivo will offer new venues in future biomedical applications. This study is the first report of in vivo synthesis of an n-doped conducting polymer (n-PBDF) within live zebrafish embryos, achieved through whole blood catalyzed polymerization of 3,7-dihydrobenzo[1,2-b:4,5-b']difuran-2,6-dione (BDF). Prior to this, the efficacy of such a polymerization was rigorously established through a sequence of in vitro experiments involving Hemin, Hemoproteins (Hemoglobin, Myoglobin, and Cytochrome C), red blood cells, and the whole blood. Ultimately, in cellulo formed n-PBDF within cultured primary neurons demonstrated enhanced bio-interfaces and led to more effective light-induced neural activation than the prefabricated polymer. This underscores the potential advantages of synthesizing conducting polymers directly in living systems for biomedical applications.

Dual-mode nanoprobe strategy integrating ultrasound and near-infrared light for targeted and synergistic arterial thrombolysis.

Efficient thrombolysis in time is crucial for prognostic improvement of patients with acute arterial thromboembolic disease, while limitations and complications still exist in conventional thrombolytic treatment methods. Herein, our study sought to investigate a novel dual-mode strategy that integrated ultrasound (US) and near-infrared light (NIR) with establishment of hollow mesoporous silica nanoprobe (HMSN) which contains Arginine-glycine-aspartate (RGD) peptide (thrombus targeting), perfluoropentane (PFP) (thrombolysis with phase-change and stable cavitation) and indocyanine green (ICG) (thrombolysis with photothermal conversion). HMSN is used as the carrier, the surface is coupled with targeted RGD to achieve high targeting and permeability of thrombus, PFP and ICG are loaded to achieve the collaborative diagnosis and treatment of thrombus by US and NIR, so as to provide a new strategy for the integration of diagnosis and treatment of arterial thrombus. From the in vitro and in vivo evaluation, RGD/ICG/PFP@HMSN can aggregate and penetrate at the site of thrombus, and finally establish the dual-mode directional development and thrombolytic treatment under the synergistic effect of US and NIR, providing strong technical support for the accurate diagnosis and treatment of arterial thrombosis.

Enantioselective copper-catalyzed azidation/click cascade reaction for access to chiral 1,2,3-triazoles.

Chiral 1,2,3-triazoles are highly attractive motifs in various fields. However, achieving catalytic asymmetric click reactions of azides and alkynes for chiral triazole synthesis remains a significant challenge, mainly due to the limited catalytic systems and substrate scope. Herein, we report an enantioselective azidation/click cascade reaction of N-propargyl-ß-ketoamides with a readily available and potent azido transfer reagent via copper catalysis, which affords a variety of chiral 1,2,3-triazoles with up to 99% yield and 95% ee under mild conditions. Notably, chiral 1,5-disubstituted triazoles that have not been accessed by previous asymmetric click reactions are also prepared with good functional group tolerance.

Value of Ultrasound Super-Resolution Imaging for the Assessment of Renal Microcirculation in Patients with Acute Kidney Injury: A Preliminary Study.

The present study aimed to explore the clinical applicability of ultrasound super-resolution imaging (US SRI) for assessing renal microcirculation in patients with acute kidney injury (AKI). A total of 62 patients with sepsis were enrolled in the present study-38 with AKI and 24 control patients-from whom renal ultrasounds and clinical data were obtained. SonoVue contrast (1.5 mL) was administered through the elbow vein and contrast-enhanced ultrasound (CEUS) images were obtained on a Mindray Resona A20 ultrasound unit for 2 min. The renal perfusion time-intensity curve (TIC) was analyzed and, after 15 min, additional images were obtained to create a microscopic blood flow map. Microvascular density (MVD) was calculated and its correlation with serum creatinine (Scr) levels was analyzed. There were significant differences in heart rate, Scr, blood urea nitrogen, urine volume at 24 h, and glomerular filtration rate between the two groups (p < 0.01), whereas other characteristics, such as renal morphology, did not differ significantly between the AKI group and control group (p > 0.05). The time to peak and mean transit times of the renal cortex in the AKI group were prolonged compared to those in the control group (p < 0.01), while the peak intensity and area under the TIC were lower than those in the control group (p < 0.05). The MVD of the renal cortex in the AKI group was lower than that in the control group (18.46 ± 5.90% vs. 44.93 ± 11.65%; p < 0.01) and the MVD in the AKI group showed a negative correlation with Scr (R = -0.84; p < 0.01). Based on the aforementioned results, US SRI can effectively assess renal microcirculation in patients with AKI and is a noninvasive technique for the diagnosis of AKI and quantitative evaluation of renal microcirculation.

Molecular basis for Gßγ-mediated activation of phosphoinositide 3-kinase γ.

The conversion of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-triphosphate by phosphoinositide 3-kinase γ (PI3Kγ) is critical for neutrophil chemotaxis and cancer metastasis. PI3Kγ is activated by Gßγ heterodimers released from G protein-coupled receptors responding to extracellular signals. Here we determined cryo-electron microscopy structures of Sus scrofa PI3Kγ-human Gßγ complexes in the presence of substrates/analogs, revealing two Gßγ binding sites: one on the p110γ helical domain and another on the p101 C-terminal domain. Comparison with PI3Kγ alone reveals conformational changes in the kinase domain upon Gßγ binding that are similar to Ras·GTP-induced changes. Assays of variants perturbing the Gßγ binding sites and interdomain contacts altered by Gßγ binding suggest that Gßγ recruits the enzyme to membranes and allosterically regulates activity via both sites. Studies of zebrafish neutrophil migration align with these findings, paving the way for in-depth investigation of Gßγ-mediated activation mechanisms in this enzyme family and drug development for PI3Kγ.

Sphingomonas lacusdianchii sp. nov., an attached bacterium inhibited by metabolites from its symbiotic cyanobacterium.

An alpha-proteobacterial strain JXJ CY 53 T was isolated from the cyanosphere of Microcystis sp. FACHB-905 (MF-905) collected from Lake Dianchi, China. JXJ CY 53 T was observed to be an aerobic, Gram-stain-negative, oval shaped, and mucus-secreting bacterium. It had C18:1ω7c and C16:0 as the major cellular fatty acids, Q-10 as the predominant ubiquinone, and sphingoglycolipid, diphosphatidylglycerol, phosphatidylcholine, and phosphatidylmethylethanolamine as the polar lipids. The G + C content of DNA was 65.85%. The bacterium had 16S rRNA gene sequence identities of 98.9% and 98.7% with Sphingomonas panni DSM 15761 T and Sphingomonas hankookensis KCTC 22579 T, respectively, while less than 97.4% identities with other members of the genus. Further taxonomic analysis indicated that JXJ CY 53 T represented a new member of Sphingomonas, and the species epithet was proposed as Sphingomonas lacusdianchii sp. nov. (type strain JXJ CY 53 T = KCTC 72813 T = CGMCC 1.17657 T). JXJ CY 53 T promoted the growth of MF-905 by providing bio-available phosphorus and nitrogen, plant hormones, vitamins, and carotenoids. It could modulate the relative abundances of nonculturable bacteria associated with MF-905 and influence the interactions of MF-905 and other bacteria isolated from the cyanobacterium, in addition to microcystin production characteristics. Meanwhile, MF-905 could provide JXJ CY 53 T dissolved organic carbon for growth, and control the growth of JXJ CY 53 T by secreting specific chemicals other than microcystins. Overall, these results suggest that the interactions between Microcystis and its attached bacteria are complex and dynamic, and may influence the growth characteristics of the cyanobacterium. This study provided new ideas to understand the interactions between Microcystis and its attached bacteria. KEY POINTS: • A novel bacterium (JXJCY 53 T) was isolated from the cyanosphere of Microcystis sp. FACHB-905 (MF-905) • JXJCY 53 T modulated the growth and microcystin production of MF-905 • MF-905 could control the attached bacteria by specific chemicals other than microcystins (MCs).

Beyond silence: evolving ultrasound strategies in the battle against cardiovascular thrombotic challenges.

Cardiovascular thrombotic events have long been a perplexing factor in clinical settings, influencing patient prognoses significantly. Ultrasound-mediated acoustic therapy, an innovative thrombolytic treatment method known for its high efficiency, non-invasiveness, safety, and convenience, has demonstrated promising potential for clinical applications and has gradually become a focal point in cardiovascular thrombotic disease research. The current challenge lies in the technical complexities of preparing ultrasound-responsive carriers with thrombus-targeting capabilities and high thrombolytic efficiency. Additionally, optimizing the corresponding acoustic treatment mode is crucial to markedly enhance the thrombolytic effectiveness of ultrasound-mediated acoustic therapy. In light of the current status, this article provides a comprehensive review of the research progress in innovative ultrasound-mediated acoustic therapy for cardiovascular thrombotic diseases. It explores the impact of technical methods, therapeutic mechanisms, and influencing factors on the thrombolytic efficiency and clinical potential of ultrasound-mediated acoustic therapy. The review places particular emphasis on identifying solutions and key considerations in addressing the challenges associated with this cutting-edge therapeutic approach.

Associations of fasting plasma glucose with all-cause mortality and cardiovascular events in older Chinese diabetes patients: A population-based cohort study.

AIMS/INTRODUCTION: Our aim was to investigate the optimal fasting glucose (FPG) range in Chinese older adults with type 2 diabetes, and to clarify whether the optimal range varies according to the control of risk factors. MATERIALS AND METHODS: The baseline survey for the cohort study began in 2018, with follow up ending in 2022. Our study enrolled 59,030 older diabetes patients with no history of cardiovascular disease (CVD). Participants were divided into nine groups based on their baseline glycemic status. The association between FPG and the risk of adverse outcomes was mainly estimated by multivariate Cox proportional risk models and restricted spline analysis. RESULTS: During the 4-year follow-up period, a total of 5,637 deaths and 4,904 CVD events occurred. The associations of FPG with mortality and CVD events showed J-shaped curves. Among all-cause deaths, the hazard ratios for FPG ≤4.50 and >11.50 mmol/L were 1.50 (95% confidence interval [CI] 1.31-1.71) and 1.84 (95% CI 1.67-2.02). Among CVD, the hazard ratios for FPG ≤4.50 and >11.50 mmol/L were 1.31 (95% CI 1.13-1.53) and 1.71 (95% CI 1.54-1.89), respectively. The optimal FPG ranges of all-cause mortality and CVD were 5.50-7.50 and 4.50-7.50 mmol/L, respectively. For participants with at least two risk factors, the optimal FPG levels were higher than those with fewer risk factors. CONCLUSIONS: In older Chinese diabetes patients, the FPG ranges related to the minimum death and CVD event rates were 5.50-7.50 and 4.50-7.50 mmol/L, respectively. Patients with more cardiovascular risk factors had higher optimal blood glucose ranges than those with fewer risk factors.

Ubiquity of Synthetic Phenolic Antioxidants in Children's Cerebrospinal Fluid from South China: First Evidence for Their Penetration across the Blood-Cerebrospinal Fluid Barrier.

Synthetic phenolic antioxidants (SPAs) and relevant transformation products (TPs) are potentially neurotoxic pollutants to which humans are widely exposed. However, their penetration behavior across the brain barrier and associated exposure to the central nervous system (CNS) remain unknown. This study is the first to investigate a wide range of 30 SPAs and TPs, including emerging SPAs, in matched serum and cerebrospinal fluid (CSF) samples from children in Guangzhou, China. Sixty-two children of either sex aged <14 years with nonbloody CSF and complete clinical information were included. The findings demonstrated the ubiquitous occurrence of many SPAs and TPs, particularly BHT, 2,4-di-tert-butylphenol (DBP), AO 1010, AO 1076, BHT-Q, and BHT-quinol, not only in serum but also in the CSF. Median total concentrations of SPAs and TPs were up to 22.0 and 2.63 ng/mL in serum and 14.5 and 2.11 ng/mL in CSF, respectively. On calculating the penetration efficiencies across the blood-CSF barrier (BCSFB) (RCSF/serum, CCSF/Cserum) for selected SPAs and TPs, their RCSF/serum values (median 0.52-1.41) were highly related to their physicochemical properties, indicating that passive diffusion may be the potential mechanism of BCSFB penetration. In addition, the RCSF/serum values were positively correlated with the barrier permeability index RAlb (AlbuminCSF/Albuminserum), indicating that barrier integrity is an important determinant of BCSFB penetration. Overall, these results will improve our perception of human internal exposure to SPAs and lay a solid foundation for assessing the risk of CNS exposure to various SPAs.

ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis.

ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive ARID1A-mutant lymphomas through the formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.

SMARCA4 is a haploinsufficient B cell lymphoma tumor suppressor that fine-tunes centrocyte cell fate decisions.

SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 (PU.1), IRF family, and NF-κB. Loss of activity for these factors phenocopied aberrant BCL6 activity within murine centrocytes and human Burkitt lymphoma cells. SMARCA4 therefore facilitates chromatin accessibility for TFs that shape centrocyte trajectories, and loss of fine-control of these programs biases toward centroblast cell-fate, GC hyperplasia and lymphoma.

Comprehensive Identification and Ubiquitous Occurrence of Eight Classes of Rubber-Derived Vulcanization Accelerators in Urban Dusts.

Vulcanization accelerators (VAs) serve as crucial additives in synthetic rubber on a global scale. Despite their widespread use, the environmental presence, distribution, and associated exposure risks of VAs remain poorly understood. This study compiled a target list and conducted a screening for eight classes encompassing 42 VAs in diverse urban dust samples from South China. A total of 40 of the 42 target VAs were detectable across all four studied regions, among which 30 were identified for the first time in the environment. Among the eight structure-classified VA classes, xanthates exhibited the highest concentrations (median: 3810-81,300 ng/g), followed by thiazoles, guanidines, sulfenamides, dithiocarbamates, thiurams, thioureas, and others. The median total concentrations of all target VAs (∑VAs) were determined to be 5060 ng/g in road dust, 5730 ng/g in parking lot dust, 29,200 ng/g in vehicle repair plant dust, and 84,300 ng/g in household dust, indicating the widespread presence of numerous rubber-derived VAs in various urban environments. This study marked the first systematic effort to identify a wide range of emerging rubber-derived VAs prevalent in urban environments. The findings call for increased attention to these widely utilized but less well-evaluated chemicals in future research and environmental management efforts.

Evaluating public opinions: informing public health policy adaptations in China amid the COVID-19 pandemic.

Public concern regarding safety policies serious consequences is anticipated to persist over an extended duration. A study examining a case of rapid public health policy adaptation in China during the COVID-19 epidemic was conducted by gathering public opinion data from major social media platforms. A systematic approach to comprehend public opinion was developed. Five fundamental elements and four dimensions were delineated. An indicator system was established utilizing the K-means text clustering model. Public prediction, expectation, and their evolution underlying public concern were elucidated employing TF-IDF text mining models. The HMM elucidated the way public opinion influences policy adjustments. The findings underscore that public concern regarding enduring events undergoes temporal shifts, mirroring the evolution of public opinion towards policy. Public opinion aroused by both the original event and derived events collaboratively influence policy adjustments. In China, public opinion serves as a mechanism for policy feedback and oversight; notably, negative public sentiment plays a pivotal role in expediting policy transitions. These findings aid in refining policies to mitigate emergencies through a feedback loop, thereby averting the emergence of safety risks such as social unrest prompted by public opinion.

Targeted Ultrasound Nanobubbles Therapy for Prostate Cancer via Immuno-Sonodynamic Effect.

Background: Prostate cancer (PCa) poses a significant global health threaten. Immunotherapy has emerged as a novel strategy to augment the inhibition of tumor proliferation. However, the sole use of anti-PD-L1 Ab for PCa has not yielded improvements, mirroring outcomes observed in other tumor types. Methods: This study employed the thin film hydration method to develop lipid nanobubbles (NBs) encapsulating chlorin e6 (Ce6) and anti-PD-L1 Ab (Ce6@aPD-L1 NBs). Our experimental approach included cellular assays and mouse immunization, providing a comprehensive evaluation of Ce6@aPD-L1 NBs' impact. Results: The Ce6@aPD-L1 NBs effectively induced reactive oxygen species generation, leading to tumor cells death. In mice, they demonstrated a remarkable enhancement of immune responses compared to control groups. These immune responses encompassed immunogenic cell death induced by sonodynamic therapy and PD-1/PD-L1 blockade, activating dendritic cells maturation and effectively stimulating CD8+T cells. Conclusion: Ce6@aPD-L1 NBs facilitate tumor-targeted delivery, activating anti-tumor effects through direct sonodynamic therapy action and immune system reactivation in the tumor microenvironment. Ce6@aPD-L1 NBs exhibit substantial potential for achieving synergistic anti-cancer effects in PCa.

Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies.

Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.

Elucidating the mechanisms underlying astrocyte-microglia crosstalk in hippocampal neuroinflammation induced by acute diquat exposure.

The transition from paraquat (PQ) to diquat (DQ), both organic dication herbicides, in China has led to significant increases in the number of acute DQ poisoning cases. Case studies have shown that acute DQ poisoning resulted in injury to the central nervous system (CNS), but the mechanism underlying the injury remains to be explored. The present study aimed to investigate how DQ influenced purinergic signaling between astrocytes and microglia and whether extracellular ATP (eATP) was involved in promoting neuroinflammation induced by acute DQ toxicity through the activation of the P2X4/NLRP3 signaling pathway. We constructed a rat model of acute DQ toxicity to observe the pathological changes in hippocampal tissues after DQ exposure and measure the expression levels of IL-1ß and TNF-α in the hippocampal tissue. We also established an in vitro co-culture model of C6 astrocytes and BV-2 microglia using transwell chambers, measured the amount of eATP secreted into C6 astrocytes after DQ treatment, and assessed the inflammatory response and changes in the P2X4/NLRP3 signaling pathway in BV-2 microglia. The results showed that the neurons in the hippocampal tissue of rats exhibited loose arrangement, nuclear consolidation, and necrosis after DQ exposure, and IL-1ß and TNF-α levels were signification higher in the hippocampal tissue after DQ exposure. DQ exposure to the co-cultured cells induced an increase in ATP secretion from C6 astrocytes as well as a significant increase of P2X4, NLRP3, IL-1ß, and IL-18 expression in BV-2 microglia. In contrast, pretreatment of C6 astrocytes with apyrase (an ATP hydrolase) resulted in a significant decrease of P2X4, NLRP3, IL-1ß, and IL-18 expression in BV-2 microglia. Furthermore, inhibition of P2X4 expression in BV-2 microglia by transfection with si-P2X4 effectively reversed the increase of NLRP3, IL-1ß, and IL-18 in BV-2 microglia induced by DQ when co-cultured with C6 astrocytes. These results indicate that astrocytes can activate the P2X4/NLRP3 signaling pathway in microglia through the DQ-induced extracellular release of ATP to promote neuroinflammation in rat hippocampal tissue.