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.

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.

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.

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.

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.

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.

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.

Low­intensity pulsed ultrasound accelerates diabetic wound healing by ADSC­derived exosomes via promoting the uptake of exosomes and enhancing angiogenesis.

Diabetic wounds remain a great challenge for clinicians globally as a lack of effective radical treatment often results in poor prognosis. Exosomes derived from adipose­derived stem cells (ADSC­Exos) have been explored as an appealing nanodrug delivery system in the treatment of diabetic wounds. However, the short half­life and low utilization efficiency of exosomes limit their therapeutic effects. Low­intensity pulsed ultrasound (LIPUS) provides a non­invasive mechanical stimulus to cells and exerts a number of biological effects such as cavitation and thermal effects. In the present study, whether LIPUS could enhance ADSC­Exo­mediated diabetic wound repair was investigated and its possible mechanism of action was explored. After isolation and characterization, ADSC­Exos were injected into mice with diabetic wounds, then the mice were exposed to LIPUS irradiation. The control mice were subcutaneously injected with PBS. Wound healing assays, laser Doppler perfusion, Masson's staining and angiogenesis assays were used to assess treatment efficiency. Then, ADSC­Exos were cocultured with human umbilical vein endothelial cells (HUVECs), and the proliferation, migration and tube formation of HUVECs were assessed. Moreover, the cellular uptake of ADSC­Exos in vitro and in vivo was assessed to explore the synergistic mechanisms underlying the effects of LIPUS. The in vivo results demonstrated that LIPUS increased the uptake of exosomes and prolonged the residence of exosomes in the wound area, thus enhancing angiogenesis and accelerating wound repair in diabetic mice. The in vitro results further confirmed that LIPUS enhanced the uptake efficiency of ADSC­Exos by 10.93­fold and significantly increased the proliferation, migration and tubular formation of HUVECs. Therefore, the present study indicates that LIPUS is a promising strategy to improve the therapeutic effects of ADSC­Exos in diabetic wounds by promoting the cellular uptake of exosomes and enhancing angiogenesis.

Devosia lacusdianchii sp. nov., an attached bacterium inhibited by metabolites from its symbiotic Microcystis.

A novel alphaproteobacterial strain JXJ CY 41T was isolated from a culture mass of Microcystis, collected from Lake Dianchi, south-west, China. Strain JXJ CY 41T was gram-strain-negative, aerobic, motile, with rod-shaped cells (0.4-1.0 × 1.7-3.5 µm). It was positive for catalase and starch hydrolysis, negative for oxidase and hydrolysis of Tweens (20, 40, and 80). Growth occurred at 10-44 °C, pH 5.0-10.0, and 0-5.0% (w/v) NaCl. Major fatty acids included C16:0 (28.1%), 11-methyl C18:1 ω7c (36.7%) and C18:1 ω7c (20.8%). Q10 was the sole ubiquinone. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, glycolipid, and an unidentified lipid. The DNA G + C content was 63.1%. Its 16S rRNA gene sequence showed high similarities with Devosia oryziradicis G19T (99.5%; not validly published), D. yakushimensis Yak96BT (98.3%) and D. ginsengisoli Gsoil 520T (98.1%), and less than 98.1% similarities with other members of the genus Devosia. The digital DNA-DNA hybridization (dDDH) and average nucleotide identity (ANI) values between strain JXJ CY 41T and its 5 closest similar strains were 19.9-24.1% and 75.7-80.5%, respectively. Based on the data above, strain JXJ CY 41T was identified as a novel species of the genus Devosia, for which the epithet Devosia lacusdianchii sp. nov. was proposed. The type strain is JXJ CY 41T (= KCTC 72812T = CGMCC 1.17502T). Strain JXJ CY 41T exhibited different interactions with Microcystis aeruginosa FACHB-905 (Maf) under different conditions, and Maf could control the bacterial cellular density by secreting unknown specific chemical compounds according to its nutritional requirements.

Disease and Economic Burden of Kashin-Beck Disease - China, 2021 .

What is already known about this topic?: Kashin-Beck disease (KBD) is a chronic and degenerative osteoarthropathy characterized by cartilage degeneration. It is an endemic disease that is highly prevalent among the Chinese population and poses a significant health risk. What is added by this report?: This is the first national report on the economic burden of KBD in China. According to the data from 2021, KBD has caused significant disease and economic burdens. The most substantial reduction in healthy life expectancy was observed among patients with degree II severity and those aged 60 years and older, resulting in a total indirect economic burden of 112.74 million Chinese Yuan (CNY). What are the implications for public health practice?: The results of this study will contribute to informing the development of tailored prevention and control strategies by the government. These strategies will include targeted policies and recommendations for appropriate healthcare and financial subsidies, which will be based on the demographic characteristics of the endemic areas.

First Evidence of Hindered Amine Light Stabilizers As Abundant, Ubiquitous, Emerging Pollutants in Dust and Air Particles: A New Concern for Human Health.

Hindered amine light stabilizers (HALSs) represent a crucial class of polymer additives that are extensively used in plastics and other polymeric materials. However, their environmental presence and related exposure risks have until now remained unexplored. This study addressed this critical knowledge by examining dust and air particles collected in South China, utilizing a comprehensive analytical approach to identify and quantify nine monomeric HALSs. A total of seven of the nine studied HALSs were detected in the samples, with bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate (Tinuvin 770) and methyl 1,2,2,6,6-pentamethyl-4-piperidyl sebacate (HS-508) identified as the most abundant and widespread pollutants. Median total concentrations of HALSs ranged from 417 to 8,830 ng/g in urban dust samples and from 28.6 to 70.9 pg/m3 in urban air particles. Notably, dust concentrations of HALSs significantly exceeded those of traditional well-known light stabilizers such as UV absorbers. Human exposure assessment indicated that in contrast to air inhalation dust ingestion represented a more substantial exposure pathway owing to the relatively low volatility of these newly identified chemicals. Predictive modeling suggests that many of the examined HALSs exhibited characteristics of persistence, high toxicity, or strong potential for long-range transport, underscoring their hazardous nature. This study represents the first comprehensive investigation into the prevalence of HALSs as a class of emerging pollutants widespread in the environment, necessitating heightened attention and further research in the future.

Macrophage-targeted ultrasound nanobubbles for highly efficient sonodynamic therapy of atherosclerotic plaques by modulating M1-to-M2 polarization.

BACKGROUND AND AIMS: Sonodynamic therapy (SDT) is a new approach for the treatment of atherosclerosis (AS), yet the poor targeting ability of sonosensitizers limits its therapeutic efficacy. Herein, we reported a plaque-targeted nanoplatform modified with macrophage type A scavenger receptor (SR-A)-targeted peptide (designated as SR-A-Ce6NB) to augment the efficacy of low-intensity pulsed ultrasound (LIPUS)-mediated SDT of atherosclerotic plaque. METHODS: SR-A-Ce6NB was fabricated by thin hydration method and biotin-avidin system, and its physicochemical properties, biocompatibility and plaque-targeting ability were investigated. RAW 264.7 cells were used for in vitro experimental studies. Male 6-week-old apolipoprotein E-deficient mice were fed a high-fat diet for 16 weeks to induce aortic atherosclerotic plaques. Plaque-bearing mice were randomly allocated into five groups (n = 6): control group, Ce6 + LIPUS group, Ce6NB + LIPUS group, SR-A-Ce6NB + LIPUS group and atorvastatin group. After treatment in each group, the aortic artery was harvested for Oil red O, H&E, Masson's trichrome staining, immunohistochemical and immunofluorescent staining. RESULTS: SR-A-Ce6NB with high stability and excellent biocompatibility was successfully fabricated. SR-A-Ce6NB could actively target activated macrophages and selectively accumulate in the plaque. SR-A-Ce6NB could be triggered by LIPUS and had a more potent sonodynamic effect than free Ce6 to potentiate SDT. SR-A-Ce6NB-mediated SDT enhanced the anti-atherogenic effect via modulating M1-to-M2 macrophage polarization and had an earlier onset of action on plaque than the statin-mediated effect. No apparent side effect was observed after intravenous SR-A-Ce6NB injection and LIPUS exposure. CONCLUSIONS: Macrophage-targeted nanoplatform SR-A-Ce6NB-mediated SDT provides a safe, effective and preferable anti-atherogenic therapy by mediating M1-to-M2 macrophage polarization.

Aconine attenuates osteoclast-mediated bone resorption and ferroptosis to improve osteoporosis via inhibiting NF-κB signaling.

Osteoporosis (OP), a prevalent public health concern primarily caused by osteoclast-induced bone resorption, requires potential therapeutic interventions. Natural compounds show potential as therapeutics for postmenopausal OP. Emerging evidence from in vitro osteoclastogenesis assay suggests that aconine (AC) serves as an osteoclast differentiation regulator without causing cytotoxicity. However, the in vivo functions of AC in various OP models need clarification. To address this, we administered intraperitoneal injections of AC to ovariectomy (OVX)-induced OP mice for 8 weeks and found that AC effectively reversed the OP phenotype of OVX mice, leading to a reduction in vertebral bone loss and restoration of high bone turnover markers. Specifically, AC significantly suppressed osteoclastogenesis in vivo and in vitro by decreasing the expression of osteoclast-specific genes such as NFATc1, c-Fos, Cathepsin K, and Mmp9. Importantly, AC can regulate osteoclast ferroptosis by suppressing Gpx4 and upregulating Acsl4, which is achieved through inhibition of the phosphorylation of I-κB and p65 in the NF-κB signaling pathway. These findings suggest that AC is a potential therapeutic option for managing OP by suppressing NF-κB signaling-mediated osteoclast ferroptosis and formation.

Low-intensity pulsed ultrasound of different intensities differently affects myocardial ischemia/reperfusion injury by modulating cardiac oxidative stress and inflammatory reaction.

Introduction: The prevalence of ischemic heart disease has reached pandemic levels worldwide. Early revascularization is currently the most effective therapy for ischemic heart diseases but paradoxically induces myocardial ischemia/reperfusion (MI/R) injury. Cardiac inflammatory reaction and oxidative stress are primarily involved in the pathology of MI/R injury. Low-intensity pulsed ultrasound (LIPUS) has been demonstrated to reduce cell injury by protecting against inflammatory reaction and oxidative stress in many diseases, including cardiovascular diseases, but rarely on MI/R injury. Methods: This study was designed to clarify whether LIPUS alleviates MI/R injury by alleviating inflammatory reaction and oxidative stress. Simultaneously, we have also tried to confirm which intensity of the LIPUS might be more suitable to ameliorate the MI/R injury, as well as to clarify the signaling mechanisms. MI/R and simulated ischemia/reperfusion (SI/R) were respectively induced in Sprague Dawley rats and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). LIPUS treatment, biochemical measurements, cell death assay, estimation of cardiac oxidative stress and inflammatory reaction, and protein detections by western blotting were performed according to the protocol. Results: In our study, both in vivo and in vitro, LIPUS of 0.1 W/cm2 (LIPUS0.1) and 0.5 W/cm2 (LIPUS0.5) make no significant difference in the cardiomyocytes under normoxic condition. Under the hypoxic condition, MI/R injury, inflammatory reaction, and oxidative stress were partially ameliorated by LIPUS0.5 but were significantly aggravated by LIPUS of 2.5 W/cm2 (LIPUS2.5) both in vivo and in vitro. The activation of the apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) pathway in cardiomyocytes with MI/R injury was partly rectified LIPUS0.5 both in vivo and in vitro. Conclusion: Our study firstly demonstrated that LIPUS of different intensities differently affects MI/R injury by regulating cardiac inflammatory reaction and oxidative stress. Modulations on the ASK1/JNK pathway are the signaling mechanism by which LIPUS0.5 exerts cardioprotective effects. LIPUS0.5 is promising for clinical translation in protecting against MI/R injury. This will be great welfare for patients suffering from MI/R injury.

Loss of p53 and mutational heterogeneity drives immune resistance in an autochthonous mouse lung cancer model with high tumor mutational burden.

The role of tumor mutational burden (TMB) in shaping tumor immunity is a key question that has not been addressable using genetically engineered mouse models (GEMMs) of lung cancer. To induce TMB in lung GEMMs, we expressed an ultra-mutator variant of DNA polymerase-E (POLE)P286R in lung epithelial cells. Introduction of PoleP286R allele into KrasG12D and KrasG12D; p53L/L (KP) models significantly increase their TMB. Immunogenicity and sensitivity to immune checkpoint blockade (ICB) induced by Pole is partially dependent on p53. Corroborating these observations, survival of NSCLC patients whose tumors have TP53truncating mutations is shorter than those with TP53WT with immunotherapy. Immune resistance is in part through reduced antigen presentation and in part due to mutational heterogeneity. Total STING protein levels are elevated in Pole mutated KP tumors creating a vulnerability. A stable polyvalent STING agonist or p53 induction increases sensitivity to immunotherapy offering therapeutic options in these polyclonal tumors.

Atypical peripheral actin band formation via overactivation of RhoA and nonmuscle myosin II in mitofusin 2-deficient cells.

Cell spreading and migration play central roles in many physiological and pathophysiological processes. We have previously shown that MFN2 regulates the migration of human neutrophil-like cells via suppressing Rac activation. Here, we show that in mouse embryonic fibroblasts, MFN2 suppresses RhoA activation and supports cell polarization. After initial spreading, the wild-type cells polarize and migrate, whereas the Mfn2-/- cells maintain a circular shape. Increased cytosolic Ca2+ resulting from the loss of Mfn2 is directly responsible for this phenotype, which can be rescued by expressing an artificial tether to bring mitochondria and endoplasmic reticulum to close vicinity. Elevated cytosolic Ca2+ activates Ca2+/calmodulin-dependent protein kinase II, RhoA, and myosin light-chain kinase, causing an overactivation of nonmuscle myosin II, leading to a formation of a prominent F-actin ring at the cell periphery and increased cell contractility. The peripheral actin band alters cell physics and is dependent on substrate rigidity. Our results provide a novel molecular basis to understand how MFN2 regulates distinct signaling pathways in different cells and tissue environments, which is instrumental in understanding and treating MFN2-related diseases.

A single-cell atlas of CD19 chimeric antigen receptor T cells.

Li et al. present a resource of single-cell RNA sequencing (scRNA-seq) data from the infusion products of relapsed or refractory large B cell lymphoma (rrLBCL) patients treated with standard-of-care axicabtagene ciloleucel and identify features that are significantly different between products from responders and non-responders at 3-month followup by PET/CT, an important landmark for long-term outcomes.