Anti-lung cancer synergy of low-dose doxorubicin and PD-L1 blocker co-delivered via mild photothermia-responsive black phosphorus.

We have previously identified a latent interaction mechanism between non-small cell lung cancer cells (NSCLCC) and their associated macrophages (TAM) mediated by mutual paracrine activation of the HMGB1/RAGE/NF-κB signaling. Activation of this mechanism results in TAM stimulation and PD-L1 upregulation in the NSCLCC. In the present work, we found that free DOX at a low concentration that does not cause DNA damage could activate the HMGB1/RAGE/NF-κB/PD-L1 pathway byinducing oxidative stress. It was thus proposed that a combination of low-dose DOX and a PD-L1 blocker delivered in the NSCLC tumor would achieve synergistic TAM stimulation and thereby synergetic anti-tumor potency. To prove this idea, DOX and BMS-202 (a PD-L1 blocker) were loaded to black phosphorus (BP) nanoparticles after dosage titration to yield the BMS-202/DOX@BP composites that rapidly disintegrated and released drug cargo upon mild photothermal heating at 40 °C. In vitro experiments then demonstrated that low-dose DOX and BMS-202 delivered via BMS-202/DOX@BP under mild photothermia displayed enhanced tumor cell toxicity with a potent synergism only in the presence of TAM. This enhanced synergism was due to an anti-tumor M1-like TAM phenotype that was synergistically induced by low dose DOX plus BMS-202 only in the presence of the tumor cells, indicating the damaged tumor cells to be the cardinal contributor to the M1-like TAM stimulation. In vivo, BMS-202/DOX@BP under mild photothermia exhibited targeted delivery to NSCLC graft tumors in mice and synergistic anti-tumor efficacy of delivered DOX and BMS-202. In conclusion, low-dose DOX in combination with a PD-L1 blocker is an effective strategy to turn TAM against their host tumor cells exploiting the HMGB1/RAGE/NF-κB/PD-L1 pathway. The synergetic actions involved highlight the value of TAM and the significance of modulating tumor cell-TAM cross-talk in tumor therapy. Photothermia-responsive BP provides an efficient platform to translate this strategy into targeted, efficacious tumor therapy.

Ruthenium-Cobalt Solid-Solution Alloy Nanoparticles for Enhanced Photopromoted Thermocatalytic CO2 Hydrogenation to Methane.

Bimetallic alloy nanoparticles have garnered substantial attention for diverse catalytic applications owing to their abundant active sites and tunable electronic structures, whereas the synthesis of ultrafine alloy nanoparticles with atomic-level homogeneity for bulk-state immiscible couples remains a formidable challenge. Herein, we present the synthesis of RuxCo1-x solid-solution alloy nanoparticles (ca. 2 nm) across the entire composition range, for highly efficient, durable, and selective CO2 hydrogenation to CH4 under mild conditions. Notably, Ru0.88Co0.12/TiO2 and Ru0.74Co0.26/TiO2 catalysts, with 12 and 26 atom % of Ru being substituted by Co, exhibit enhanced catalytic activity compared with the monometallic Ru/TiO2 counterparts both in dark and under light irradiation. The comprehensive experimental investigations and density functional theory calculations unveil that the electronic state of Ru is subtly modulated owing to the intimate interaction between Ru and Co in the alloy nanoparticles, and this effect results in the decline in the CO2 conversion energy barrier, thus ultimately culminating in an elevated catalytic performance relative to monometallic Ru and Co catalysts. In the photopromoted thermocatalytic process, the photoinduced charge carriers and localized photothermal effect play a pivotal role in facilitating the chemical reaction process, which accounts for the further boosted CO2 methanation performance.

Cancer Cell-Mimicking Prussian Blue Nanoplatform for Synergistic Mild Photothermal/Chemotherapy via Heat Shock Protein Inhibition.

Combined mild-temperature photothermal/chemotherapy has emerged as a highly promising modality for tumor therapy. However, its therapeutic efficacy is drastically compromised by the heat-induced overexpression of heat shock proteins (HSPs) by the cells, which resist heat stress and apoptosis. The purpose of this study was to downregulate HSPs and enhance the mild-temperature photothermal/chemotherapy effect. In detail, the colon cancer cell membrane (CT26M)-camouflaged HSP90 inhibitor ganetespib and the chemotherapeutic agent doxorubicin (DOX)-coloaded hollow mesoporous Prussian blue (HMPB) nanoplatform (named PGDM) were designed for synergistic mild photothermal/chemotherapy via HSP inhibition. In addition to being a photothermal agent with a high efficiency of photothermal conversion (24.13%), HMPB offers a hollow hole that can be filled with drugs. Concurrently, the cancer cell membrane camouflaging enhances tumor accumulation through a homologous targeting mechanism and gives the nanoplatform the potential to evade the immune system. When exposed to NIR radiation, HMPB's photothermal action (44 °C) not only causes tumor cells to undergo apoptosis but also causes ganetespib to be released on demand. This inhibits the formation of HSP90, which enhances the mild photothermal/chemotherapy effect. The results confirmed that the combined treatment regimen of mild photothermal therapy (PTT) and chemotherapy showed a better therapeutic efficacy than the individual treatment methods. Therefore, this multimodal nanoparticle can advance the development of drugs for the treatment of malignancies, such as colon cancer, and has prospects for clinical application.

Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression.

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

High synthetic cost-amino acids reduce member interactions of acetate-degrading methanogenic microbial community.

Introduction: The cooperation among members of microbial communities based on the exchange of public goods such as 20 protein amino acids (AAs) has attracted widespread attention. However, little is known about how AAs availability affects interactions among members of complex microbial communities and the structure and function of a community. Methods: To investigate this question, trace amounts of AAs combinations with different synthetic costs (low-cost, medium-cost, high-cost, and all 20 AAs) were supplemented separately to acetate-degrading thermophilic methanogenic reactors, and the differences in microbial community structure and co-occurring networks of main members were compared to a control reactor without AA supplementation. Results: The structure of the microbial community and the interaction of community members were influenced by AAs supplementation and the AAs with different synthetic costs had different impacts. The number of nodes, links, positive links, and the average degree of nodes in the co-occurrence network of the microbial communities with AAs supplementation was significantly lower than that of the control without AAs supplementation, especially for all 20 AAs supplementation followed by the medium- and high-cost AAs supplementation. The average proportion of positive interactions of microbial members in the systems supplemented with low-cost, medium-cost, high-cost, all AAs, and the control group were 0.42, 0.38, 0.15, 0.4, and 0.45, respectively. In addition, the ecological functions of community members possibly changed with the supplementation of different cost AAs. Discussion: These findings highlight the effects of AAs availability on the interactions among members of complex microbial communities, as well as on community function.

The endoplasmic reticulum plays a key role in α-cell intracellular Ca2+ dynamics and glucose-regulated glucagon secretion in mouse islets.

Glucagon is secreted by pancreatic α-cells to counteract hypoglycaemia. How glucose regulates glucagon secretion remains unclear. Here, using mouse islets, we studied the role of transmembrane and endoplasmic reticulum (ER) Ca2+ on intrinsic α-cell glucagon secretion. Blocking isradipine-sensitive L-type voltage-gated Ca2+ (Cav) channels abolished α-cell electrical activity but had little impact on its cytosolic Ca2+ oscillations or low-glucose-stimulated glucagon secretion. In contrast, depleting ER Ca2+ with cyclopiazonic acid or blocking ER Ca2+-releasing ryanodine receptors abolished α-cell glucose sensitivity and low-glucose-stimulated glucagon secretion. ER Ca2+ mobilization in α-cells is regulated by intracellular ATP and likely to be coupled to Ca2+ influx through P/Q-type Cav channels. ω-Agatoxin IVA blocked α-cell ER Ca2+ release and cell exocytosis, but had no additive effect on glucagon secretion when combined with ryanodine. We conclude that glucose regulates glucagon secretion through the control of ER Ca2+ mobilization, a mechanism that can be independent of α-cell electrical activity.

The BTB-BACK-TAZ domain protein MdBT2 reduces drought resistance by weakening the positive regulatory effect of MdHDZ27 on apple drought tolerance via ubiquitination.

Drought stress is one of the dominating challenges to the growth and productivity in crop plants. Elucidating the molecular mechanisms of plants responses to drought stress is fundamental to improve fruit quality. However, such molecular mechanisms are poorly understood in apple (Malus domestica Borkh.). In this study, we explored that the BTB-BACK-TAZ protein, MdBT2, negatively modulates the drought tolerance of apple plantlets. Moreover, we identified a novel Homeodomain-leucine zipper (HD-Zip) transcription factor, MdHDZ27, using a yeast two-hybrid (Y2H) screen with MdBT2 as the bait. Overexpression of MdHDZ27 in apple plantlets, calli, and tomato plantlets enhanced their drought tolerance by promoting the expression of drought tolerance-related genes [responsive to dehydration 29A (MdRD29A) and MdRD29B]. Biochemical analyses demonstrated that MdHDZ27 directly binds to and activates the promoters of MdRD29A and MdRD29B. Furthermore, in vitro and in vivo assays indicate that MdBT2 interacts with and ubiquitinates MdHDZ27, via the ubiquitin/26S proteasome pathway. This ubiquitination results in the degradation of MdHDZ27 and weakens the transcriptional activation of MdHDZ27 on MdRD29A and MdRD29B. Finally, a series of transgenic analyses in apple plantlets further clarified the role of the relationship between MdBT2 and MdHDZ27, as well as the effect of their interaction on drought resistance in apple plantlets. Collectively, our findings reveal a novel mechanism by which the MdBT2-MdHDZ27 regulatory module controls drought tolerance, which is of great significance for enhancing the drought resistance of apple and other plants.

Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating neurological disease causing severe sensorimotor dysfunction and cognitive decline, yet there is no effective treatment strategy to alleviate outcomes of these patients. The Mas axis-mediated neuroprotection is involved in the pathology of various neurological diseases, however, the role of the Mas receptor in the setting of ICH remains to be elucidated. METHODS: C57BL/6 mice were used to establish the ICH model by injection of collagenase into mice striatum. The Mas receptor agonist AVE0991 was administered intranasally (0.9 mg/kg) after ICH. Using a combination of behavioral tests, Western blots, immunofluorescence staining, hematoma volume, brain edema, quantitative-PCR, TUNEL staining, Fluoro-Jade C staining, Nissl staining, and pharmacological methods, we examined the impact of intranasal application of AVE0991 on hematoma absorption and neurological outcomes following ICH and investigated the underlying mechanism. RESULTS: Mas receptor was found to be significantly expressed in activated microglia/macrophages, and the peak expression of Mas receptor in microglia/macrophages was observed at approximately 3-5 days, followed by a subsequent decline. Activation of Mas by AVE0991 post-treatment promoted hematoma absorption, reduced brain edema, and improved both short- and long-term neurological functions in ICH mice. Moreover, AVE0991 treatment effectively attenuated neuronal apoptosis, inhibited neutrophil infiltration, and reduced the release of inflammatory cytokines in perihematomal areas after ICH. Mechanistically, AVE0991 post-treatment significantly promoted the transformation of microglia/macrophages towards an anti-inflammatory, phagocytic, and reparative phenotype, and this functional phenotypic transition of microglia/macrophages by Mas activation was abolished by both Mas inhibitor A779 and Nrf2 inhibitor ML385. Furthermore, hematoma clearance and neuroprotective effects of AVE0991 treatment were reversed after microglia depletion in ICH. CONCLUSIONS: Mas activation can promote hematoma absorption, ameliorate neurological deficits, alleviate neuron apoptosis, reduced neuroinflammation, and regulate the function and phenotype of microglia/macrophages via Akt/Nrf2 signaling pathway after ICH. Thus, intranasal application of Mas agonist ACE0991 may provide promising strategy for clinical treatment of ICH patients.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

BACKGROUND: Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. AIM: To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. METHODS: This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. RESULTS: Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1ß, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. CONCLUSION: SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Understanding Risk Factors for Suicide Among Older People in Rural China: A Systematic Review.

Background and Objectives: In China, rural older adults face a significantly heightened risk of suicide. However, there has been no comprehensive review of the literature examining the risk factors associated with suicide among older people in rural China. Therefore, a comprehensive understanding of risk factors for this phenomenon among rural older people must be gained. We conducted a systematic literature review on risk factors for suicide among older people in rural China. Research Design and Methods: Seven English electronic databases (PubMed, EMBASE, PsycINFO, Cochrane, CINAHL, ScienceDirect, and Web of Science) and 3 Chinese electronic databases (CNKI, CQVIP, and Wanfang) were searched for peer-reviewed articles published in English or Chinese, from inception to July 25, 2022. For data collection, scientific strategies were used for searching and selecting literature within the electronic databases. The collected data were then synthesized using the thematic analysis method. The study was conducted under PRISMA 2020 guidelines. Results: The final analysis included 16 studies. The identified risk factors were categorized under 6 themes: navigating the challenges of illness, unmet basic needs, experiencing abuse from children, feelings of loneliness, negative life events, and altruistic motivation to benefit children. Discussion and Implications: Multiple factors affect suicide among older people in rural China. This invaluable information can be used to develop targeted prevention strategies particularly relevant to this age group.

Large language model for horizontal transfer of resistance gene: From resistance gene prevalence detection to plasmid conjugation rate evaluation.

The burgeoning issue of plasmid-mediated resistance genes (ARGs) dissemination poses a significant threat to environmental integrity. However, the prediction of ARGs prevalence is overlooked, especially for emerging ARGs that are potentially evolving gene exchange hotspot. Here, we explored to classify plasmid or chromosome sequences and detect resistance gene prevalence by using DNABERT. Initially, the DNABERT fine-tuned in plasmid and chromosome sequences followed by multilayer perceptron (MLP) classifier could achieve 0.764 AUC (Area under curve) on external datasets across 23 genera, outperforming 0.02 AUC than traditional statistic-based model. Furthermore, Escherichia, Pseudomonas single genera based model were also be trained to explore its predict performance to ARGs prevalence detection. By integrating K-mer frequency attributes, our model could boost the performance to predict the prevalence of ARGs in an external dataset in Escherichia with 0.0281-0.0615 AUC and Pseudomonas with 0.0196-0.0928 AUC. Finally, we established a random forest model aimed at forecasting the relative conjugation transfer rate of plasmids with 0.7956 AUC, drawing on data from existing literature. It identifies the plasmid's repression status, cellular density, and temperature as the most important factors influencing transfer frequency. With these two models combined, they provide useful reference for quick and low-cost integrated evaluation of resistance gene transfer, accelerating the process of computer-assisted quantitative risk assessment of ARGs transfer in environmental field.

MiRNA-296-5p promotes the sensitivity of nasopharyngeal carcinoma cells to cisplatin via targeted inhibition of STAT3/KLF4 signaling axis.

Improving drug sensitivity is an important strategy in chemotherapy of cancer and accumulating evidence indicates that miRNAs are involved in the regulation of drug sensitivity, but the specific mechanism is still unclear. Our previous study has found that miR-296-5p was significantly downregulated in nasopharyngeal carcinoma (NPC). Here, we aim to explore whether miR-296-5p is involved in regulating cisplatin sensitivity in NPC by regulating STAT3/KLF4 signaling axis. The cell proliferation and clonogenic capacity of NPC cells were evaluated by CCK8 Assay and plate colony assay, respectively. The Annexin V-FITC staining kit was used to determine and quantify the apoptotic cells using flow cytometry. The drug efflux ability of NPC cells were determined by Rhodamine 123 efflux experiment. The expression of miR-296-5p, apoptosis-related genes and protein in NPC cell lines were detected by qPCR and Western blot, respectively. Animal study was used to evaluate the sensitivity of NPC cells to DDP treatment in vivo. Our results showed that elevated miR-296-5p expression obviously promoted the sensitivity of NPC cells to DDP by inhibiting cell proliferation and clonogenic capacity, and inducing apoptosis. In addition, we found that miR-296-5p inhibited the expression of STAT3 and KLF4 in NPC cells, while overexpression of exogenous STAT3 reversed miR-296-5p-mediated enhancement in cell death of DDP-treated NPC cells. In vivo studies further confirmed that miR-296-5p promotes the sensitivity of NPC cells to DDP treatment. miRNA-296-5p enhances the drug sensitivity of nasopharyngeal carcinoma cells to cisplatin via STAT3/KLF4 signaling pathway.

Delayed neurological dysfunction following posterior laminectomy with lateral mass screw fixation: A case report and review of literature.

BACKGROUND: While most complications of cervical surgery are reversible, some, such as symptomatic postoperative spinal epidural hematoma (SEH), which generally occurs within 24 h, are associated with increased morbidity and mortality. Delayed neurological dysfunction is diagnosed in cases when symptoms present > 3 d postoperatively. Owing to its rarity, the risk factors for delayed neurological dysfunction are unclear. Consequently, this condition can result in irreversible neurological deficits and serious consequences. In this paper, we present a case of postoperative SEH that developed three days after hematoma evacuation. CASE SUMMARY: A 68-year-old man with an American Spinal Injury Association (ASIA) grade C injury was admitted to our hospital with neck pain and tetraplegia following a fall. The C3-C7 posterior laminectomy and the lateral mass screw fixation surgery were performed on the tenth day. Postoperatively, the patient showed no changes in muscle strength or ASIA grade. The patient experienced neck pain and subcutaneous swelling on the third day postoperatively, his muscle strength decreased, and his ASIA score was grade A. Magnetic resonance imaging showed hypointense signals on T1 weighted image (T1WI) and T2WI located behind the epidural space, with spinal cord compression. Emergency surgical intervention for the hematoma was performed 12 h after onset. Although hypoproteinemia and pleural effusion did not improve in the perioperative period, the patient recovered to ASIA grade C on day 30 after surgery, and was transferred to a functional rehabilitation exercise unit. CONCLUSION: This case shows that amelioration of low blood albumin and pleural effusion is an important aspect of the perioperative management of cervical surgery. Surgery to relieve the pressure on the spinal cord should be performed as soon as possible to decrease neurological disabilities.

Mechanism of Porphyra Yezoensis Polysaccharides in Inhibiting Hyperoxalate-Induced Renal Injury and Crystal Deposition.

Oxidative damage to the kidneys is a primary factor in the occurrence of kidney stones. This study explores the inhibitory effect of Porphyra yezoensis polysaccharides (PYP) on oxalate-induced renal injury by detecting levels of oxidative damage, expression of adhesion molecules, and damage to intracellular organelles and revealed the molecular mechanism by molecular biology methods. Additionally, we validated the role of PYP in vivo using a crystallization model of hyperoxalate-induced rats. PYP effectively scavenged the overproduction of reactive oxygen species (ROS) in HK-2 cells, inhibited the adhesion of calcium oxalate (CaOx) crystals on the cell surface, unblocked the cell cycle, restored the depolarization of the mitochondrial membrane potential, and inhibited cell death. PYP upregulated the expression of antioxidant proteins, including Nrf2, HO-1, SOD, and CAT, while decreasing the expression of Keap-1, thereby activating the Keap1/Nrf2 signaling pathway. PYP inhibited CaOx deposition in renal tubules in the rat crystallization model, significantly reduced high oxalate-induced renal injury, decreased the levels of the cell surface adhesion proteins, improved renal function in rats, and ultimately inhibited the formation of kidney stones. Therefore, PYP, which has crystallization inhibition and antioxidant properties, may be a therapeutic option for the treatment of kidney stones.

Ethical dilemmas for palliative care nurses: systematic review.

BACKGROUND: Nurses play a unique and critical role in palliative care, and it is noteworthy that nurses often encounter ethical dilemmas in this field. OBJECTIVE: This review aims to conduct a summarised synthesis of the latest research on the ethical considerations nurses faced in palliative care. METHODS: We conducted a rigorous systematic review of relevant existing studies published in high-quality English peer-reviewed journals from January 2017 to July 2023. We identified a total of 4492 articles (1029 in Web of Science, 1570 in PubMed and 1893 in Science Direct). Out of these, only 13 studies met the inclusion criteria. RESULTS: Following the thematic analysis, the ethical considerations reported in these 13 studies were grouped into three main themes and four subthemes: ethical issues in communication (ethical issues in communication with patients, ethical issues in communication with families), ethical issues in decision-making (autonomy, dignity) and moral distress in palliative care. CONCLUSION: This study elaborated on the ethical challenges faced by nurses in their communication with patients and families as well as decision-making and analysed the causes and effects of ethical distress, hoping to give a hand to ethical issues for nurses' work in palliative care.

Targeting Neutrophil Extracellular Trap under Flow in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura.

Neutrophil NETosis is a unique form of cell death, characterized by release of decondensed chromatin and anti-microbial contents to the extracellular space, involved in infection, inflammation, and thrombosis. However, the role of NETosis in pathogenesis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) and how a targeted therapy affects the accumulation of neutrophil extracellular traps (NETs) under flow remain to be determined. Flow cytometry demonstrated that the percentage of neutrophils undergoing NETosis in whole blood from iTTP patients on admission is significantly increased with a concurrent decrease in the capacity of inducible NETosis by shigatoxin. Following therapy, the percentage of H3Cit+MPO+ neutrophils was significantly reduced with an improvement of inducible NETosis in these patients. Additionally, little to no NET and thrombus formation was detected under flow in whole blood from iTTP patients when platelet counts were very low, but the NET and thrombus formation were dramatically increased following therapy when platelet count rose to 50x109/L or was restored to normal with donor platelets. Similarly, there was no thrombus and NET accumulation under flow in whole blood from vwf-/- mice, but NET accumulation was significantly higher in Adamts13-/- than wild-type mice. Finally, recombinant ADAMTS13 or caplacizumab (or anfibatide) prevents the NET and thrombus formation under flow in whole blood from iTTP patients (or Adamts13-/- mice). These results indicate that neutrophil NETosis and NET formation depend on platelets and VWF in iTTP, and a targeted therapy such as recombinant ADAMTS13 or caplacizumab may prevent the NET and thrombus formation under flow in iTTP.

Abnormal microstructure of corpus callosum in children with primary nocturnal enuresis: a DTI study.

Primary nocturnal enuresis (PNE) is a common childhood disorder with abnormal sleep or arousal. The corpus callosum (CC) continues to develop into adulthood and plays an important role in sleep arousal. This study aimed to evaluate the microstructure of the CC in children with PNE. Diffusion tensor imaging (DTI) indices were extracted throughout the CC and its seven subregions were compared between the children with PNE and healthy children (HC). The correlation between abnormal DTI indices of the CC and cognitive condition was also tested. Compared to HC, decreased fiber number (NF) (F = 8.492, PFDR = 0.032) and fractional anisotropy (FA) value (F = 8.442, PFDR = 0.040) were found in the posterior midbody of the CC, increased RD was found in the posterior midbody (F = 6.888, PFDR = 0.040) and isthmus (F = 7.967, PFDR = 0.040) in children with PNE. The reduction of FA value was more obvious in boys than girls with PNE. In children with PNE, there was a significant positive correlation between the NF of the posterior midbody and full IQ (r = 0.322, P = 0.025) and between the FA value and the general knowledge memory (r = 0.293, P = 0.043). This study provides imaging evidence for abnormalities in the microstructure of the CC in children with PNE, especially in male PNE, which might affect the children's cognitive performance.

MRI evaluation of cranial nerve abnormalities and extraocular muscle fibrosis in duane retraction syndrome and congenital extraocular muscle fibrosis.

PURPOSE: To investigate the alterations in extraocular muscles (EOMs) by magnetic resonance imaging (MRI) among patients diagnosed with Duane retraction yndrome (DRS) and congenital fibrosis of the extraocular muscles (CFEOM), who present with various cranial nerve anomalies in an attempt to enhance the clinical diagnostic process. METHODS: A case-control study was conducted to evaluate 27 patients with DRS and 14 patients with CFEOM. All patients underwent MRI scans of the brainstem and orbital examination. Neurodevelopmental assessments were conducted through MRI, and maximum cross-sectional area and volumes of EOMs were obtained. Three types of models were constructed using machine learning decision tree algorithms based on EOMs to predict disease diagnosis, cranial nerve abnormalities, and clinical subtypes. RESULTS: Patients with bilateral CN VI abnormalities had smaller volumes of LR, MR, and IR muscles compared to those with unilateral involvement (P < 0.05). Similarly, patients with CFEOM and unilateral third cranial nerve abnormalities had a smaller maximum cross-section of the affected eye's SR compared to the contralateral eye (P < 0.05). In patients with both CN III and CN VI abnormalities, the volume of SR was smaller than in patients with CN III abnormalities alone (P < 0.05). The prediction model using EOMs volume showed a diagnostic precision of 82.5% for clinical cases and 60.1% for predicting cranial nerve abnormalities. Nonetheless, the precision for identifying clinical subtypes was relatively modest, at only 41.7%. CONCLUSION: The distinctive volumetric alterations in EOMs among individuals exhibiting distinct cranial nerve anomalies associated with DRS or CFEOM provide valuable diagnostic insights into to Congenital Cranial Neurodevelopmental Disorders (CCDDs). MRI analysis of EOMs should thus be regarded as a crucial diagnostic modality.

"Four-in-One" Nanozyme for Amplified Catalytic-Photothermal Therapy.

The cancer therapeutic efficacy of the peroxidase (POD)-mimicking nanozyme-based monotherapy is significantly hindered due to insufficient intratumoral hydrogen peroxide (H2O2) and glutathione (GSH) consumption effect on reactive oxygen species (ROS). In this study, we present the development of poly(o-phenylenediamine)@gold nanoparticles (AuNPs) (PoPD@Au) nanocomposites for multifunctional catalytic-photothermal therapy. These nanocomposites exhibit triple distinct nanozymatic activities, i.e., POD-like activity that catalyzes H2O2 to ROS, glucose oxidase (GOx)-like activity that supplements endogenous H2O2, and GSH depleting activity that decreases the ROS consumption efficiency. This open source and reduce expenditure strategy for ROS generation allows for the amplification of tumor oxidative stress, thereby enhancing anti-tumor efficiency. Additionally, the PoPD@Au nanocomposites demonstrate outstanding photothermal conversion efficiency, contributing to the synergistic effect between PoPD and AuNPs. Moreover, we reveal the improved photothermal performance of PoPD@Au triggered by the tumor microenvironment pH, which provides additional benefits for targeted catalytic-photothermal therapy. This "four-in-one" design of PoPD@Au enables efficient anti-tumor effects both in vitro and in vivo, making it a universal strategy for engineering catalytic-photothermal therapeutic nanoagents.

Maternal prednisone exposure during pregnancy elevates susceptibility to osteoporosis in female offspring: The role of mitophagy/FNDC5 alteration in skeletal muscle.

Maternal exposure to glucocorticoids has been associated with adverse outcomes in offspring. However, the consequences and mechanisms of gestational exposure to prednisone on susceptibility to osteoporosis in the offspring remain unclear. Here, we found that gestational prednisone exposure enhanced susceptibility to osteoporosis in adult mouse offspring. In a further exploration of myogenic mechanisms, results showed that gestational prednisone exposure down-regulated FNDC5/irisin protein expression and activation of OPTN-dependent mitophagy in skeletal muscle of adult offspring. Additional experiments elucidated that activated mitophagy significantly inhibited the expression of FNDC5/irisin in skeletal muscle cells. Likewise, we observed delayed fetal bone development, downregulated FNDC5/irisin expression, and activated mitophagy in fetal skeletal muscle upon gestational prednisone exposure. In addition, an elevated total m6A level was observed in fetal skeletal muscle after gestational prednisone exposure. Finally, gestational supplementation with S-adenosylhomocysteine (SAH), an inhibitor of m6A activity, attenuated mitophagy and restored FNDC5/irisin expression in fetal skeletal muscle, which in turn reversed fetal bone development. Overall, these data indicate that gestational prednisone exposure increases m6A modification, activates mitophagy, and decreases FNDC5/irisin expression in skeletal muscle, thus elevating osteoporosis susceptibility in adult offspring. Our results provide a new perspective on the earlier prevention and treatment of fetal-derived osteoporosis.