Glioblastoma Margin as a Diffusion Barrier Revealed by Photoactivation of Plasmonic Nanovesicles.

Glioblastoma (GBM) is the most complex and lethal primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including the angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.

Efficacy and safety of immune checkpoint inhibitors for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review, meta-analysis, and network meta-analysis.

BACKGROUND: The clinical benefits of immune checkpoint inhibitor (ICI)-based treatments in treating individuals with advanced EGFR-mutated non-small-cell lung cancer (NSCLC) who have progressed on EGFR tyrosine-kinase inhibitors (TKIs) remain controversial. We aimed to review the literature to comprehensively investigate the individual and comparative clinical outcomes of various ICI-based treatment strategies in this population. METHODS: In this systematic review and meta-analysis, we used single-arm, pairwise, and network meta-analytical approaches. We searched PubMed, Embase, Cochrane Library, Web of Science, ClinicalTrials.gov, and relevant international conference proceedings from database inception to Jan 31, 2024, without language restrictions, to identify eligible clinical trials that assessed ICI-based treatments for individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs. Studies considered eligible were published and unpublished phase 1, 2, or 3 clinical trials enrolling participants with histologically or cytologically confirmed advanced EGFR-mutated NSCLC who had progressed after at least one EGFR-TKI treatment, and that evaluated ICI-based treatment strategies on at least one of the clinical outcomes of interest. The primary outcome analysed was progression-free survival. The protocol is registered with PROSPERO, CRD42021292626. FINDINGS: 17 single-arm trials and 15 randomised controlled trials, involving 2886 participants and seven ICI-based treatment strategies (ICI monotherapy, ICI plus chemotherapy [ICI-chemo], ICI plus antiangiogenesis [ICI-antiangio], ICI plus antiangiogenesis plus chemotherapy [ICI-antiangio-chemo], dual ICIs [ICI-ICI], dual ICIs plus chemotherapy [ICI-ICI-chemo], and ICI plus EGFR-TKI [ICI-TKI]), were included. Three of these strategies-ICI monotherapy, ICI-antiangio-chemo, and ICI-chemo-had sufficient data across the included studies to perform a pairwise meta-analysis. The pairwise meta-analysis showed that, compared with chemotherapy, ICI monotherapy led to shorter progression-free survival (hazard ratio [HR] 1·73 [95% CI 1·30-2·29], I2=0%), whereas ICI-antiangio-chemo (HR 0·54 [0·44-0·67], I2=0%) and ICI-chemo (HR 0·77 [0·67-0·88], I2=0%) prolonged progression-free survival. The network meta-analysis showed that ICI-antiangio-chemo yielded the best progression-free survival results, with substantial benefits over ICI-chemo (HR 0·71 [95% credible interval 0·59-0·85]), ICI monotherapy (HR 0·30 [0·22-0·41]), and non-ICI treatment strategies including antiangio-chemo (HR 0·76 [0·58-1·00]) and chemotherapy alone (HR 0·54 [0·45-0·64]). ICI-antiangio-chemo was associated with higher risks of both any-grade and grade 3 or worse adverse events over ICI-chemo and chemotherapy in the network meta-analysis. INTERPRETATION: For individuals with advanced EGFR-mutated NSCLC who progressed on EGFR-TKIs, ICI-antiangio-chemo was identified as the optimal treatment option. The toxicity of this treatment was acceptable but needs careful attention. ICI-chemo showed appreciably greater efficacy than the standard-of-care chemotherapy. These findings clarified the roles of ICI-based treatment strategies in this difficult-to-treat refractory population, potentially complementing recent guidelines. FUNDING: None.

Diagnosis and Vulnerability Risk Assessment of Atherosclerotic Plaques Using an Amino Acid-Assembled Near-Infrared Ratiometric Nanoprobe.

To reduce the risk of atherosclerotic disease, it is necessary to not only diagnose the presence of atherosclerotic plaques but also assess the vulnerability risk of plaques. Accurate detection of the reactive oxygen species (ROS) level at plaque sites represents a reliable way to assess the plaque vulnerability. Herein, through a simple one-pot reaction, two near-infrared (NIR) fluorescent dyes, one is ROS responsive and the other is inert to ROS, are coassembled in an amphiphilic amino acid-assembled nanoparticle. In the prepared NIR fluorescent amino acid nanoparticle (named FANP), the fluorescent properties and ROS-responsive behaviors of the two fluorescent dyes are well maintained. Surface camouflage through red blood cell membrane (RBCM) encapsulation endows the finally obtained FANP@RBCM nanoprobe with not only further reduced cytotoxicity and improved biocompatibility but also increased immune escape capability, prolonged blood circulation time, and thus enhanced accumulation at atherosclerotic plaque sites. In vitro and in vivo experiments demonstrate that FANP@RBCM not only works well in probing the occurrence of atherosclerotic plaques but also enables plaque vulnerability assessment through the accurate detection of the ROS level at plaque sites in a reliable ratiometric mode, thereby holding great promise as a versatile tool for the diagnosis and risk assessment of atherosclerotic disease.

Th2-skewed peripheral T-helper cells drive B-cells in allergic bronchopulmonary aspergillosis.

INTRODUCTION: Patients with allergic bronchopulmonary aspergillosis (ABPA) suffer from repeated exacerbations. The involvement of T-cell subsets remains unclear. METHODS: We enrolled ABPA patients, asthma patients and healthy controls. T-helper type 1 (Th1), 2 (Th2) and 17 (Th17) cells, regulatory T-cells (Treg) and interleukin (IL)-21+CD4+T-cells in total or sorted subsets of peripheral blood mononuclear cells and ABPA bronchoalveolar lavage fluid (BALF) were analysed using flow cytometry. RNA sequencing of subsets of CD4+T-cells was done in exacerbated ABPA patients and healthy controls. Antibodies of T-/B-cell co-cultures in vitro were measured. RESULTS: ABPA patients had increased Th2 cells, similar numbers of Treg cells and decreased circulating Th1 and Th17 cells. IL-5+IL-13+IL-21+CD4+T-cells were rarely detected in healthy controls, but significantly elevated in the blood of ABPA patients, especially the exacerbated ones. We found that IL-5+IL-13+IL-21+CD4+T-cells were mainly peripheral T-helper (Tph) cells (PD-1+CXCR5-), which also presented in the BALF of ABPA patients. The proportions of circulating Tph cells were similar among ABPA patients, asthma patients and healthy controls, while IL-5+IL-13+IL-21+ Tph cells significantly increased in ABPA patients. Transcriptome data showed that Tph cells of ABPA patients were Th2-skewed and exhibited signatures of follicular T-helper cells. When co-cultured in vitro, Tph cells of ABPA patients induced the differentiation of autologous B-cells into plasmablasts and significantly enhanced the production of IgE. CONCLUSION: We identified a distinctly elevated population of circulating Th2-skewed Tph cells that induced the production of IgE in ABPA patients. It may be a biomarker and therapeutic target for ABPA.

Multi-omics insights into the microbiota-gut-brain axis and cognitive improvement post-bariatric surgery.

BACKGROUND: Although numerous studies have shown that bariatric surgery results in sustained weight loss and modifications in gut microbiota composition and cognitive function, the exact underlying mechanisms are unclear. This study aimed to investigate the effects of bariatric surgery on cognitive function through the microbiota-gut-brain axis (MGBA). METHODS: Demographic data, serum samples, fecal samples, cognitive assessment scales, and resting-state functional connectivity magnetic resonance imaging (rs-fMRI) scans were obtained from 39 obese patients before and after (6 months) laparoscopic sleeve gastrectomy (LSG). PCA analysis, OPLS-DA analysis, and permutation tests were used to conduct fecal 16 S microbiota profiling, serum metabolomics, and neuroimaging analyses, and a bariatric surgery-specific rs-fMRI brain functional connectivity network was constructed. Spearman correlation analysis and Co-inertia analysis were employed to correlate significant alterations in cognitive assessment scales and resting-state functional connectivity difference networks with differential serum metabolites and 16 S microbiota data to identify key gut microbiota and serum metabolic factors. RESULTS: LSG significantly reduced the weight of obese patients, with reductions of up to 28%. Furthermore, cognitive assessment scale measurements revealed that LSG enhanced cognitive functions, including memory (HVLT, p = 0.000) and executive function (SCWT, p = 0.008). Also, LSG significantly altered gut microbiota composition (p = 0.001), with increased microbial abundance and diversity (p < 0.05). Moreover, serum metabolite levels were significantly altered, revealing intergroup differences in 229 metabolites mapped to 72 metabolic pathways (p < 0.05, VIP > 1). Spearman correlation analysis among cognitive assessment scales, gut microbiota species, and serum metabolites revealed correlations with 68 gut microbiota species and 138 serum metabolites (p < 0.05). Furthermore, pairwise correlations were detected between gut microbiota and serum metabolites (p < 0.05). Functional neuroimaging analysis revealed that LSG increased functional connectivity in cognitive-related frontotemporal networks (FPN, p < 0.01). Additionally, normalization of the default mode network (DMN) and salience network (SN) connectivity was observed after LSG (p < 0.001). Further canonical correlation and correlation analysis suggested that the cognitive-related brain network changes induced by LSG were associated with key gut microbiota species (Akkermansia, Blautia, Collinsella, Phascolarctobacterium, and Ruminococcus, p < 0.05) and neuroactive metabolites (Glycine, L-Serine, DL-Dopa, SM (d18:1/24:1(15Z), p < 0.05). CONCLUSION: These findings indicate the pathophysiological role of the microbiota-gut-brain axis in enhancing cognitive function after bariatric surgery, and the study provides a basis for clinical dietary adjustments, probiotic supplementation, and guidance for bariatric surgery, but further research is still needed. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100049403. Registered 02 August 2021, https://www.chictr.org.cn/ .

Association between triglyceride-glucose index and intracranial/extracranial atherosclerotic stenosis: findings from a retrospective study.

OBJECTIVE: The association of the triglyceride-glucose (TyG) index with intracranial atherosclerotic stenosis (ICAS) and extracranial atherosclerotic stenosis (ECAS) is unclear. This study aimed to investigate the relationship of TyG index with the distribution and severity of ICAS and ECAS. METHOD: Patients who underwent digital subtraction angiography (DSA) for evaluating ICAS/ECAS in Zhongnan Hospital of Wuhan University from January 2017 to October 2021 were retrospectively enrolled in our study. Clinical characteristics, DSA data, blood routine, lipid profile and fasting glucose were recorded. The association of TyG index and ICAS/ECAS status were investigated in four aspects: location and distribution of stenosis, stenosis severity and whether stenosis is symptomatic. Logistic regression models were used to evaluate the association. Restricted cubic splines were constructed to model the non-linear relationship between the TyG index and different arterial stenosis status. RESULTS: Among 1129 included patients, the median age was 62 (IQR 55-68) years, and 71.3% were male. The median TyG index was 8.81 (8.40, 9.21). Elevated TyG index was significantly associated with ICAS, combined ICAS/ECAS, anterior circulation stenosis, posterior circulation stenosis, combined anterior/posterior circulation stenosis, severe stenosis, both asymptomatic and symptomatic stenosis. This association was maintained after adjusting for age, sex, smoking, drinking, medical history of hypertension and stroke, platelet, total cholesterol, high-density lipoprotein, and low-density lipoprotein. Multivariable-adjusted spline regression models showed that a progressively increasing risk of arterial stenosis was related to an elevated TyG index. CONCLUSION: Elevated TyG index was associated with ICAS/ECAS. TyG index might be a useful indicator of ICAS and severe stenosis.

The role of NLRP3 inflammasome in aging and age-related diseases.

The gradual aging of the global population has led to a surge in age-related diseases, which seriously threaten human health. Researchers are dedicated to understanding and coping with the complexities of aging, constantly uncovering the substances and mechanism related to aging like chronic low-grade inflammation. The NOD-like receptor protein 3 (NLRP3), a key regulator of the innate immune response, recognizes molecular patterns associated with pathogens and injury, initiating an intrinsic inflammatory immune response. Dysfunctional NLRP3 is linked to the onset of related diseases, particularly in the context of aging. Therefore, a profound comprehension of the regulatory mechanisms of the NLRP3 inflammasome in aging-related diseases holds the potential to enhance treatment strategies for these conditions. In this article, we review the significance of the NLRP3 inflammasome in the initiation and progression of diverse aging-related diseases. Furthermore, we explore preventive and therapeutic strategies for aging and related diseases by manipulating the NLRP3 inflammasome, along with its upstream and downstream mechanisms.

Prevalence and association of uncorrected refractive error among Chinese adolescents: a cross-sectional study.

BACKGROUND: Uncorrected refractive error (URE) is one of the main causes of visual impairments. URE may reduce interaction and learning in the classroom, leading to social isolation, irreversible amblyopia, lack of external knowledge, and restrictions on education and employment opportunities. Our aim was to investigate the prevalence and related factors of URE in adolescents using epidemiological surveys and questionnaire surveys related to lifestyle habits. METHODS: A cross-sectional school-based study was conducted in Nantong, China, including adolescents 12-19 years of age from 16 schools. URE was defined as presenting visual acuity worse than 6/12 and improving to ≥ 1 lines after correction in either eye. Univariate and multivariate logistic regression analyses were used to investigate specific correlations between URE and related lifestyle parameters. Non-cycloplegic autorefraction was assessed for each adolescent. RESULTS: A total of 2,910 adolescents were analyzed, of which 50.3% (n = 1,465) were male, and 49.7% (n = 1,445) were female. The mean age was 15.23 ± 1.77 years. The overall prevalence of URE was 23.7%. The total prevalence of REC and eREC was 85.1% and 71.7%, respectively, and both of them showed an increasing trend with age (Ptrend = 0.018 and Ptrend = 0.019, respectively). A higher prevalence of URE was related to myopia, anisometropia, and increased daily use of electronic products. Timely visual examination by medical institutions, more extracurricular homework, and older age were protective factors for URE. Among the 689 adolescents with URE, 362 (52.5%) did not receive any refractive correction, and 327 (47.5%) used corrected glasses. CONCLUSION: URE was highly prevalent among adolescents in China. Myopia was the most important risk factor for URE. The impact of anisometropia and increased daily use of electronic devices on URE was significant. Timely visual examinations by medical institutions served as an effective protective factor against URE. Further research on adjusting intervention strategies is therefore needed to eliminate preventable visual impairments.

Molecular architecture of proliferative lupus nephritis as elucidated using 50-plex imaging mass cytometry proteomics.

Due to unique advantages that allow high-dimensional tissue profiling, we postulated imaging mass cytometry (IMC) may shed novel insights on the molecular makeup of proliferative lupus nephritis (LN). This study interrogates the spatial expression profiles of 50 target proteins in LN and control kidneys. Proliferative LN glomeruli are marked by podocyte loss with immune infiltration dominated by CD45RO+, HLA-DR+ memory CD4 and CD8 T-cells, and CD163+ macrophages, with similar changes in tubulointerstitial regions. Macrophages are the predominant HLA-DR expressing antigen presenting cells with little expression elsewhere, while macrophages and T-cells predominate cellular crescents. End-stage sclerotic glomeruli are encircled by an acellular fibro-epithelial Bowman's space surrounded by immune infiltrates, all enmeshed in fibronectin. Proliferative LN also shows signs indicative of epithelial to mesenchymal plasticity of tubular cells and parietal epithelial cells. IMC enabled proteomics is a powerful tool to delineate the spatial architecture of LN at the protein level.

Nanoscale, antigen encounter-dependent, IL-12 delivery by CAR T cells plus PD-L1 blockade for cancer treatment.

BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies for the treatment of hematological malignancies experienced tremendous progress in the last decade. However, essential limitations need to be addressed to further improve efficacy and reduce toxicity to assure CAR-T cell persistence, trafficking to the tumor site, resistance to an hostile tumor microenvironment (TME), and containment of toxicity restricting production of powerful but potentially toxic bioproducts to the TME; the last could be achieved through contextual release upon tumor antigen encounter of factors capable of converting an immune suppressive TME into one conducive to immune rejection. METHODS: We created an HER2-targeting CAR-T (RB-312) using a clustered regularly interspaced short palindromic repeats (CRISPR) activation (CRISPRa) system, which induces the expression of the IL-12 heterodimer via conditional transcription of its two endogenous subunits p35 and p40. This circuit includes two lentiviral constructs. The first one (HER2-TEV) expresses an anti-human epidermal growth factor receptor 2 (HER2) CAR single chain variable fragment (scFv), with CD28 and CD3z co-stimulatory domains linked to the tobacco etch virus (TEV) protease and two single guide RNAs (sgRNA) targeting the interleukin (IL)-12A and IL12B transcription start site (TSS), respectively. The second construct (LdCV) encodes linker for activation of T cells (LAT) fused to nuclease-deactivated Streptococcus Pyogenes Cas9 (dCas9)-VP64-p65-Rta (VPR) via a TEV-cleavable sequence (TCS). Activation of the CAR brings HER2-TEV in close proximity to LdCV releasing dCas9 for nuclear localization. This conditional circuit leads to conditional and reversible induction of the IL-12/p70 heterodimer. RB-312 was compared in vitro to controls (cRB-312), lacking the IL-12 sgRNAs and conventional HER2 CAR (convCAR). RESULTS: The inducible CRISPRa system activated endogenous IL-12 expression resulting in enhanced secondary interferon (FN)-γ production, cytotoxicity, and CAR-T proliferation in vitro, prolonged in vivo persistence and greater suppression of HER2+ FaDu oropharyngeal cancer cell growth compared to the conventional CAR-T cell product. No systemic IL-12 was detected in the peripheral circulation. Moreover, the combination with programmed death ligand (PD-L1) blockade demonstrated robust synergistic effects. CONCLUSIONS: RB-312, the first clinically relevant product incorporating a CRISPRa system with non-gene editing and reversible upregulation of endogenous gene expression that promotes CAR-T cells persistence and effectiveness against HER2-expressing tumors. The autocrine effects of reversible, nanoscale IL-12 production limits the risk of off-tumor leakage and systemic toxicity.

CO2 Adsorption on N-Doped Porous Biocarbon Synthesized from Biomass Corncobs in Simulated Flue Gas.

This study was to develop a low-cost N-doped porous biocarbon adsorbent that can directly adsorb CO2 in high-temperature flue gas from fossil fuel combustion. The porous biocarbon was prepared by nitrogen doping and nitrogen-oxygen codoping through K2CO3 activation. Results showed that these samples exhibited a high specific surface area of 1209-2307 m2/g with a pore volume of 0.492-0.868 cm3/g and a nitrogen content of 0.41-3.3 wt %. The optimized sample CNNK-1 exhibited a high adsorption capacity of 1.30 and 0.27 mmol/g in the simulated flue gas (14.4 vol % CO2 + 85.6 vol % N2) and a high CO2/N2 selectivity of 80 and 20 at 25 and 100 °C and 1 bar, respectively. Studies revealed that too many microporous pores could hinder CO2 diffusion and adsorption due to the decrease of CO2 partial pressure and thermodynamic driving force in the simulated flue gas. The CO2 adsorption of the samples was mainly chemical adsorption at 100 °C, which depended on the surface nitrogen functional groups. Nitrogen functional groups (pyridinic-N and primary and secondary amines) reacted chemically with CO2 to produce graphitic-N, pyrrolic-like structures, and carboxyl functional groups (-N-COOH). Nitrogen and oxygen codoping increased the amount of nitrogen doping content in the sample, but acidic oxygen functional groups (carboxyl groups, lactones, and phenols) were introduced, which weakened the acid-base interactions between the sample and CO2 molecules. It was demonstrated that SO2 and water vapor had inhibition effects on CO2 adsorption, while NO nearly has no effect on the complex flue gas. Cyclic regenerative adsorption showed that CNNK-1 possessed excellent regeneration and stabilization ability in complex flue gases, indicating that corncob-derived biocarbon had excellent CO2 adsorption in high-temperature flue gas.

Do testosterone and sex hormone-binding globulin affect cancer risk? A Mendelian randomization and bioinformatics study.

Using Mendelian Randomization (MR) and large-scale Genome-Wide Association Study (GWAS) data, this study aimed to investigate the potential causative relationship between testosterone and sex hormone-binding globulin (SHBG) levels and the onset of several cancers, including pathway enrichment analyses of single nucleotide polymorphisms (SNPs) associated with cancer allowed for a comprehensive bioinformatics approach, which offered a deeper biological understanding of these relationships. The results indicated that increased testosterone levels in women were associated with a higher risk of breast and cervical cancers but a lower risk of ovarian cancer. Conversely, increased testosterone was linked to lower stomach cancer risk for men, whereas high SHBG levels were related to decreased risks of breast and prostate cancers. The corresponding genes of the identified SNPs, as revealed by pathway enrichment analysis, were involved in significant metabolic and proliferative pathways. These findings emphasize the need for further research into the biological mechanisms behind these associations, paving the way for potential targeted interventions in preventing and treating these cancers.

Performance evaluation of PLT-H (hybrid-channel platelet) under various interferences and application studies for platelet transfusion decisions.

The hybrid-channel platelet counting method (PLT-H) is a new platelet counting technique proposed by Mindray of China. In this study, we aimed to evaluate the accuracy of this technique in various situations and its reliability in platelet transfusion decision-making. A total of 378 venous blood samples were tested. Using the immunological PLT counting method recommended by the International Council for Standardization in Hematology as the reference method (PLT-IRM), Passing-Bablok regression and Bland-Altman analysis were performed on the PLT-H results. The anti-interference performance of PLT-H under different interference levels was explored using intergroup comparisons, and confusion matrices were analyzed at various transfusion cutoff values. In the absence of interference, there was a strong correlation between PLT-H and PLT-IRM (r = 0.993, 95% CI: 0.990-0.996). Under various interference conditions, the correlation between PLT-H and PLT-IRM was between 0.963 and 0.992, with an average deviation of -14.56 to -2.02. The performance of PLT-H against interference did not change significantly with increasing levels of small RBCs, large PLTs, and RBC fragments (P = .5704, 0.0832, 0.9893). In low-value samples (PLT <100 × 109/L), the coefficient of variation (CV) for PLT-H was less than 7.6%, regardless of the presence or absence of interfering substances. In addition, there was a high agreement between PLT-H and PLT-IRM (ICC = 0.972). Confusion matrice analysis at each medical decision level showed similarity to methods using the fluorescence channel (PLT-O) and superiority to the impedance channel (PLT-I). Compared with PLT-I, PLT-H has higher accuracy in PLT counting, stronger anti-interference ability, better performance in low-value samples at no extra economic cost and can be more useful for platelet transfusion decision-making. PLT-H is a novel method for platelet counting that offers higher accuracy, providing physicians with the ability to make better medical decisions, particularly in cases where values are low, or interference is present. As it does not require additional reagents, it is highly likely to replace PLT-I and become the mainstream method for platelet counting in the future.

Measurement and Modeling of Transport Across the Blood-Brain Barrier.

The blood-brain barrier (BBB) is a dynamic regulatory barrier at the interface of blood circulation and the brain parenchyma, which plays a critical role in protecting homeostasis in the central nervous system. However, it also significantly impedes drug delivery to the brain. Understanding the transport across BBB and brain distribution will facilitate the prediction of drug delivery efficiency and the development of new therapies. To date, various methods and models have been developed to study drug transport at the BBB interface, including in vivo brain uptake measurement methods, in vitro BBB models, and mathematic brain vascular models. Since the in vitro BBB models have been extensively reviewed elsewhere, we provide a comprehensive summary of the brain transport mechanisms and the currently available in vivo methods and mathematic models in studying the molecule delivery process at the BBB interface. In particular, we reviewed the emerging in vivo imaging techniques in observing drug transport across the BBB. We discussed the advantages and disadvantages associated with each model to serve as a guide for model selection in studying drug transport across the BBB. In summary, we envision future directions to improve the accuracy of mathematical models, establish noninvasive in vivo measurement techniques, and bridge the preclinical studies with clinical translation by taking the altered BBB physiological conditions into consideration. We believe these are critical in guiding new drug development and precise drug administration in brain disease treatment.

Canagliflozin ameliorates hypobaric hypoxia-induced pulmonary arterial hypertension by inhibiting pulmonary arterial smooth muscle cell proliferation.

Pulmonary arterial hypertension (PAH) is a disease with a high mortality and few treatment options to prevent the development of pulmonary vessel remodeling, pulmonary vascular resistance, and right ventricular failure. Canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is originally used in diabetes patients which could assist the glucose excretion and decrease blood glucose. Recently, a few studies have reported the protective effect of SGLT2 inhibitor on monocrotaline-induced PAH. However, the effects of canagliflozin on hypobaric hypoxia-induced PAH as well as its mechanism still unclear. In this study, we used hypobaric hypoxia-induced PAH mice model to demonstrate if canagliflozin could alleviate PAH and prevent pulmonary vessel remodeling. We found that daily canagliflozin administration significantly improved survival in mice with hypobaric hypoxia-induced PAH compared to vehicle control. Canagliflozin treatment significantly reduced right ventricular systolic pressure and increased pulmonary acceleration time determined by hemodynamic assessments. Canagliflozin significantly reduced medial wall thickening and decreased muscularization of pulmonary arterioles compared to vehicle treated mice. In addition, canagliflozin inhibited the proliferation and migration of pulmonary arterial smooth muscle cells through suppressing glycolysis and reactivating AMP-activated protein kinase signaling pathway under hypoxia condition. In summary, our findings suggest that canagliflozin is sufficient to inhibit pulmonary arterial remodeling which is a potential therapeutic strategy for PAH treatment.

Structure-guided engineering of the affinity and specificity of CARs against Tn-glycopeptides.

The potency of adoptive T cell therapies targeting the cell surface antigen CD19 has been demonstrated in hematopoietic cancers. It has been difficult to identify appropriate targets in nonhematopoietic tumors, but one class of antigens that have shown promise is aberrant O-glycoprotein epitopes. It has long been known that dysregulated synthesis of O-linked (threonine or serine) sugars occurs in many cancers, and that this can lead to the expression of cell surface proteins containing O-glycans comprised of a single N-acetylgalactosamine (GalNAc, known as Tn antigen) rather than the normally extended carbohydrate. Previously, we used the scFv fragment of antibody 237 as a chimeric antigen receptor (CAR) to mediate recognition of mouse tumor cells that bear its cognate Tn-glycopeptide epitope in podoplanin, also called OTS8. Guided by the structure of the 237 Fab:Tn-OTS8-glycopeptide complex, here we conducted a deep mutational scan showing that residues flanking the Tn-glycan contributed significant binding energy to the interaction. Design of 237-scFv libraries in the yeast display system allowed us to isolate scFv variants with higher affinity for Tn-OTS8. Selection with a noncognate human antigen, Tn-MUC1, yielded scFv variants that were broadly reactive with multiple Tn-glycoproteins. When configured as CARs, engineered T cells expressing these scFv variants showed improved activity against mouse and human cancer cell lines defective in O-linked glycosylation. This strategy provides CARs with Tn-peptide specificities, all based on a single scFv scaffold, that allows the same CAR to be tested for toxicity in mice and efficacy against mouse and human tumors.

Expression and functional analysis of transformer-2 in Phytoseiulus persimilis and other genes potentially participating in reproductive regulation.

Transformer-2 (tra-2) is an important sex-determining gene in insects. It also plays a role in the reproduction of phytoseiid mites. We performed bioinformatic analyses for the tra-2 ortholog in Phytoseiulus persimilis (termed Pptra-2), measured its expression at different stages and quantitatively identified its function in reproduction. This gene encodes 288 amino acids with a conserved RRM domain. The peak of its expression was observed in adult females, especially ca. 5 days after mating. In addition, expression is also higher in eggs than in other stages and adult males. When Pptra-2 was silenced through RNA interference with oral delivery of dsRNA, 56% of the females had their egg hatching rates decreased in the first 5 days, from ca. 100% to ca. 20%, and maintained at low levels during the rest of the oviposition period. To detect other genes functionally related to Pptra-2, transcriptome analyses were performed on day 5 after mating. We compared mRNA expressions among interfered females with significantly reduced egg hatching rate, interfered females without significant hatching rate and CK. In total 403 differential genes were identified, of which 42 functional genes involved in the regulation of female reproduction and embryonic development were screened and discussed.

Promising M2CO2/MoX2 (M = Hf, Zr; X = S, Se, Te) Heterostructures for Multifunctional Solar Energy Applications.

Two-dimensional van der Waals (vdW) heterostructures are potential candidates for clean energy conversion materials to address the global energy crisis and environmental issues. In this work, we have comprehensively studied the geometrical, electronic, and optical properties of M2CO2/MoX2 (M = Hf, Zr; X = S, Se, Te) vdW heterostructures, as well as their applications in the fields of photocatalytic and photovoltaic using density functional theory calculations. The lattice dynamic and thermal stabilities of designed M2CO2/MoX2 heterostructures are confirmed. Interestingly, all the M2CO2/MoX2 heterostructures exhibit intrinsic type-II band structure features, which effectively inhibit the electron-hole pair recombination and enhance the photocatalytic performance. Furthermore, the internal built-in electric field and high anisotropic carrier mobility can separate the photo-generated carriers efficiently. It is noted that M2CO2/MoX2 heterostructures exhibit suitable band gaps in comparison to the M2CO2 and MoX2 monolayers, which enhance the optical-harvesting abilities in the visible and ultraviolet light zones. Zr2CO2/MoSe2 and Hf2CO2/MoSe2 heterostructures possess suitable band edge positions to provide the competent driving force for water splitting as photocatalysts. In addition, Hf2CO2/MoS2 and Zr2CO2/MoS2 heterostructures deliver a power conversion efficiency of 19.75% and 17.13% for solar cell applications, respectively. These results pave the way for exploring efficient MXenes/TMDCs vdW heterostructures as photocatalytic and photovoltaic materials.

The Role of the Art of Chinese Calligraphy and Music in Developing Creative Thinking Skills in Preschoolers Using Flipped Technology.

The article aims to study the influence of music and music-calligraphy practice on the development of creative thinking among preschool children. The study used the general screening model of the Torrance Thinking Creatively in Action and Movement test (TCAMt) to assess the level of motor creativity in children. The study participants were 120 4-5 year-old children. The results of the calculations demonstrate an increase in the values of the four factors after the interventions. Fluency increased on average: for group A, which practiced musical intervention, by 28%; for group B, which practiced musical-calligraphic intervention, by 29%. The imagination factor increased for group A by 23.5% and for group B by 45.5%. This study has shown that the use of musical-calligraphic practice provides higher creative thinking skills in the categories of "imagination" and "originality", while "fluency" and "flexibility" are not different from the use of a single musical practice. This study has practical and scientific value, as it proves the influence of music and music-calligraphy practices on creativity development in children. The study results can be applied in preschool educational institutions, which are interested in increasing students' creativity.

Target-Binding Accelerated Response for Sensitive Detection of Basal H2O2 in Tumor Cells and Tissues via a Dual-Functional Fluorescence Probe.

Aberrant production of H2O2 is involved in cancer. The levels of H2O2 are significantly higher in tumor cells than in normal cells. It is important to develop fluorescent probes to image basal H2O2 selectively in tumor cells. So far, a cancer cell-targeting probe to image basal H2O2 has not been reported. Thus, we developed a fluorescent probe, BBHP, which contains benzil as a H2O2-recognition site and biotin as a target binding motif for the selective and sufficient detection of H2O2 in tumor cells. BBHP enables a selective fluorescence turn-on response to H2O2. The binding of the probe with biotin receptors can greatly accelerate the fluorescence response to H2O2. As a result, BBHP can sufficiently image basal H2O2 in biotin receptor-positive cancer cells and tumor tissues. Finally, BBHP was successfully applied to discriminate between cancerous and normal tissues.