Selective Generation of Reactive Oxygen Species in Photocatalytic Oxidation by Tuning Porphyrin-Based COFs' Dimensionality.

Regulating the selective generation of reactive oxygen species (ROS) is a significant challenge in the field of photocatalytic oxidation, with successful approaches still being limited. Herein, we present a strategy to selectively generate singlet oxygen (1O2) and superoxide radicals (O2•-) by tuning the dimensionality of porphyrin-based covalent organic frameworks (COFs). The transformation of COFs from three-dimensional (3D) solids to two-dimensional (2D) sheets was achieved through the reversible protonation of the imine bond. Upon irradiation, both bulk and thin-layer COF-367 can transfer energy to O2 to generate 1O2. However, thin-layer COF-367 exhibited a superior performance compared to its bulk counterpart in activating O2 to form the O2•- radicals via electron transfer. After excluding the influences of the band structure, O2 adsorption energy, and frontier orbital composition attributed to the dimensionality of the COFs, it is reasonably speculated that the variance in ROS generation arises from the differential exposure ratios of the active surfaces, leading to distinct reaction pathways between the carrier and O2. This study is the first to explore the modulation mechanism of COF dimensionality on the activation of the O2 pathway, underscoring the importance of considering COF dimensionality in photocatalytic reactions.

RTP4 Enhances Corneal HSV-1 Infection in Mice With Type 2 Diabetes Mellitus.

Purpose: The purpose of this study was to investigate whether corneal lesions in mice with type 2 diabetes mellitus (T2D) infected with herpes simplex virus (HSV)-1 are more severe, and to elucidate the specific underlying mechanism. Methods: The corneas of control mice and T2D mice induced by a high-fat diet combined with streptozotocin were infected with the HSV-1 Mckrae strain to assess corneal infection, opacity, and HSV-1 replication. RNA sequencing of the corneal epithelium from wild-type and db/db mice (a genetic T2D mouse model) was conducted to identify the key gene affecting T2D infection. Immunofluorescence staining was performed on corneal sections from T2D mice and patients with T2D. The effect of small interfering RNA (siRNA) knockdown on corneal HSV-1 infection was evaluated in both in vitro and in vivo models. Results: T2D mice exhibited a more severe infection phenotype following HSV-1 infection, characterized by augmented corneal opacity scores, elevated viral titers, and transcripts compared to control mice. Transcriptome analysis of corneal epithelium revealed a hyperactive viral response in T2D mice, highlighting the differentially expressed gene Rtp4 (encoding receptor transporter protein 4). Receptor transporter protein 4 (RTP4) expression was enhanced in the corneal epithelium of T2D mice and patients with T2D. Virus binding assays demonstrated that RTP4 facilitated HSV-1 binding to human corneal epithelial cells. Silencing RTP4 alleviated HSV-1 infection in both in vitro and in vivo T2D models. Conclusions: The findings indicate that elevated RTP4 exacerbates HSV-1 infection by enhancing its binding to corneal epithelial cells, whereas Rtp4 knockdown mitigated corneal lesions in T2D mice. This implies RTP4 as a potential target for intervention in diabetic HSV-1 infection.

Tau biosensor on aptamer-modified interdigitated electrode for monitoring neurological effect caused by anesthesia.

General anesthesia is significantly gaining prominence and becoming unavoidable in modern medicine. Since neuroprotein fluctuations are common during anesthetic procedures, it is essential to monitor protein levels to identify neuro-related issues. Tau protein fluctuations are often found in the anesthetic process, and higher levels of tau are highly related to various neuro-related issues. Researchers are focusing on monitoring tau levels during and after anesthesia. This research has developed a high-sensitive tau biosensor on a gold nanomaterial-modified interdigitated electrode, measured at 0-2 V on a dual-probe station. Aptamer and antibody were used as capture and detection molecules, and a biotin-streptavidin strategy was employed to attach a higher number of aptamers on the electrode. These immobilized aptamers recognize the tau protein and form a sandwich with antibodies, lowering the detection of tau protein to 1 fM on a linear regression from 0.001 to 100 pM (y = 2.0651x - 1.3813, R2 = 0.987). Further, tau-spiked cerebrospinal fluid increases the current flow without any interferences, confirming the selective detection of tau protein.

Acceptance of family doctors among residents in China: a cross-sectional study.

Objectives: This study aimed to investigate the level of acceptance of family doctors (FDs) exhibited by residents in China. Methods: A cross-sectional study based on a structured self-administered questionnaire was conducted to investigate residents in eastern, central, and western China between September and December 2021. A multivariable stepwise logistic regression model was employed to identify the factors associated with health-seeking behavior after the signing of agreements concerning family doctor contract services (FDCS) as well as residents' willingness to change FDs. Results: Among the 2,394 respondents included in this research, 55.8% sought primary care from their FDs when they became ill, whereas 9.7% expressed a willingness to change FDs. Residents who reported high levels of satisfaction with FDCS [odds ratio (OR) = 2.162] and trust in FDs (OR = 1.430) were more likely to seek initial help from FDs. In addition, residents from central China (OR = 0.546) and western China (OR = 0.704) and those who exhibited a high level of trust in FDs (OR = 0.238) were less likely to change FDs. Conclusion: The level of FD acceptance among Chinese residents was relatively high. Satisfaction with FDCS and trust in FDs were associated with the acceptance of FDs among residents. FDs should make efforts to enhance the quality of health services as well as the overall health experience of residents.

Distinct pathway activities are associated with prognosis and response to bortezomib-containing treatment in MCL1-M based molecular subtypes of multiple myeloma.

Multiple myeloma (MM) is the second most prevalent hematological malignancy and remains incurable with remarkable heterogeneity in prognosis and treatment response across the patients. Clinical diagnosis and the existing molecular classification systems are inadequate for predicting treatment responses. Based on the convergence between plasma cell development and MM pathogenesis, we identified a gene co-expression module centered on the plasma cell survival regulator MCL1 (MCL1 module, MCL1-M) in the transcriptomes of pre-treated MM, which enabled stratification of MM patients into MCL1-M high and MCL1-M low molecular subtypes with subtype-specific prognosis and response to bortezomib-containing treatment. Here, we aimed to examine the mechanism underlying the disparate prognosis and treatment responses between the two molecular subtypes. Our findings reveal that MCL1-M high MM displays significant activation of pathways associated with cell proliferation, while MCL1-M low MM exhibits activation of immune-related signaling pathways. The relative enrichment of immune cells within the bone marrow microenvironment of MCL1-M low MM, particularly plasmacytoid dendritic cells, likely contributes to the activation of immune-related signaling pathways in this subset of myeloma cells. Using phase III trial data, we show that responses to bortezomib-containing treatment are associated with the extent of unfolded protein response (UPR) signaling activity. Further, bortezomib-mediated killing of MM cells could be enhanced or inhibited by in vitro manipulation of UPR activities in representative cell lines. In conclusion, MCL1-M based molecular subtypes of MM are characterized by distinct signaling activities from both malignant cells and bone marrow microenvironment, which may drive distinct prognosis and treatment responses.

Pillar[5]arene-based Polymer Network for Efficiently Removing Perfluorooctanoic Acid through Synergistic Binding Interactions.

Perfluorooctanoic acid (PFOA) is currently one of the most important chemicals posing environmental risks, and there is an urgent need to find methods to efficiently remove PFOA from environmental media. Here, two decaamino-pillar[5]arene-based fluorine-rich polymer networks, called FA2P-P and FA6P-P, were constructed using a convenient method. FA6P-P had an excellent ability to take up PFOA, and had a capacity of 1423 (mg PFOA) (g FA6P-P) -1, which is the second highest adsorption capacity reported for any PFOA sorbent. FA6P-P removed >99% of the PFOA from a solution and decreased the PFOA concentration from 1000 µg L-1 in 5 min at an exceedingly low adsorbent loading of 0.7 mg L-1, giving a final PFOA concentration <4 ng L-1, which is lower than the most recent enforceable maximum concentration set by the United States Environmental Protection Agency. A high rate constant (kobs) of 55.8 g mg-1 h-1 was observed. Pillar[5]arene gives the material hydrophobic properties and also amino sites and hydrophobic chains, which are synergistic PFOA binding sites. The polymer was very stable and readily regenerated. The results indicated that pillar[5]arene-based porous organic polymer sorbents are excellent candidates for capturing PFOA.

Reversible Structural Phase Transitions in Zero-dimensional Cu(I)-Based Metal Halides for Dynamically Tunable Emissions.

Exploring structural phase transitions and luminescence mechanisms in Zero-dimensional (0D) metal halides poses significant challenges, that are crucial for unlocking the full potential of tunable optical properties and diversifying their functional capabilities. Herein, we have designed two inter-transformable 0D Cu(I)-based metal halides, namely (C19H18P)2CuI3 and (C19H18P)2Cu4I6, through distinct synthesis conditions utilizing identical reactants. Their optical properties and luminescence mechanisms were systematically elucidated by experiments combined with density functional theory calculations. The bright cyan-fluorescent (C19H18P)2CuI3 with high photoluminescence quantum yield (PLQY) of 77% is attributed to the self-trapped exciton emission. Differently, the broad yellow-orange fluorescence of (C19H18P)2Cu4I6 displays a remarkable PLQY of 83%. Its luminescence mechanism is mainly attributed to the combined effects of metal/halide-to-ligand charge transfer and cluster-centered charge transfer, which effects stem from the strong Cu-Cu bonding interactions in the (Cu4I6)2- clusters. Moreover, (C19H18P)2CuI3 and (C19H18P)2Cu4I6 exhibit reversible structural phase transitions. The elucidation of the phase transitions mechanism has paved the way for an unforgeable anti-counterfeiting system. This system dynamically shifts between cyan and yellow-orange fluorescence, triggered by the phase transitions, bolstering security and authenticity. This work enriches the luminescence theory of 0D metal halides, offering novel strategies for optical property modulation and fostering optical applications.

Soil organic carbon fractions and their stability under different land uses in wind erosion area of Northeast China.

Exploring the physical fractions of organic carbon and influencing mechanisms in grassland, forest, and farmland soils in wind erosion area can provide scientific basis for carbon sequestration, land utilization, wind prevention measure making, and fertility restoration of sloping farmland in the region. We examined the differentiation of aggregate organic carbon and density fractionation organic carbon in 0-15 cm soil layer across grassland, forest, and sloping farmland with 350 m long and 5° slope gradient in the wind erosion area of Meilisi District, Qiqihar, Heilongjiang, as well as the sloping farmland in the downhill section, middle section, and uphill section with every 100 m apart from the bottom to the top. The results showed that soil aggregates >2 mm were all destroyed across grassland, forest, and farmland soils, while the percentage of aggregates <0.053 mm was significantly higher than that of other sizes. The percentage of various soil aggregates, organic carbon content from density fractionations, and the proportion of organic carbon in the heavy fraction aggregates in farmland were significantly lower than that in grassland and forest soils. Soil aggregates in the uphill section of farmland were completely destroyed, and organic carbon content in various size aggregates and density fractionations gradually decreased with increasing slope. The proportion of organic carbon in the heavy fraction aggregates decreased, but that in light fraction aggregates increased gradually. Soil organic carbon and available potassium were key factors affecting aggregate stability, aggregate organic carbon content, and organic carbon content in density fractionations, while the loss of organic carbon in aggregate led to a decrease in aggregate stability. In summary, compared with grassland and forest soils, the stability of soil aggregates, the aggregate organic carbon content, the organic carbon content in density fractionations, and the proportion of organic carbon in heavy fraction aggregates in farmland all decreased in the wind erosion area of Northeast China. With the increases of slope, the aggregate organic carbon content, the organic carbon content in density fractionations, and the proportion of organic carbon in the heavy fraction aggregates in sloping farmland all decreased. Planting trees, conserving and expanding grassland area, and increasing the application of organic materials in sloping farmland in wind erosion area are effective approaches to stabilize and increase carbon storage, improve soil structure, and enhance soil quality.

1D Anionic Covalent Organic Frameworks With Directed Migration of Alkali Metal Ions for High Ionic Conductivity.

Rational construction of high-performance ionic conductors is a critical challenge in the field of energy storage. In this study, a series of 1D anionic titanium-based covalent organic frameworks (COFs) containing abundant alkali metal ion migration sites, namely, COF-M-R (M = Li, Na, K; R = H, Me, Et), is constructed. The integration of negative TiO6 2- sites on 1D anionic COFs allows alkali metal cations to migrate directly through the channels. Meanwhile, the π-π stacking of 1D chain-to-chain allows the distribution of ion-migration sites in 2D planes. In view of this, multidimensional ionic transport in COFs is realized to achieve high ionic conductivity. COF-M-Rs exhibit an increased ionic conductivity as the counterions change from Li+ to Na+ to K+. Notably, COF-Na-Et has an impressive ionic conductivity as high as 0.81 × 10-3 S cm-1. The different decorated groups (H, Me, and Et) on the skeleton influence the dissociation of the cation from the polyanion. This study offers deep insights into the design of COF-based solid-state electrolytes to achieve high ionic conductivity by increasing the ionic transport dimensions.

Effects of dietary factors on hyperuricaemia and gout: a systematic review and meta-analysis of observational studies.

This study aimed to gather the best evidence on the relationship between dietary factors and hyperuricaemia and gout. We searched databases including PubMed, Embase, Cochrane, and Web of Science from database creation to July 2023. Meta-analysis showed that consumption of alcohol (OR: 1.41, 95% CI: 1.29-1.55; 1.60, 95% CI: 1.33-1.93, respectively), red meat (OR:1.27, 95% CI: 1.18-1.37; 1.32, 95% CI: 1.18-1.47, respectively), fructose (OR: 1.29, 95% CI: 1.21-1.38; 1.65, 95% CI: 1.36-2.01, respectively) and seafoods (OR: 1.40, 95% CI: 1.20-1.64; 1.29, 95% CI: 1.00-1.67, respectively) were positively associated with the risk of hyperuricaemia and gout, while vegetables (OR: 0.78, 95% CI: 0.71-0.85; 0.96,95% CI 0.74-1.24, respectively) were inversely associated. Dairy products (OR: 0.69, 95% CI: 0.61-0.78) and nuts (OR: 0.75, 95% CI: 0.60-0.93) were also inversely associated with the risk of hyperuricaemia. Soy products (OR: 0.86, 95% CI: 0.75-0.98) and coffee (OR: 0.56, 95% CI: 0.39-0.81) were negatively associated with the risk of gout.

Exploring expression levels of the cGAS-STING pathway genes in peripheral blood mononuclear cells of spinal tuberculosis patients.

BACKGROUND: This study aimed to investigate the differential expression levels of the cGAS-STING pathway in peripheral blood mononuclear cells (PBMCs) of spinal tuberculosis (TB) patients with different progression and its feasibility as a diagnostic marker. METHODS: Peripheral blood and medical records of 25 patients with spinal TB and 10 healthy individuals, were prospectively collected and analyzed. PBMCs and serum were extracted from peripheral blood and the expression levels of the cGAS-STING pathway in PBMCs were measured by real-time PCR (RT-PCR) and serum interferon ß (IFN-ß) expression levels were measured by enzyme-linked immunosorbent assay (ELISA). The expression of Interferon regulatory Factor 3 (IRF3) in PBMCs was measured using western blot. Statistical analysis was performed using the SPSS 26.0 statistical package. RESULTS: The results showed that the expression level of the TANK-binding kinase 1 (TBK1) and IRF3 was significantly higher in PBMCs (P < 0.05), in patients with active lesions than in patients with stable lesions. The serum concentration of IFN-ß was significantly higher in patients with active lesions (P = 0.028). Compared with healthy individuals, the expression level of the cGAS-STING pathway was elevated in PBMCs of TB patients (P < 0.05), and the difference in the expression level of IFN-ß was not statistically significant (P > 0.05), and the serum IFN-ß concentration was elevated (P < 0.05). The calculated AUC values for TBK1 and IRF3 in PBMCs, IFN-ß in serum and erythrocyte sedimentation rate (ESR) to distinguish between patients with active and stable lesions were 0.732, 0.714, 0.839, and 0.714 respectively. CONCLUSIONS: The expression level of TBK1 and IRF3 in PBMCs, and IFN-ß in the serum of patients with spinal TB is positively correlated with disease activity. TBK1 has higher specificity and IFN-ß in serum has higher sensitivity when used to differentiate between patients with active and stable lesions.

A review of the immunogenicity and safety of booster doses of omicron variant-containing mRNA-1273 COVID-19 vaccines in adults and children.

INTRODUCTION: Vaccination against SARS-CoV-2 is an integral pillar of the public health approach to COVID-19. With the emergence of variants of concern that increase transmissibility and escape from vaccine- or infection-induced protection, vaccines have been developed to more closely match the newly circulating SARS-CoV-2 strains to improve protection. The safety and immunogenicity of multiple authorized messenger RNA (mRNA)-based COVID-19 vaccines targeting the omicron sublineage (BA.1, BA.4/BA.5, and XBB.1.5) have been demonstrated in several clinical trials among adults and children. AREAS COVERED: This review will comprehensively detail the available evidence (published through July 2024) from ongoing clinical trials on omicron variant-containing mRNA-1273 vaccines administered as additional doses in previously vaccinated target demographics. EXPERT OPINION: Across three clinical trials, omicron variant-containing mRNA-1273 vaccines induced immune responses to vaccine-matched omicron strains as well as ancestral SARS-CoV-2, with a safety and reactogenicity profile comparable to the original mRNA-1273 vaccine. Combined with pivotal data demonstrating the safety, efficacy, and effectiveness of the original mRNA-1273 vaccine, these findings support the use of variant-containing mRNA-1273 vaccines and provide confidence that expeditious development of updated vaccines using this established mRNA platform can maintain protection against COVID-19.

Brain-computer interfaces: the innovative key to unlocking neurological conditions.

Neurological disorders such as Parkinson's disease, stroke, and spinal cord injury can pose significant threats to human mortality, morbidity, and functional independence. Brain-Computer Interface (BCI) technology, which facilitates direct communication between the brain and external devices, emerges as an innovative key to unlocking neurological conditions, demonstrating significant promise in this context. This comprehensive review uniquely synthesizes the latest advancements in BCI research across multiple neurological disorders, offering an interdisciplinary perspective on both clinical applications and emerging technologies. We explore the progress in BCI research and its applications in addressing various neurological conditions, with a particular focus on recent clinical studies and prospective developments. Initially, the review provides an up-to-date overview of BCI technology, encompassing its classification, operational principles, and prevalent paradigms. It then critically examines specific BCI applications in movement disorders, disorders of consciousness, cognitive and mental disorders, as well as sensory disorders, highlighting novel approaches and their potential impact on patient care. This review reveals emerging trends in BCI applications, such as the integration of artificial intelligence and the development of closed-loop systems, which represent significant advancements over previous technologies. The review concludes by discussing the prospects and directions of BCI technology, underscoring the need for interdisciplinary collaboration and ethical considerations. It emphasizes the importance of prioritizing bidirectional and high-performance BCIs, areas that have been underexplored in previous reviews. Additionally, we identify crucial gaps in current research, particularly in long-term clinical efficacy and the need for standardized protocols. The role of neurosurgery in spearheading the clinical translation of BCI research is highlighted. Our comprehensive analysis presents BCI technology as an innovative key to unlocking neurological disorders, offering a transformative approach to diagnosing, treating, and rehabilitating neurological conditions, with substantial potential to enhance patients' quality of life and advance the field of neurotechnology.

Protocol for preparing mammalian skin samples encompassing hair follicles for spatial transcriptomics.

Spatial transcriptomics enables a single-cell resolution view of gene expression patterns in tissues, providing insight into their biological functions. However, applying this approach to the skin presents inherent challenges. Here, we present a protocol for preparing mammalian skin samples encompassing hair follicles for spatial transcriptomics. We describe steps for sample preparation, embedding, acquisition of frozen slices, RNA quality control, tissue mounting, fixation, staining, and imaging. We then detail procedures for permeabilization, reverse transcription, and cDNA collection. For complete details on the use and execution of this protocol, please refer to Chen et al.1.

Neurophysiological effects of cognitive behavioral therapy in social anxiety: An ERP study using a dot-probe task.

BACKGROUND: Social anxious individuals show attention bias towards emotional stimuli, this phenomenon is considered to be an important cause of anxiety generation and maintenance. Cognitive-behavioral therapy (CBT) is a standard psychotherapy for social anxiety disorder. CBT decreases attention biases by correcting the maladaptive beliefs of socially anxious individuals, but it is not clear whether CBT alters neurophysiological features of socially anxious individuals at early automatic and/or late cognitive strategy stage of attentional processing. METHOD: To address this knowledge gap, we collected pre-treatment event-related potential data of 22 socially anxious individuals while they performed a dot-probe task. These participants then received eight weeks of CBT, and post-treatment ERP data were collected after completion of CBT treatment. We also included 29 healthy controls and compared them with individuals with social anxiety to determine the neural mechanisms underlying the effectiveness of CBT. RESULTS: Participants' social anxiety level was significantly alleviated with CBT. ERP results revealed that (1) compared to pre-treatment phase, P1 amplitudes induced by probes significantly decreased at post-treatment phase, whereas P3 amplitudes increased at post-treatment phase; the P1 amplitudes induced by probes following happy-neutral face pairs in socially anxious individuals after treatment was significantly different with that in healthy controls; (2) amplitude of components elicited by face pairs did not change significantly between pre-treatment and post-treatment phases; (3) changes of Liebowitz Social Anxiety Scale were positively correlated with changes of P1 amplitude, and negatively correlated with changes of N1 amplitude. LIMITATIONS: Our sample was university students and lacked randomization, which limits the generalizability of the results. CONCLUSION: The present results demonstrated that CBT may adjust cognitive strategies in the later stage of attentional processing, indicating by changed ERPs appeared in probe-presenting stage for social anxiety.

Value of bronchoalveolar lavage fluid metagenomic next-generation sequencing in acute exacerbation of fibrosing interstitial lung disease: an individualized treatment protocol based on microbiological evidence.

BACKGROUND: Acute exacerbation of fibrosing interstitial lung diseases (AE-ILD) is a serious life-threatening event per year. Methylprednisolone and/or immunosuppressive agents (ISA) are a mainstay in any regimen, under the premise that pulmonary infection has been promptly identified and controlled. We investigated the value of bronchoalveolar lavage fluid (BALF) metagenomic next-generation sequencing (mNGS) on the treatment adjustment of AE-ILD. METHODS: We conducted a cross-sectional observational study. All data were collected prospectively and retrospectively analyzed. We included fifty-six patients with AE-ILD and nineteen stable ILD who underwent BALF mNGS at the beginning of admission. RESULTS: Patients with a variety of ILD classification were included. Connective-tissue disease related ILD (CTD-ILD) occupy the most common underlying non-idiopathic pulmonary fibrosis (non-IPF). The infection-triggered AE accounted for 39.29%, with the majority of cases being mixed infections. The microorganisms load in the AE-ILD group was significantly higher. After adjusted by mNGS, the therapy coverage number of pathogens was significantly higher compared to the initial treatment (p < 0.001). After treatment, the GGO score and the consolidation score were significantly lower during follow up in survivors (1.57 ± 0.53 vs. 2.38 ± 0.83 with p < 0.001, 1.11 ± 0.24 vs. 1.49 ± 0.47 with p < 0.001, respectively). Some detected microorganisms, such as Tropheryma whipplei, Mycobacterium, Aspergillus, and mixed infections were difficult to be fully covered by empirical medication. BALF mNGS was also very helpful for excluding infections and early administration of methylprednisolone and/or ISA. CONCLUSIONS: mNGS has been shown to be a useful tool to determine pathogens in patients with AE-ILD, the results should be fully analyzed. The comprehensive treatment protocol based on mNGS has been shown crucial in AE-ILD patients.

PTBP1-mediated repression of neuron-specific CDC42 splicing constitutes a genomic alteration-independent, developmentally conserved vulnerability in IDH-wildtype glioblastoma.

Gene co-expression networks may encode hitherto inadequately recognized vulnerabilities for adult gliomas. By identifying evolutionally conserved gene co-expression modules around EGFR (EM) or PDGFRA (PM), we recently proposed an EM/PM classification scheme, which assigns IDH-wildtype glioblastomas (GBM) into the EM subtype committed in neural stem cell compartment, IDH-mutant astrocytomas and oligodendrogliomas into the PM subtype committed in early oligodendrocyte lineage. Here, we report the identification of EM/PM subtype-specific gene co-expression networks and the characterization of hub gene polypyrimidine tract-binding protein 1 (PTBP1) as a genomic alteration-independent vulnerability in IDH-wildtype GBM. Supervised by the EM/PM classification scheme, we applied weighted gene co-expression network analysis to identify subtype-specific global gene co-expression modules. These gene co-expression modules were characterized for their clinical relevance, cellular origin and conserved expression pattern during brain development. Using lentiviral vector-mediated constitutive or inducible knockdown, we characterized the effects of PTBP1 on the survival of IDH-wildtype GBM cells, which was complemented with the analysis of PTBP1-depedent splicing pattern and overexpression of splicing target neuron-specific CDC42 (CDC42-N) isoform.  Transcriptomes of adult gliomas can be robustly assigned into 4 large gene co-expression modules that are prognostically relevant and are derived from either malignant cells of the EM/PM subtypes or tumor microenvironment. The EM subtype is associated with a malignant cell-intrinsic gene module involved in pre-mRNA splicing, DNA replication and damage response, and chromosome segregation, and a microenvironment-derived gene module predominantly involved in extracellular matrix organization and infiltrating immune cells. The PM subtype is associated with two malignant cell-intrinsic gene modules predominantly involved in transcriptional regulation and mRNA translation, respectively. Expression levels of these gene modules are independent prognostic factors and malignant cell-intrinsic gene modules are conserved during brain development. Focusing on the EM subtype, we identified PTBP1 as the most significant hub for the malignant cell-intrinsic gene module. PTBP1 is not altered in most glioma genomes. PTBP1 represses the conserved splicing of CDC42-N. PTBP1 knockdown or CDC42-N overexpression disrupts actin cytoskeleton dynamics, causing accumulation of reactive oxygen species and cell apoptosis. PTBP1-mediated repression of CDC42-N splicing represents a potential genomic alteration-independent, developmentally conserved vulnerability in IDH-wildtype GBM.

In a Canine Model of Septic Shock, Cardiomyopathy Occurs Independent of Catecholamine Surges and Cardiac Microvascular Ischemia.

BACKGROUND: High levels of catecholamines are cardiotoxic and associated with stress-induced cardiomyopathies. Using a septic shock model that reproduces the reversible cardiomyopathy seen over 10 days associated with human septic shock, we investigated the effects of catecholamines on microcirculatory perfusion and cardiac dysfunction. METHODS AND RESULTS: Purpose-bred beagles received intrabronchial Staphylococcus aureus (n=30) or saline (n=6). The septic animals were than randomized to epinephrine (1 µg/kg per minute, n=15) or saline (n=15) infusions from 4 to 44 hours. Serial cardiac magnetic resonance imaging, catecholamine levels, and troponins were collected over 92 hours. Serial adenosine-stress perfusion cardiac magnetic resonance imaging was performed on septic animals randomized to receive saline (n=8 out of 15) or epinephrine (n=8 out of 15). High-dose sedation was given to suppress endogenous catecholamine release. Despite catecholamine levels largely remaining within the normal range throughout, by 48 hours, septic animals receiving saline versus nonseptic animals still developed significant worsening of left ventricular ejection fraction, circumferential strain, and ventricular-aortic coupling. In septic animals that received epinephrine versus saline infusions, plasma epinephrine levels increased 800-fold, but epinephrine produced no significant further worsening of left ventricular ejection fraction, circumferential strain, or ventricular-aortic coupling. Septic animals receiving saline had a significant increase in microcirculatory reserve without troponin elevations. Septic animals receiving epinephrine had decreased edema, blunted microcirculatory perfusion, and elevated troponin levels that persisted for hours after the epinephrine infusion stopped. CONCLUSIONS: Cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor due to decreased microvascular perfusion-induced ischemia. However, epinephrine itself has potentially harmful long-lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion.

An Integrated Nanoplatform via Dual Channel Excitation for Both Precise Fluorescence Imaging and Photodynamic Therapy of Orthotopic Breast Tumor in NIR-II Region.

Although research on photodynamic therapy (PDT) of malignant tumor has made considerable progress in recent years, it is a remaining challenge to extend PDT to the second near-infrared window (NIR-II) along with real-time and accurate NIR-II fluorescence imaging to determine drug enrichment status and achieve high treatment efficacy. In this work, lanthanide nanoparticles (Ln NPs)-based nanoplatform (LCR) equipped with photosensitizer Chlorin e6 (Ce6) and targeting molecular NH2-PEG1000-cRGDfK are developed, which can achieve NIR-II photodynamic therapy (PDT) and NIR-II fluorescence imaging by dual channel excitation. Under 808 nm excitation, Nd3+ in the outer layer can absorb the energy and transfer inward to emit strong NIR-II emissions (1064 and 1525 nm). Due to the low background noise of NIR-II light and the targeting effect of NH2-PEG1000-cRGDfK, LCR can recognize tiny tumor tissue (≈3 mm) and monitor drug distribution in vivo. Under 1530 nm excitation, internal Er3+ can be self-sensitized, generating intense upconversion emission (662 nm) that can effectively activate Ce6 for in vivo PDT due to the deep tissue penetration of NIR-II light. This study provides a paradigm of theranostic nanoplatform for both real-time fluorescence imaging and PDT of orthotopic breast tumor in NIR-II window.