The extracellular cyclophilin A-integrin ß2 complex as a therapeutic target of viral pneumonia.

The acute respiratory virus infection can induce uncontrolled inflammatory responses, such as cytokine storm and viral pneumonia, which are the major causes of death in clinical cases. Cyclophilin A (CypA) is mainly distributed in the cytoplasm of resting cells and released into the extracellular space in response to inflammatory stimuli. Extracellular CypA (eCypA) is upregulated and promotes inflammatory response in severe COVID-19 patients. However, how eCypA promotes virus-induced inflammatory response remains elusive. Here, we observe that eCypA is induced by influenza A and B viruses and SARS-CoV-2 in cells, mice, or patients. Anti-CypA mAb reduces pro-inflammatory cytokines production, leukocytes infiltration, and lung injury in virus-infected mice. Mechanistically, eCypA binding to integrin ß2 triggers integrin activation, thereby facilitating leukocyte trafficking and cytokines production via the focal adhesion kinase (FAK)/GTPase and FAK/ERK/P65 pathways, respectively. These functions are suppressed by the anti-CypA mAb that specifically blocks eCypA-integrin ß2 interaction. Overall, our findings reveal that eCypA-integrin ß2 signaling mediates virus-induced inflammatory response, indicating that eCypA is a potential target for antibody therapy against viral pneumonia.

A community challenge to predict clinical outcomes after immune checkpoint blockade in non-small cell lung cancer.

BACKGROUND: Predictive biomarkers of immune checkpoint inhibitor (ICI) efficacy are currently lacking for non-small cell lung cancer (NSCLC). Here, we describe the results from the Anti-PD-1 Response Prediction DREAM Challenge, a crowdsourced initiative that enabled the assessment of predictive models by using data from two randomized controlled clinical trials (RCTs) of ICIs in first-line metastatic NSCLC. METHODS: Participants developed and trained models using public resources. These were evaluated with data from the CheckMate 026 trial (NCT02041533), according to the model-to-data paradigm to maintain patient confidentiality. The generalizability of the models with the best predictive performance was assessed using data from the CheckMate 227 trial (NCT02477826). Both trials were phase III RCTs with a chemotherapy control arm, which supported the differentiation between predictive and prognostic models. Isolated model containers were evaluated using a bespoke strategy that considered the challenges of handling transcriptome data from clinical trials. RESULTS: A total of 59 teams participated, with 417 models submitted. Multiple predictive models, as opposed to a prognostic model, were generated for predicting overall survival, progression-free survival, and progressive disease status with ICIs. Variables within the models submitted by participants included tumor mutational burden (TMB), programmed death ligand 1 (PD-L1) expression, and gene-expression-based signatures. The best-performing models showed improved predictive power over reference variables, including TMB or PD-L1. CONCLUSIONS: This DREAM Challenge is the first successful attempt to use protected phase III clinical data for a crowdsourced effort towards generating predictive models for ICI clinical outcomes and could serve as a blueprint for similar efforts in other tumor types and disease states, setting a benchmark for future studies aiming to identify biomarkers predictive of ICI efficacy. TRIAL REGISTRATION: CheckMate 026; NCT02041533, registered January 22, 2014. CheckMate 227; NCT02477826, registered June 23, 2015.

The binding of extracellular cyclophilin A to ACE2 and CD147 triggers psoriasis-like inflammation.

Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.

Enhancing microstructure and device performance of InGaN quantum dot micro-LEDs through substrate off-cut angle modulation.

InGaN quantum dots (QDs) are regarded as a compelling candidate material for the fabrication of high-quality GaN-based micro-LEDs. In this work, to study the impact of a substrate structure on InGaN QDs and QD-based micro-LEDs, GaN-on-sapphire substrates with off-cut angles toward the a-axis of 0.2°, 0.4°, and 0.7° were utilized as templates for the fabrication of InGaN QDs and InGaN QDs-based micro-LEDs. Experimental results show that GaN template with 0.4° off-cut angle exhibits the narrowest terrace width and enables InGaN QDs to be higher and more uniform. The InGaN QD sample grown on 0.4° substrate has a very small wavelength shift of 2.5 nm with temperature increasing and owns the longest photoluminescence peak wavelength implying the highest In content. Furthermore, electroluminescence (EL) spectra demonstrate that QD-based micro-LED array has excellent wavelength stability under various injection currents, and the stability can be improved further on a GaN template with narrower terraces. The results indicate that altering the terrace width of GaN template is a feasible scheme for improving the properties of GaN-based micro-LEDs.

Assessing perceptions of stigmatization by others for seeking help in China: psychometric characteristics and measurement invariance across gender and therapy experience.

The stigma of social networks may be more noticeable in collectivist societies like China, but research in this area has largely been overlooked due to a lack of reliable measurement. To address this gap, this study tested the psychometric properties of the Chinese version of the Perceptions of Stigmatization by Others for Seeking Help (PSOSH) scale in the Chinese general population, and tested its invariance across gender and prior therapy experience. In a national online survey, 640 adults completed the PSOSH and conceptually related scales: Self-stigma of Seeking Help (SSOSH), Stigma of Seeking Professional Psychological Help Scale (SSPPH, i.e., public stigma) and Attitudes toward Seeking Professional Psychological Help Scale-Short Form (ATSPPH-SF). Confirmatory factor analysis supported the unidimensional structure of the original PSOSH. The Cronbach's α coefficient was 0.84 and the 3-week test-retest reliability of was 0.77. The PSOSH showed moderate correlations with the three conceptually related scales, supporting its concurrent validity. Importantly, the PSOSH significantly predicted self-stigma scores, even when considering demographic variables and public stigma, supporting its incremental validity. The scale also demonstrated scalar invariance across gender and across subgroups who had vs. did not have previous therapy experience, supporting comparisons of latent means across these groups. The PSOSH is a reliable and valid instrument for assessing social network stigmatization of professional help-seeking in Chinese community samples.

Hypothalamic-Pituitary-Adrenal Axis and Epilepsy.

Epilepsy is a recurrent, transient seizure disorder of the nervous system that affects the intellectual development, life and work, and psychological health of patients. People with epilepsy worldwide experience great suffering. Stressful stimuli such as infection, mental stress, and sleep deprivation are important triggers of epilepsy, and chronic stressful stimuli can lead to frequent seizures and comorbidities. The hypothalamic-pituitary-adrenal (HPA) axis is the most important system involved in the body's stress response, and dysfunction thereof is thought to be associated with core epilepsy symptoms and related psychopathology. This article explores the intrinsic relationships of corticotropin-releasing hormone, adrenocorticotropic hormone, and glucocorticoids with epilepsy in order to reveal the role of the HPA axis in the pathogenesis of epilepsy. We hope that this information will yield future possible directions and ideas for fully understanding the pathogenesis of epilepsy and developing antiepileptic drugs.

Role of cyclophilin A in aggravation of myocardial ischemia reperfusion injury via regulation of apoptosis mediated by thioredoxin-interacting protein.

BACKGROUND: The progression and persistence of myocardial ischemia/reperfusion injury (MI/RI) are strongly linked to local inflammatory responses and oxidative stress. Cyclophilin A (CypA), a pro-inflammatory factor, is involved in various cardiovascular diseases. However, the role and mechanism of action of CypA in MI/RI are still not fully understood. METHODS: We used the Gene Expression Omnibus (GEO) database for bioinformatic analysis. We collected blood samples from patients and controls for detecting the levels of serum CypA using enzyme-linked immunosorbent assay (ELISA) kits. We then developed a myocardial ischemia/reperfusion (I/R) injury model in wild-type (WT) mice and Ppia-/- mice. We utilized echocardiography, hemodynamic measurements, hematoxylin and eosin (H&E) staining, immunohistochemistry, enzyme-linked immunosorbent assay, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining to determine the role of CypA in myocardial I/R injury. Finally, we conducted an in vitrostudy, cell transfection, flow cytometry, RNA interference, and a co-immunoprecipitation assay to clarify the mechanism of CypA in aggravating cardiomyocyte apoptosis. RESULTS: We found that CypA inhibited TXNIP degradation to enhance oxidative stress-induced cardiomyocyte apoptosis during MI/RI. By comparing and analyzing CypA expression in patients with coronary atherosclerotic heart disease and in healthy controls, we found that CypA was upregulated in patients with Coronary Atmospheric Heart Disease, and its expression was positively correlated with Gensini scores. In addition, CypA deficiency decreased cytokine expression, oxidative stress, and cardiomyocyte apoptosis in I/R-treated mice, eventually alleviating cardiac dysfunction. CypA knockdown also reduced H2O2-induced apoptosis in H9c2 cells. Mechanistically, we found that CypA inhibited K48-linked ubiquitination mediated by atrophin-interacting protein 4 (AIP4) and proteasomal degradation of TXNIP, a thioredoxin-binding protein that mediates oxidative stress and induces apoptosis. CONCLUSION: These findings highlight the critical role CypA plays in myocardial injury caused by oxidative stress-induced apoptosis, indicating that CypA can be a viable biomarker and a therapeutic target candidate for MI/RI.

Flexible bidirectional self-powered photodetector with significantly reduced volume and accelerated response speed based on hydrogel and lift-off GaN-based nanowires.

Due to the wide range of potential applications for next-generation multi-functional devices, the flexible self-powered photodetector (PD) with polarity-switchable behavior is essential but very challenging to be realized. Herein, a wearable bidirectional self-powered PD based on detached (Al,Ga)N and (In,Ga)N nanowires has been proposed and demonstrated successfully. Arising from the photovoltage-competing dynamics across (Al,Ga)N and (In,Ga)N nanowire photoelectrodes, such PD can generate the positive (33.3 mA W -1) and negative (-0.019 mA W -1) photo-responsivity under ultraviolet (UV) and visible illumination, respectively, leading to the bidirectional photocurrent behavior. Thanks to the introduction of quasi solid-state hydrogel, the PD can work without the liquid-electrolyte, thus remarkably reducing the volume from about 482 cm3 to only 0.18 cm3. Furthermore, the use of hydrogel is found to enhance response speed in the UV range by reducing the response time for more than 95%, which is mainly attributed to the increased open circuit potential and reduced ion transport distance. As the GaN connecting segment is pretty thin, the piezoelectric charges generated by stress are proposed to have only a limited effect on the photocurrent density. Therefore, both the stable on-off switching characteristics and photocurrent densities can still be achieved after being bent 400 times. With an excellent flexibility, this work creates opportunities for technological applications of bidirectional photocurrent PDs in flexible optoelectronic devices, e.g., wearable intelligent sensors.

Tracing unknown tumor origins with a biological-pathway-based transformer model.

Cancer of unknown primary (CUP) represents metastatic cancer where the primary site remains unidentified despite standard diagnostic procedures. To determine the tumor origin in such cases, we developed BPformer, a deep learning method integrating the transformer model with prior knowledge of biological pathways. Trained on transcriptomes from 10,410 primary tumors across 32 cancer types, BPformer achieved remarkable accuracy rates of 94%, 92%, and 89% in primary tumors and primary and metastatic sites of metastatic tumors, respectively, surpassing existing methods. Additionally, BPformer was validated in a retrospective study, demonstrating consistency with tumor sites diagnosed through immunohistochemistry and histopathology. Furthermore, BPformer was able to rank pathways based on their contribution to tumor origin identification, which helped to classify oncogenic signaling pathways into those that are highly conservative among different cancers versus those that are highly variable depending on their origins.