Notch3 as a novel therapeutic target for the treatment of ADPKD by regulating cell proliferation and renal cyst development.

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic kidney disease. Emerging research indicates that the Notch signaling pathway plays an indispensable role in the pathogenesis of numerous kidney diseases, including ADPKD. Herein, we identified that Notch3 but not other Notch receptors was overexpressed in renal tissues from mice with ADPKD and ADPKD patients. Inhibiting Notch3 with γ-secretase inhibitors, which block a proteolytic cleavage required for Notch3 activation, or shRNA knockdown of Notch3 significantly delayed renal cyst growth in vitro and in vivo. Subsequent mechanistic study elucidated that the cleaved intracellular domain of Notch3 (N3ICD) and Hes1 could bind to the PTEN promoter, leading to transcriptional inhibition of PTEN. This further activated the downstream PI3K-AKT-mTOR pathway and promoted renal epithelial cell proliferation. Overall, Notch3 was identified as a novel contributor to renal epithelial cell proliferation and cystogenesis in ADPKD. We envision that Notch3 represents a promising target for ADPKD treatment.

MiR-423-5p promotes Müller cell activation via targeting NGF signaling in diabetic retinopathy.

AIMS: Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus and one of the major causes of visual impairment and blindness in industrialized countries. The early neuro-glial perturbations, especially retinal Müller cells (rMC) activation, intimately associated with the vascular alterations. MicroRNAs (miRNAs) have been reported to play critical roles in the progression of DR. Here, we aimed to further explore the role and underlying mechanism of miR-423-5p in Müller cell activation in streptozotocin (STZ)-induced diabetic mice and oxygen-induced retinopathy (OIR) model. MATERIALS AND METHODS: Retinal histology, optical coherence tomography (OCT) and biochemical markers were assessed. KEY FINDINGS: Our data revealed that the expression of miR-423-5p was significantly increased under high-glucose environment. We also demonstrated that miR-423-5p overexpression markedly accelerated retinal vascular leakage, leukocytosis, and rMC activation. This response was ameliorated in animals pre-treated with the inhibition of miR-423-5p. Specifically, miR-423-5p bound to the nerve growth factor (NGF) 3' UTR region to induce its silencing. NGF inhibition significantly promoted retinal microvascular dysfunction. SIGNIFICANCE: These findings demonstrate that miR-423-5p is a critical miRNA that promotes microvascular dysfunction in DR.

Dynamic Metal-Ligand Coordination Boosts CO2 Electroreduction.

The interfacial structure of heterogeneous catalysts determines the reaction rate by adjusting the adsorption behavior of reaction intermediates. Unfortunately, the catalytic performance of conventionally static active sites has always been limited by the adsorbate linear scaling relationship. Herein, we develop a triazole-modified Ag crystal (Ag crystal-triazole) with dynamic and reversible interfacial structures to break such a relationship for boosting the catalytic activity of CO2 electroreduction into CO. On the basis of surface science measurements and theoretical calculations, we demonstrated the dynamic transformation between adsorbed triazole and adsorbed triazolyl on the Ag(111) facet induced by metal-ligand conjugation. During CO2 electroreduction, Ag crystal-triazole with the dynamically reversible transformation of ligands exhibited a faradic efficiency for CO of 98% with a partial current density for CO as high as -802.5 mA cm-2. The dynamic metal-ligand coordination not only reduced the activation barriers of CO2 protonation but also switched the rate-determining step from CO2 protonation to the breakage of C-OH in the adsorbed COOH intermediate. This work provided an atomic-level insight into the interfacial engineering of the heterogeneous catalysts toward highly efficient CO2 electroreduction.

Long Noncoding RNA PPT2-EGFL8 Regulates Pathological Retinal Neovascularization in PDR by Functioning as a Competing Endogenous RNA.

Diabetic retinopathy (DR) is a common complication in patients with diabetes, and proliferative DR (PDR) has become an important cause of blindness; however, the mechanisms involved have not been fully elucidated. miRNAs and long noncoding RNAs can play an important role in DR, and they can accurately regulate the expression of target genes through a new regulatory model: competing endogenous RNAs. We isolated total RNA of extracellular vesicles (EVs) in the serum of healthy individuals and individuals with diabetes without DR, non-PDR, or PDR, and performed deep sequencing. We found aberrantly low expression of PPT2-EGFL8 and significantly increased level of miR-423-5p. PPT2-EGFL8 adsorbs miR-423-5p as a molecular sponge and inhibits hypoxia-induced human retinal microvascular endothelial cells proliferation. In an oxygen-induced retinopathy (OIR) model and a streptozotocin-induced diabetes model, Egfl8-overexpression treatment reduces diabetes-related reactive gliosis, inflammation, and acellular capillaries and attenuates the development of pathological neovascularization. In addition, PPT2-EGFL8 targeting miR-423-5p plays an important role in hypoxia-induced peroxisome proliferator-activated receptor-ß/δ (PPARD)/angiopoietin-like 4 (ANGPTL4) signaling activation, especially the expression of the C-terminal ANGPTL4 fragment. Finally, ANGPTL4 significantly induces retinal vessel breakage in the inner limiting membrane and facilitates retinal vessel sprouting into the vitreous in the OIR mice. Thus, either new biomarkers or new therapeutic targets may be identified with translation of these findings.

A domain-agnostic approach for characterization of lifelong learning systems.

Despite the advancement of machine learning techniques in recent years, state-of-the-art systems lack robustness to "real world" events, where the input distributions and tasks encountered by the deployed systems will not be limited to the original training context, and systems will instead need to adapt to novel distributions and tasks while deployed. This critical gap may be addressed through the development of "Lifelong Learning" systems that are capable of (1) Continuous Learning, (2) Transfer and Adaptation, and (3) Scalability. Unfortunately, efforts to improve these capabilities are typically treated as distinct areas of research that are assessed independently, without regard to the impact of each separate capability on other aspects of the system. We instead propose a holistic approach, using a suite of metrics and an evaluation framework to assess Lifelong Learning in a principled way that is agnostic to specific domains or system techniques. Through five case studies, we show that this suite of metrics can inform the development of varied and complex Lifelong Learning systems. We highlight how the proposed suite of metrics quantifies performance trade-offs present during Lifelong Learning system development - both the widely discussed Stability-Plasticity dilemma and the newly proposed relationship between Sample Efficient and Robust Learning. Further, we make recommendations for the formulation and use of metrics to guide the continuing development of Lifelong Learning systems and assess their progress in the future.

A Novel Nomogram Combined the Aggregate Index of Systemic Inflammation and PIRADS Score to Predict the Risk of Clinically Significant Prostate Cancer.

Background: This study is aimed at constructing a nomogram to predict the risk of clinically significant prostate cancer (csPCa) based on the aggregate index of systemic inflammation (AISI) and prostate imaging-reporting and data system version (PIRADS) score. Methods: Clinical data on patients who had undergone initial prostate biopsy from January 2019 to December 2021 were collected. Patients were randomized in a 7 : 3 ratio to the training cohort and the validation cohort. Potential risk factors for csPCa were identified by univariable and multivariate logistic regression. Nomogram was conducted with these independent risk factors, and calibration curves, the receiver operating characteristic (ROC), and decision curve analysis (DCA) were employed to assess the nomogram's ability for prediction. Results: A total of 1219 patients were enrolled in this study. Multivariate logistic regression identified that age, AISI, total prostatic specific-antigen (tPSA), free to total PSA (f/tPSA), prostate volume (PV), and PIRADS score were potential risk predictors of csPCa, and the nomogram was developed based on these factors. The area under the curve (AUC) of the training cohort and validation cohort was 0.884 (95% CI: 0.862-0.906) and 0.899 (95% CI: 0.867-0.931). The calibration curves showed that the apparent curves were closer to the ideal curves. The DCA results revealed that the nomogram model seemed to have clinical application value per DCA. Conclusion: The nomogram model can efficiently predict the risk of csPCa and may assist clinicians in determining if a prostate biopsy is necessary.

Enhancing CO2 Electroreduction Selectivity toward Multicarbon Products via Tuning the Local H2O/CO2 Molar Ratio.

Mass transfer plays an important role in controlling the surface coverage of reactants and the kinetics of surface reactions, thus significantly adjusting the catalytic performance. Herein, we reported that H2O diffusion was modulated by controlling the thicknesses of the carbon black (CB) layer between the gas diffusion electrode (GDE) of Cu and the electrolyte. As a consequence, the product distribution over the GDE of Cu was effectively regulated during CO2 electroreduction. Interestingly, a volcano-type relationship between the thickness of the CB layer and the faradaic efficiency (FE) for multicarbon (C2+) products was observed over the GDE of Cu. Especially, when the applied total current density was set as 800 mA cm-2, the FE for the C2+ products over the GDE of Cu coated by a CB layer with a thickness of 6.6 µm reached 63.2%, which was 2.8 times higher than that (16.8%) over the GDE of Cu without a CB layer.

An enhanced EEG microstate recognition framework based on deep neural networks: an application to Parkinson's disease.

Variations in brain activity patterns reveal impairments of motor and cognitive functions in the human brain. Electroencephalogram (EEG) microstates embody brain activity patterns at a microscopic time scale. However, current microstate analysis method can only recognize less than 90% of EEG signals per subject, which severely limits the characterization of dynamic brain activity. As an application to early Parkinson's disease (PD), we propose an enhanced EEG microstate recognition framework based on deep neural networks, which yields recognition rates from 90% to 99%, as accompanied by a strong anti-artifact property. Additionally, gradient-weighted class activation mapping, as a visualization technique, is employed to locate the activated functional brain regions of each microstate class. We find that each microstate class corresponds to a particular activated brain region. Finally, based on the improved identification of microstate sequences, we explore the EEG microstate characteristics and their clinical associations. We show that the decreased occurrences of a particular microstate class reflect the degree of cognitive decline in early PD, and reduced transitions between certain microstates suggest injury in motor-related brain regions. The novel EEG microstate recognition framework paves the way to revealing more effective biomarkers for early PD.

LXA4 protects against blue-light induced retinal degeneration in human A2E-laden RPE cells and Balb-c mice.

BACKGROUND: Age-related macular degeneration (AMD) is one of the leading causes of permanent visual impairment in the elderly. Blue light (BL) has been reported to cause retinal damage and contribute to the onset and development of severe AMD. N-retinylidene-N-retinylethanolamine (A2E), a lipofuscin fluorophore, accumulates with ageing in the retinal pigment epithelium (RPE) cells. Once exposed to BL, A2E easily oxidizes to A2E-epoxides, causing oxidative-stress injury to the retina. Lipoxin A4 (LXA4), an endogenous anti-antioxidant lipid, plays a key role in multiple organs by binding to the formyl-peptide receptor-like 1 (FPRL1). This study examined the protective effects of LXA4 on oxidative-stress injury induced by BL exposure, and clarified the underlying mechanisms in cultured RPE cells and Balb-c mice. METHODS: LXA4 diluent was orally administered to mice before retinal degeneration was established. Optical coherence tomography, retinal histology, and RPE cell injury were assessed. RESULTS: LXA4 administration significantly ameliorated retinal damage as evidenced by the thicknesses of the retinal layers and the tight junctions of RPE cells in vivo. LXA4 inhibited BL-induced reactive oxygen species (ROS) production, reduced tight junctions, and the death of A2E-laden RPE cells. LXA4 also potently increased the expression of haem oxygenase-1 (HO1) and NAD(P)H quinone oxidoreductase 1 (NQO1), probably by decreasing the association between nuclear factor erythroid 2-related factor 2 (NRF2) and Kelch-like ECH (Epichlorohydrin) -associated protein 1 (Keap1), and ameliorating NRF2 nuclear translocation and the antioxidant response element (ARE) deoxyribonucleic acid (DNA) binding activity. CONCLUSIONS: Our results showed that LXA4 ameliorated retinal degeneration, and should be considered in the prevention and treatment of AMD.

Evidence for a higher-order topological insulator in a three-dimensional material built from van der Waals stacking of bismuth-halide chains.

Low-dimensional van der Waals materials have been extensively studied as a platform with which to generate quantum effects. Advancing this research, topological quantum materials with van der Waals structures are currently receiving a great deal of attention. Here, we use the concept of designing topological materials by the van der Waals stacking of quantum spin Hall insulators. Most interestingly, we find that a slight shift of inversion centre in the unit cell caused by a modification of stacking induces a transition from a trivial insulator to a higher-order topological insulator. Based on this, we present angle-resolved photoemission spectroscopy results showing that the real three-dimensional material Bi4Br4 is a higher-order topological insulator. Our demonstration that various topological states can be selected by stacking chains differently, combined with the advantages of van der Waals materials, offers a playground for engineering topologically non-trivial edge states towards future spintronics applications.

Nanoscale Conductivity Imaging of Correlated Electronic States in WSe_{2}/WS_{2} Moiré Superlattices.

We report the nanoscale conductivity imaging of correlated electronic states in angle-aligned WSe_{2}/WS_{2} heterostructures using microwave impedance microscopy. The noncontact microwave probe allows us to observe the Mott insulating state with one hole per moiré unit cell that persists for temperatures up to 150 K, consistent with other characterization techniques. In addition, we identify for the first time a Mott insulating state at one electron per moiré unit cell. Appreciable inhomogeneity of the correlated states is directly visualized in the heterobilayer region, indicative of local disorders in the moiré superlattice potential or electrostatic doping. Our work provides important insights on 2D moiré systems down to the microscopic level.

Lithium-ion electrolytic substrates for sub-1V high-performance transition metal dichalcogenide transistors and amplifiers.

Electrostatic gating of two-dimensional (2D) materials with ionic liquids (ILs), leading to the accumulation of high surface charge carrier densities, has been often exploited in 2D devices. However, the intrinsic liquid nature of ILs, their sensitivity to humidity, and the stress induced in frozen liquids inhibit ILs from constituting an ideal platform for electrostatic gating. Here we report a lithium-ion solid electrolyte substrate, demonstrating its application in high-performance back-gated n-type MoS2 and p-type WSe2 transistors with sub-threshold values approaching the ideal limit of 60 mV/dec and complementary inverter amplifier gain of 34, the highest among comparable amplifiers. Remarkably, these outstanding values were obtained under 1 V power supply. Microscopic studies of the transistor channel using microwave impedance microscopy reveal a homogeneous channel formation, indicative of a smooth interface between the TMD and underlying electrolytic substrate. These results establish lithium-ion substrates as a promising alternative to ILs for advanced thin-film devices.