Gp93 inhibits unfolded protein response-mediated c-Jun N-terminal kinase activation and cell invasion.

In eukaryotes, Hsp90B1 serves as a vital chaperonin, facilitating the accurate folding of proteins. Interestingly, Hsp90B1 exhibits contrasting roles in the development of various types of cancers, although the underlying reasons for this duality remain enigmatic. Through the utilization of the Drosophila model, this study unveils the functional significance of Gp93, the Drosophila ortholog of Hsp90B1, which hitherto had limited reported developmental functions. Employing the Drosophila cell invasion model, we elucidated the pivotal role of Gp93 in regulating cell invasion and modulating c-Jun N-terminal kinase (JNK) activation. Furthermore, our investigation highlights the involvement of the unfolded protein response-associated IRE1/XBP1 pathway in governing Gp93 depletion-induced, JNK-dependent cell invasion. Collectively, these findings not only uncover a novel molecular function of Gp93 in Drosophila, but also underscore a significant consideration pertaining to the testing of Hsp90B1 inhibitors in cancer therapy.

High-fidelity intracellular imaging of multiple miRNAs via stimulus-responsive nanocarriers and catalytic hairpin assembly.

An advanced nanoplatform was developed by integrating catalytic hairpin assembly (CHA) with glutathione-responsive nanocarriers, enabling superior imaging of dual cancer-related miRNAs. Two distinct CHA circuits for the sensing of miRNA-21 and miRNA-155 were functionalized on biodegraded MnO2. In the presence of GSH and the corresponding miRNAs, the degraded MnO2 released the DNA cargos, activating the CHA circuits and recovering the fluorescence. This approach offers a reliable sensing performance with highly selective cell-identification capacity, positioning it as a pivotal tool for imaging multiple biomarkers in living cells.

Palladium-Catalyzed Atroposelective Kinetic C-H Olefination and Allylation for the Synthesis of C-B Axial Chirality.

The direct C-H functionalization of 1,2-benzazaborines, especially asymmetric version, remains a great challenge. Here we report a palladium-catalyzed enantioselective C-H olefination and allylation reactions of 1,2-benzazaborines. This asymmetric approach is a kinetic resolution (KR), providing various C-B axially chiral 2-aryl-1,2-benzazaborines and 3-substituted 2-aryl-1,2-benzazaborines in generally high yields with excellent enantioselectivities (selectivity (S) factor up to 354). The synthetic potential of this reaction is showcased by late-stage modification of complex molecules, scale-up reaction, and applications.

Regulating highly photoelectrochemical activity of Zr-based mixed-linker metal-organic frameworks toward sensitive electrogenerated chemiluminescence sensing of α-glucosidase.

The conductivity and emission efficiency of metal-organic frameworks (MOFs) remain challenging factors that limit their electrogenerated chemiluminescence (ECL) sensing applications. Herein, we report a facile approach to address these challenges by integrating an electroactive linker (H2-TCPP) with an ECL active electrogenerated chemiluminescence linker (H4-TBAPy) to construct a highly photoelectrochemical active mixed-linker MOFs (ML-MOFs). ECL results revealed a remarkable 15.4-fold enhancement for the top-performing ML-MOFs (M6-MOFs), surpassing the single linker MOFs. In addition, M6-MOFs also exhibit a remarkable 73-fold enhancement in ECL efficiency compared to commercial Ru (bpy)32+. This improvement should be attributed to the synergistic effects resulting from the combination of two linkers. Furthermore, M6-MOFs are found to be served as a model ECLphore for sensitive and selective detection of α-glucosidase for the first time with good potential practicability in human serum samples. This work represents a promising direction to guide for designing good conductivity and high ECL efficiency MOFs in terms of linker functionalization and thus bandgap modulation for advancing their ECL sensing applications.

DNA-modulated single-atom nanozymes with enhanced enzyme-like activity for ultrasensitive detection of dopamine.

Despite the current progress in optimizing and tailoring the performance of nanozymes through structural and synthetic adaptation, there is still a lack of dynamic modulation approaches to alter their catalytic activity. Here, we demonstrate that DNA can act as an auxiliary regulator via a straightforward incubation method with Fe-N-C single-atom nanozymes (SAzymes), causing a leap in the enzyme-like activity of Fe-N-C from moderate to a higher level. The DNA-assisted enhancement is attributed to the increased substrate affinity of Fe-N-C nanozymes through electrostatic attraction between the substrate and DNA. Based on the prepared DNA/Fe-N-C system, colorimetric sensors for dopamine (DA) detection were constructed. Surprisingly, the incorporation of DNA not only enabled the detection of DA in a low concentration range, but also greatly improved the sensitivity with a 436-fold decrease in detection limit. The quantitative determination of DA was achieved in two-segment linear ranges of 0.01-4 µM and 5-100 µM with an ultralow detection limit of 9.56 nM. The DNA/Fe-N-C system shows superior performance compared to the original Fe-N-C system, making it an ideal choice for nanozyme-based biosensors. This simple design approach has paved the way for enhancing nanozyme activity and is expected to serve as a general strategy for optimizing biosensor performance.

Integrating features from lymph node stations for metastatic lymph node detection.

Metastasis on lymph nodes (LNs), the most common way of spread for primary tumor cells, is a sign of increased mortality. However, metastatic LNs are time-consuming and challenging to detect even for professional radiologists due to their small sizes, high sparsity, and ambiguity in appearance. It is desired to leverage recent development in deep learning to automatically detect metastatic LNs. Besides a two-stage detection network, we here introduce an additional branch to leverage information about LN stations, an important reference for radiologists during metastatic LN diagnosis, as supplementary information for metastatic LN detection. The branch targets to solve a closely related task on the LN station level, i.e., classifying whether an LN station contains metastatic LN or not, so as to learn representations for LN stations. Considering that a metastatic LN station is expected to significantly affect the nearby ones, a GCN-based structure is adopted by the branch to model the relationship among different LN stations. At the classification stage of metastatic LN detection, the above learned LN station features, as well as the features reflecting the distance between the LN candidate and the LN stations, are integrated with the LN features. We validate our method on a dataset containing 114 intravenous contrast-enhanced Computed Tomography (CT) images of oral squamous cell carcinoma (OSCC) patients and show that it outperforms several state-of-the-art methods on the mFROC, maxF1, and AUC scores, respectively.

Soluble ß-amyloid impaired the GABA inhibition by mediating KCC2 in early APP/PS1 mice.

Alzheimer's disease (AD) is a neurodegenerative disorder, which has become the leading cause of dementia cases globally. Synaptic failure is an early pathological feature of AD. However, the cause of synaptic failure in AD, especially the GABAergic synaptic activity remains unclear. Extensive evidence indicates that the presence of soluble amyloid-ß is an early pathological feature in AD, which triggers synaptic dysfunction and cognitive decline. Our recent study explored the relation of GABAergic transmission and soluble Aß in early APP/PS1 mice. Firstly, we found soluble Aß42 levels were significantly increased in serum, hippocampus and prefrontal cortex in 3-4 months APP/PS1 mice, which was much earlier than Aß plagues formation. In addition, we found TNF-α and BDNF expression levels were increased, while KCC2 and GABAAR expression were decreased in 3-4 months APP/PS1 hippocampus. When we treated 3-4 months APP/PS1 mice with a potent γ-secretase inhibitor, LY411575, which can reduce the soluble Aß42 levels, the TNF-α and BDNF protein levels were decreased, while KCC2 and GABAAR levels were increased. In conclusion, our study suggested soluble Aß may impaired the GABA inhibition by mediating KCC2 levels in early APP/PS1 mice. KCC2 may be served as a potential biomarker for AD.

Treatment of a Hemophilia B Mouse Model with Platelet-Targeted Expression of Factor IX Padua.

Targeting the coagulation factor IX (FIX) expression in platelets has been shown to be effective in ameliorating bleeding in hemophilia B (HB) mice. To improve the therapeutic effects and evaluate the safety of this gene therapy strategy, we generated a transgenic mouse model on an HB background with FIX Padua target expressed in platelets. The transgenic mice exhibited stable expression and storage of FIX Padua in platelets. The platelet-stored FIX Padua could be released with the activation of platelets, and the proportion of platelet-stored FIX Padua in whole blood was the same as that of platelet-stored wild-type human FIX. The platelet-derived FIX Padua showed substantially increased specific activity compared with wild-type FIX. Reduced bleeding volume in the FIX Padua transgenic mice demonstrated that bleeding in the mice was improved. Levels of thrombin-antithrombin complex, fibrinogen, D-Dimer, and blood cell counts were normal in the transgenic mice, suggesting that thrombotic risk was not increased in this mouse model. However, the leakage and failure to overcome the presence of inhibitor to wild-type FIX is also observed with FIX Padua, as expected. Taken together, our results support the conclusion that targeting FIX Padua expression in platelets may be an effective and safe gene therapy strategy for HB, and could provide an ideal model to evaluate the safety of platelet-targeted gene therapy for treating hemophilia.

Nanoscale Metal-Organic Frameworks and Their Nanomedicine Applications.

Abundant connectivity among organic ligands and inorganic metal ions makes the physical and chemical characters of metal-organic frameworks (MOFs) could be precisely devised and modulated for specific applications. Especially nanoscale MOFs (NMOFs), a unique family of hybrid nanomaterials, with merits of holding the nature as the mainstay MOFs and demonstrating particle size in nanoscale range which enable them prospect platform in clinic. Adjustability of composition and structure allows NMOFs with different constituents, shapes, and characteristics. Oriented frameworks and highly porous provide enough space for packing therapeutic cargoes and various imaging agents efficiently. Moreover, the relatively labile metal-ligand bonds make NMOFs biodegradable in nature. So far, as a significant class of biomedically relevant nanomaterials, NMOFs have been explored as drug carriers, therapeutic preparation, and biosensing and imaging preparation owing to their high porosity, multifunctionality, and biocompatibility. This review provides up-to-date developments of NMOFs in biomedical applications with emphasis on size control, synthetic approaches, and surfaces functionalization as well as stability, degradation, and toxicity. The outlooks and several crucial issues of this area are also discussed, with the expectation that it may help arouse widespread attention on exploring NMOFs in potential clinical applications.

Sodium houttuyfonate enhances the intestinal barrier and attenuates inflammation induced by Salmonella typhimurium through the NF-κB pathway in mice.

Salmonella typhimurium (ST), as an aggressive bacterium, mainly causes intestinal inflammation and diarrhea. Sodium houttuyfonate (SH) is a derivative of houttuynin in the active oil of Houttuynia cordata, which is stable in nature and has anti-inflammatory activity. In this study, we used BALB/c mice infected with ST as experimental subjects and aimed to study the regulatory effect of SH on the intestinal tract and to explain its anti-inflammatory mechanism. Compared with the ST group, SH treatment improved the morphology of jejunum mucosa and alleviated the pathological damage to colon tissue. In addition, SH protected the intestinal barrier by regulating the localization and distribution of tight junction proteins. Meanwhile, SH significantly decreased the production of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) and inflammation-related enzymes (iNOS, COX-2). Moreover, further western blot results suggested that SH inhibited the expression of p-IκBα and p-p65 in intestinal tissues. These results demonstrated that SH maintained the intestinal barrier and attenuated the production of intestinal proinflammatory cytokines by regulating the NF-κB signaling pathway, thereby providing protection for the intestine.

ApoE deficiency promotes non-alcoholic fatty liver disease in mice via impeding AMPK/mTOR mediated autophagy.

AIM: This work was to investigate the relationship between ApoE and autophagy regulated by AMPK/mTOR pathway in the pathological process of NAFLD. MAIN METHODS: Both WT and ApoE-/- mice were divided into two groups and allocated into either a normal chow (ND) or a high-fat diet (HFD) for 8 weeks. After that, we detected the indicators of lipid accumulation, hepatic injury, mitochondrial function hallmark, autophagy, apoptosis, inflammation, and oxidative stress by commercially available kits, immunohistochemistry, immunofluorescent staining, and western blot. KEY FINDING: We found the lipid levels of serum and liver, and hepatic injury were significantly increased in the ApoE-/--HFD group compared to other groups. ApoE-/- mice exhibited increased deposition of fat in liver tissue. The PGC1α, NRF1, ATP, p-AMPK, AMPK, Beclin1, and LC3 levels were downregulated and ROS, p-mTOR, and mTOR were increased in the ApoE-/--HFD group compared to WT-HFD group. When treated with AMPK and autophagy activators, AICAR and rapamycin, these pathologies and protein levels can be rescued. The expression levels of apoptosis-related proteins, inflammation, and oxidative stress were increased in the ApoE-/--HFD group compared to the WT-HFD group. SIGNIFICANCE: Our results indicated that ApoE deficiency can regulate AMPK/mTOR pathway, which leads to NAFLD most likely by modulating hepatic mitochondrial function.

Molecularly Thin Nitride Sheets Stabilized by Titanium Carbide as Efficient Bifunctional Electrocatalysts for Fiber-Shaped Rechargeable Zinc-Air Batteries.

With the ever-increasing growth in next-generation flexible and wearable electronics, fiber-shaped zinc-air batteries have attracted considerable attention due to their advantages of high energy density and low cost, though their development, however, has been seriously hampered by the unavailability of efficient electrocatalysts. In this work, we designed a trimetallic nitride electrocatalyst in an unusual molecular sheet form, which was stabilized by metallic titanium carbide sheets. Besides the expected elevation in catalytic activity toward the oxygen evolution reaction, the material simultaneously unlocked excellent catalytic activity for oxygen reduction reaction with the half-wave potential as small as 0.84 V. A flexible fiber-shaped zinc-air battery, employing the designed electrocatalyst as the air cathode and a gel as the electrolyte, demonstrated an enhanced and durable electrochemical performance, outputting a competitive energy density of 627 Wh kgzn-1. This work opens new avenues for utilizing two-dimensional sheets in future wearable and portable device applications.

Radially Aligned Hierarchical Nickel/Nickel-Iron (Oxy)hydroxide Nanotubes for Efficient Electrocatalytic Water Splitting.

Designing well-controlled hierarchical structures on micrometer and nanometer scales represents one of the most important approaches for upgrading the catalytic abilities of electrocatalysts. Although NiFe (oxy)hydroxide has been widely studied as a water oxidation catalyst due to its high catalytic capability and abundance, its structural manipulation has been greatly restricted due to its inherent crystallographic stacking feature. In this work, we report for the first time the construction of a nanotube structure of NiFe (oxy)hydroxide with an inner Ni-rich layer, which was radially aligned on a macroporous nickel foam. Such a hierarchically structured material realized several crucial factors that are essential for excellent catalytic behaviors, including abundant catalytic sites, a high surface area, efficient ionic and electronic transport, etc., and the designed catalyst exhibited competitive electrocatalytic activity for reaction of not only oxygen evolution but also hydrogen evolution, which is very rare. As a result, this novel material was well-suited for the use as a bifunctional catalyst in an integrated water-splitting electrolyzer, which could be even driven by a single AA battery or a 1.5 V solar cell, outperforming a benchmark catalyst of noble-metal ruthenium-platinum combinations and most state-of-the-art electrocatalysts. The work provided important suggestions for the rational modulation of catalysts with new structures targeted for high-performance electrodes used in electrochemical applications.