Lectin of Concanavalin A as an anti-hepatoma therapeutic agent

Liver cancer is the predominant cause of cancer mortality in males of Southern China and Taiwan. The current therapy is not satisfactory, and more effective treatments are needed. In the search for new therapies for liver tumor, we found that Concanavalin A (Con A), a lectin from Jack bean seeds, can have a potent anti-hepatoma effect. Con A after binding to the mannose moiety on the cell membrane glycoprotein is internalized preferentially to the mitochondria. An autophagy is triggered which leads to cell death. Con A as a T cell mitogen subsequently activates the immune response in the liver and results in the eradication of the tumor in a murine in situ hepatoma model. The liver tumor nodule formation is inhibited by the CD8+ T cells, and a tumor antigen-specific immune memory is established during the hepatic inflammation. The dual properties (autophagic cytotoxicity and immunomodulation) via the specific carbohydrate binding let Con A exert a potent anti-hepatoma therapeutic effect. The novel mechanism of the Con A anti-hepatoma effect is discussed. The prototype of Con with an anti-hepatoma activity gives support to the search for other natural lectins as anti-cancer compounds

Large-scale Training Data Search for Object Re-identification

We consider a scenario where we have access to the target domain, but cannot afford on-the-fly training data annotation, and instead would like to construct an alternative training set from a large-scale data pool such that a competitive model can be obtained. We propose a search and pruning (SnP) solution to this training data search problem, tailored to object re-identification (re-ID), an application aiming to match the same object captured by different cameras. Specifically, the search stage identifies and merges clusters of source identities which exhibit similar distributions with the target domain. The second stage, subject to a budget, then selects identities and their images from the Stage I output, to control the size of the resulting training set for efficient training. The two steps provide us with training sets 80\% smaller than the source pool while achieving a similar or even higher re-ID accuracy. These training sets are also shown to be superior to a few existing search methods such as random sampling and greedy sampling under the same budget on training data size. If we release the budget, training sets resulting from the first stage alone allow even higher re-ID accuracy. We provide interesting discussions on the specificity of our method to the re-ID problem and particularly its role in bridging the re-ID domain gap. The code is available at https://github.com/yorkeyao/SnP.Comment: Accepted to CVPR202

A Conserved Tripeptide in CNG and HCN Channels Regulates Ligand Gating by Controlling C-Terminal Oligomerization

AbstractCyclic nucleotides directly enhance the opening of the tetrameric CNG and HCN channels, although the mechanism remains unclear. We examined why HCN and certain CNG subunits form functional homomeric channels, whereas other CNG subunits only function in heteromeric channels. The “defect” in the CNGA4 subunit that prevents its homomeric expression was localized to its C-linker, which connects the transmembrane domain to the binding domain and contains a tripeptide that decreases the efficacy of ligand gating. Remarkably, replacement of the homologous HCN tripeptide with the CNGA4 sequence transformed cAMP into an inverse agonist that inhibits HCN channel opening. Using analytical ultracentrifugation, we identified the structural basis for this gating switch: whereas cAMP normally enhances the assembly of HCN C-terminal domains into a tetrameric gating ring, inclusion of the CNGA4 tripeptide reversed this action so that cAMP now causes gating ring disassembly. Thus, ligand gating depends on the dynamic oligomerization of C-terminal binding domains

Light-Independent Inactivation of Dengue-2 Virus by Carboxyfullerene C3 Isomer

AbstractCarboxyfullerene (C60) is known as a photosensitizer for virus inactivation. Its regioisomer with C3 symmetry, named the C3 isomer, could also inactivate the dengue-2 virus without light when the dose of C3 isomer was increased to 40 μM, indicating the possible involvement of a light-independent mechanism. Further analysis showed that the C3 isomer blocked viral replication at the attachment and penetration stages, suggesting that a direct interaction between the C3 isomer and the virion is required for inactivation. The C3 isomer with a bipolar structure showed better lipid interaction and dengue-2 virus suppression than D3, another isomer that contains evenly distributed hydrophilic side chains. Moreover, the C3 isomer selectively inactivated enveloped viruses (viz., dengue-2 virus and Japanese encephalitis virus) instead of nonenveloped viruses (viz., enterovirus 71 and coxsackievirus B3). Collectively, these findings support the hypothesis that C3 isomer suppression of enveloped viruses is effected through its hydrophobic interaction with the viral lipid envelope. Our report, which demonstrates the light-dependent and -independent mechanisms of C60 on viral inactivation, will aid in the development of novel anti-viral agents for use against enveloped viruses

Cytotoxic Necrotizing Factor 1 Downregulates CD36 Transcription in Macrophages to Induce Inflammation During Acute Urinary Tract Infections

Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) induce cystitis, pyelonephritis, and can cause kidney scarring and failure if inflammation is not under control. The detailed effects of cytotoxic necrotizing factor 1 (CNF1), the key UPEC toxin, on the pathogenicity of UPEC remain unclear. CD36 is an important scavenger receptor, responsible for pathogen and apoptotic cell clearance, and plays an essential role in host immune defense and homeostasis. Regulation of CD36 by bacterial toxins has not been reported. In this study, using a pyelonephritis mouse model, CNF1 was observed to contribute to increasing neutrophils and bacterial titers in infected bladder and kidney tissues, resulting in severe inflammation and tissue damage. CD36 expression in macrophages was found to be decreased by CNF1 in vitro and in vivo. We demonstrated that CNF1 attenuated CD36 transcription by decreasing expressions of its upstream transcription factors LXRβ and C/EBPα and their recruitment to the CD36 promotor. In addition, Cdc42 was found to be involved in CNF1-mediated downregulation of LXRβ. Our study investigated the pathogenesis of cnf1-carrying UPEC, which affected host innate immune defenses and homeostasis through regulation of CD36 in macrophages during acute UTIs

Self-controlled growth of highly uniform Ge/Si hut wires for scalable qubit devices

Semiconductor nanowires have been playing a crucial role in the development of nanoscale devices for the realization of spin qubits, Majorana fermions, single photon emitters, nanoprocessors, etc. The monolithic growth of site-controlled nanowires is a prerequisite towards the next generation of devices that will require addressability and scalability. Here, combining top-down nanofabrication and bottom-up self-assembly, we report on the growth of Ge wires on pre-patterned Si (001) substrates with controllable position, distance, length and structure. This is achieved by a novel growth process which uses a SiGe strain-relaxation template and can be generalized to other material combinations. Transport measurements show an electrically tunable spin-orbit coupling, with a spin-orbit length similar to that of III-V materials. Also, capacitive coupling between closely spaced wires is observed, which underlines their potential as a host for implementing two qubit gates. The reported results open a path towards scalable qubit devices with Si compatibility

Emodin Rescues Intrahepatic Cholestasis via Stimulating FXR/BSEP Pathway in Promoting the Canalicular Export of Accumulated Bile

AimBile salt export pump (BSEP) have been confirmed to play an important role for bile acid canalicular export in the treatment of cholestasis. In this study, we investigated the stimulatory effect of emodin on BSEP signaling pathway in cholestasis.MethodsCell and animal experiments were given different concentrations of emodin. The BSEP upstream molecule farnesoid X receptor was down-regulated by small interfering RNA (siRNA) technology or guggulsterones and up-regulated by lentivirus or GW4064. Real-time PCR and Western blotting was employed to detect the mRNA and protein levels of BSEP in LO2 cell, rat primary hepatocytes and liver tissue. Immunohistochemistry (IHC) was used to examine the expression of BSEP in liver tissues. Rat liver function and pathological changes of liver tissue were performed by biochemical test and hematoxylin and eosin (HE) staining.ResultsEmodin could increase the mRNA and protein expression of BSEP and FXR. When down-regulating farnesoid X receptor expression with the siRNA or inhibitor guggulsterones, and up-regulating farnesoid X receptor expression with the lentivirus or agonist GW4064, emodin could increase the mRNA level of BSEP and FXR and the protein level of BSEP, FXR1, and FXR2. Emodin also had a notable effect on rat primary hepatocytes experiment, rat pathological manifestation, BSEP, FXR1, and FXR2 positive staining in liver tissues and the test of liver function.ConclusionEmodin has a protective effect and a rescue activity on cholestasis via stimulating FXR/BSEP pathways in promoting the canalicular export of accumulated bile

Superconductivity at 25 K in hole doped (La1−xSrx)OFeAs(La_{1-x}Sr_x)OFeAs

By partially substituting the tri-valence element La with di-valence element Sr in $LaOFeAs$, we introduced holes into the system. For the first time, we successfully synthesized the hole doped new superconductors $(La_{1-x}Sr_x)OFeAs$. The maximum superconducting transition temperature at about 25 K was observed at a doping level of x = 0.13. It is evidenced by Hall effect measurements that the conduction in this type of material is dominated by hole-like charge carriers, rather than electron-like ones. Together with the data of the electron doped system $La(O_{1-x}F_x)FeAs$, a generic phase diagram is depicted and is revealed to be similar to that of the cuprate superconductors.Comment: 5 pages, 5 figure

ChatRadio-Valuer: A Chat Large Language Model for Generalizable Radiology Report Generation Based on Multi-institution and Multi-system Data

Radiology report generation, as a key step in medical image analysis, is critical to the quantitative analysis of clinically informed decision-making levels. However, complex and diverse radiology reports with cross-source heterogeneity pose a huge generalizability challenge to the current methods under massive data volume, mainly because the style and normativity of radiology reports are obviously distinctive among institutions, body regions inspected and radiologists. Recently, the advent of large language models (LLM) offers great potential for recognizing signs of health conditions. To resolve the above problem, we collaborate with the Second Xiangya Hospital in China and propose ChatRadio-Valuer based on the LLM, a tailored model for automatic radiology report generation that learns generalizable representations and provides a basis pattern for model adaptation in sophisticated analysts' cases. Specifically, ChatRadio-Valuer is trained based on the radiology reports from a single institution by means of supervised fine-tuning, and then adapted to disease diagnosis tasks for human multi-system evaluation (i.e., chest, abdomen, muscle-skeleton, head, and maxillofacial $\&$ neck) from six different institutions in clinical-level events. The clinical dataset utilized in this study encompasses a remarkable total of \textbf{332,673} observations. From the comprehensive results on engineering indicators, clinical efficacy and deployment cost metrics, it can be shown that ChatRadio-Valuer consistently outperforms state-of-the-art models, especially ChatGPT (GPT-3.5-Turbo) and GPT-4 et al., in terms of the diseases diagnosis from radiology reports. ChatRadio-Valuer provides an effective avenue to boost model generalization performance and alleviate the annotation workload of experts to enable the promotion of clinical AI applications in radiology reports

Concanavalin A/IFN-Gamma Triggers Autophagy-Related Necrotic Hepatocyte Death through IRGM1-Mediated Lysosomal Membrane Disruption

Interferon-gamma (IFN-γ), a potent Th1 cytokine with multiple biological functions, can induce autophagy to enhance the clearance of the invading microorganism or cause cell death. We have reported that Concanavalin A (Con A) can cause autophagic cell death in hepatocytes and induce both T cell-dependent and -independent acute hepatitis in immunocompetent and immunodeficient mice, respectively. Although IFN-γ is known to enhance liver injury in Con A-induced hepatitis, its role in autophagy-related hepatocyte death is not clear. In this study we report that IFN-γ can enhance Con A-induced autophagic flux and cell death in hepatoma cell lines. A necrotic cell death with increased lysosomal membrane permeabilization (LMP) is observed in Con A-treated hepatoma cells in the presence of IFN-γ. Cathepsin B and L were released from lysosomes to cause cell death. Furthermore, IFN-γ induces immunity related GTPase family M member 1(IRGM1) translocation to lysosomes and prolongs its activity in Con A-treated hepatoma cells. Knockdown of IRGM1 inhibits the IFN-γ/Con A-induced LMP change and cell death. Furthermore, IFN-γ−/− mice are resistant to Con A-induced autophagy-associated necrotic hepatocyte death. We conclude that IFN-γ enhances Con A-induced autophagic flux and causes an IRGM1-dependent lysosome-mediated necrotic cell death in hepatocytes