Policy and Strategy for Hepatitis C Virus Elimination at the National Level: Experience in Taiwan.

The estimated prevalence of anti-HCV was 3.1% in Taiwan. Studies have shown iatrogenic behavior was the major transmission route. It is highest in specific populations including patients with end stage renal disease (ESRD), human immunodeficiency virus infection, who inject drug (PWID), and under opioid substitution treatment. Approximately 405,160 patients were seropositive for HCV RNA and in need of treatment. Taiwan government claims to reach WHO's 2030 goal of HCV elimination by 2025 and works hard to resolve several barriers of HCV elimination including political commitment, sustainable financing, minimize reimbursement restrictions, instituted monitoring, and perform micro-elimination of specific populations. The last stage of HCV elimination is to accelerate the universal HCV screening program of populations aged 45-79 years and resolve the unawareness issue of HCV infection. Hopefully, we can achieve the targets of HCV elimination set by WHO and reach the goal earlier in 2025.

In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer.

Inhibiting a specific target in cancer cells and reducing unwanted side effects has become a promising strategy in pancreatic cancer treatment. MAP4K4 is associated with pancreatic cancer development and correlates with poor clinical outcomes. By phosphorylating MKK4, proteins associated with cell apoptosis and survival are translated. Therefore, inhibiting MAP4K4 activity in pancreatic tumours is a new therapeutic strategy. Herein, we performed a structure-based virtual screening to identify MAP4K4 inhibitors and discovered the compound F389-0746 with a potent inhibition (IC50 120.7 nM). The results of kinase profiling revealed that F389-0746 was highly selective to MAP4K4 and less likely to cause side effects. Results of in vitro experiments showed that F389-0746 significantly suppressed cancer cell growth and viability. Results of in vivo experiments showed that F389-0746 displayed comparable tumour growth inhibition with the group treated with gemcitabine. These findings suggest that F389-0746 has promising potential to be further developed as a novel pancreatic cancer treatment.

Structure-based virtual screening and biological evaluation of novel small-molecule BTK inhibitors.

Bruton tyrosine kinase (BTK) is linked to multiple signalling pathways that regulate cellular survival, activation, and proliferation. A covalent BTK inhibitor has shown favourable outcomes for treating B cell malignant leukaemia. However, covalent inhibitors require a high reactive warhead that may contribute to unexpected toxicity, poor selectivity, or reduced effectiveness in solid tumours. Herein, we report the identification of a novel noncovalent BTK inhibitor. The binding interactions (i.e. interactions from known BTK inhibitors) for the BTK binding site were identified and incorporated into a structure-based virtual screening (SBVS). Top-rank compounds were selected and testing revealed a BTK inhibitor with >50% inhibition at 10 µM concentration. Examining analogues revealed further BTK inhibitors. When tested across solid tumour cell lines, one inhibitor showed favourable inhibitory activity, suggesting its potential for targeting BTK malignant tumours. This inhibitor could serve as a basis for developing an effective BTK inhibitor targeting solid cancers.

Identification of a dual TAOK1 and MAP4K5 inhibitor using a structure-based virtual screening approach.

The STE20 kinase family is a complex signalling cascade that regulates cytoskeletal organisation and modulates the stress response. This signalling cascade includes various kinase mediators, such as TAOK1 and MAP4K5. The dysregulation of the STE20 kinase pathway is linked with cancer malignancy. A small-molecule inhibitor targeting the STE20 kinase pathway has therapeutic potential. In this study, a structure-based virtual screening (SBVS) approach was used to identify potential dual TAOK1 and MAP4K5 inhibitors. Enzymatic assays confirmed three potential dual inhibitors (>50% inhibition) from our virtual screening, and analysis of the TAOK1 and MAP4K5 binding sites indicated common interactions for dual inhibition. Compound 1 revealed potent inhibition of colorectal and lung cancer cell lines. Furthermore, compound 1 arrested cancer cells in the G0/G1 phase, which suggests the induction of apoptosis. Altogether, we show that the STE20 signalling mediators TAOK1 and MAP4K5 are promising targets for drug research.

Amide-tethered quinoline-resorcinol conjugates as a new class of HSP90 inhibitors suppressing the growth of prostate cancer cells.

The study is focused on the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor. In-vitro studies of the synthetic compounds led to the identification of compound 11, which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhibition. Compound 11 triggers degradation of HSP90 client proteins along with concomitant induction of HSP70, demonstrates apoptosis inducing ability and causes G2M phase cell cycle arrest in PC-3 cells. Molecular modeling was used to dock compound 11 into the HSP90 active site and key interactions with the amino acid residues of the HSP90 chaperone protein were determined.

Integrin-linked kinase as a novel molecular switch of the IL-6-NF-κB signaling loop in breast cancer.

Substantial evidence has clearly demonstrated the role of the IL-6-NF-κB signaling loop in promoting aggressive phenotypes in breast cancer. However, the exact mechanism by which this inflammatory loop is regulated remains to be defined. Here, we report that integrin-linked kinase (ILK) acts as a molecular switch for this feedback loop. Specifically, we show that IL-6 induces ILK expression via E2F1 upregulation, which, in turn, activates NF-κB signaling to facilitate IL-6 production. shRNA-mediated knockdown or pharmacological inhibition of ILK disrupted this IL-6-NF-κB signaling loop, and blocked IL-6-induced cancer stem cells in vitro and estrogen-independent tumor growth in vivo Together, these findings establish ILK as an intermediary effector of the IL-6-NF-κB feedback loop and a promising therapeutic target for breast cancer.

High-performance hybrid complementary logic inverter through monolithic integration of a MEMS switch and an oxide TFT.

A hybrid complementary logic inverter consisting of a microelectromechanical system switch as a promising alternative for the p-type oxide thin film transistor (TFT) and an n-type oxide TFT is presented for ultralow power integrated circuits. These heterogeneous microdevices are monolithically integrated. The resulting logic device shows a distinctive voltage transfer characteristic curve, very low static leakage, zero-short circuit current, and exceedingly high voltage gain.

Amphiplicatus metriothermophilus gen. nov., sp. nov., a thermotolerant alphaproteobacterium isolated from a hot spring.

A thermotolerant, Gram-strain-negative, non-spore-forming and strictly aerobic bacterium, designated GU51(T), was isolated from Guhai hot spring in Jimsar county, Xinjiang province, north-west China. Each cell of strain GU51(T) consisted of an oval body and two symmetrical long (3-6 µm) prosthecae. The strain moved by polar flagellum. Oxidase and catalase were produced. Strain GU51(T) grew within the ranges of 37-65 °C (optimum 48-50 °C), 0.5-7.5% (w/v) NaCl (optimum 2-3%) and pH 6.0-9.0 (optimum pH 7.5). The major respiratory quinone detected was ubiquinone 10 (U-10) and the genomic DNA G+C content was 66.7±0.4 mol%. Major fatty acids (>5%) were C(16 : 0), C(18 : 1)ω7c and 11-methyl C(18 : 1)ω7c. The polar lipids consisted of diphosphatidylglycerol, five glycolipids, phosphatidylglycerol and an unknown phospholipid. Phylogenetic analysis showed the closest relatives of strain GU51(T) were members of the genus Parvularcula with 92.3% 16S rRNA gene sequence similarity. On the basis of this polyphasic taxonomic characterization, it is suggested that strain GU51(T) represents a novel species of a new genus in the family 'Parvularculaceae', for which the name Amphiplicatus metriothermophilus gen. nov., sp. nov. is proposed. The type strain of the type species is GU51(T) ( = CGMCC 1.12710(T) = JCM 19779(T)).

Durable response after just one cycle of belotecan-based chemotherapy in a patient with relapsed primary peritoneal serous carcinoma.

The efficacy of second-line chemotherapy for relapsed primary peritoneal serous carcinoma has been numerously reported, but reports on durable response after second-line therapy have been rare. We report the case of a 66-year-old woman with relapsed primary peritoneal serous carcinoma who showed durable response after just one cycle of second-line belotecan-based therapy. The response might be a complete pathologic remission. Considering the fact that our patient suffered from neutropenic sepsis during her treatment, we concluded that belotecan-based chemotherapy could be a good option for second-line chemotherapy in some selected patients, so patient selection should be carefully performed due to the toxicity of belotecan.

COL1A1 regulates the apoptosis of embryonic stem cells by mediating the PITX1/TBX4 signaling.

PURPOSE: The purpose of this study is to explore the regulatory function of COL1A1 against the apoptosis of embryonic stem cells (ESCs) and the potential function in congenital talipes equinovarus (CTEV). METHODS: Muscle tissues were collected from 20 children with CTEV and 20 children without CTEV, followed by detecting the expression of COL1A1 using the RT-PCR method. COL1A1 was knocked down in H1 and H9 human ESCs using the RNA interference technology, followed by determining the level of COL1A1, PITX1, TBX4, HOXD10, Fas, FasL, and Bax using the Western blotting assay. RESULTS: COL1A1 was found markedly upregulated in muscle tissues of CTEV children. In H1 and H9 human ESCs, compared to the empty vector, COL1A1, PITX1, TBX4, HOXD10, Fas, FasL, and Bax were found notably downregulated after transfected with the siRNA targeting COL1A1. CONCLUSION: COL1A1 induced the apoptosis of ESCs by mediating the PITX1/TBX4 signaling and might be a potential target for treating CTEV.

In silico identification of a novel Cdc2-like kinase 2 (CLK2) inhibitor in triple negative breast cancer.

Dysregulation of RNA splicing processes is intricately linked to tumorigenesis in various cancers, especially breast cancer. Cdc2-like kinase 2 (CLK2), an oncogenic RNA-splicing kinase pivotal in breast cancer, plays a significant role, particularly in the context of triple-negative breast cancer (TNBC), a subtype marked by substantial medical challenges due to its low survival rates. In this study, we employed a structure-based virtual screening (SBVS) method to identify potential CLK2 inhibitors with novel chemical structures for treating TNBC. Compound 670551 emerged as a novel CLK2 inhibitor with a 50% inhibitory concentration (IC50) value of 619.7 nM. Importantly, Compound 670551 exhibited high selectivity for CLK2 over other protein kinases. Functionally, this compound significantly reduced the survival and proliferation of TNBC cells. Results from a cell-based assay demonstrated that this inhibitor led to a decrease in RNA splicing proteins, such as SRSF4 and SRSF6, resulting in cell apoptosis. In summary, we identified a novel CLK2 inhibitor as a promising potential treatment for TNBC therapy.

Meta-transcriptomic analysis of companion animal infectomes reveals their diversity and potential roles in animal and human disease.

Companion animals such as cats and dogs harbor diverse microbial communities that can potentially impact human health due to close and frequent contact. To better characterize their total infectomes and assess zoonotic risks, we characterized the overall infectomes of companion animals (cats and dogs) and evaluated their potential zoonotic risks. Meta-transcriptomic analyses were performed on 239 samples from cats and dogs collected across China, identifying 24 viral species, 270 bacterial genera, and two fungal genera. Differences in the overall microbiome and infectome composition were compared across different animal species (cats or dogs), sampling sites (rectal or oropharyngeal), and health status (healthy or diseased). Diversity analyses revealed that viral abundance was generally higher in diseased animals compared to healthy ones, while differences in microbial composition were mainly driven by sampling site, followed by animal species and health status. Disease association analyses validated the pathogenicity of known pathogens and suggested potential pathogenic roles of previously undescribed bacteria and newly discovered viruses. Cross-species transmission analyses identified seven pathogens shared between cats and dogs, such as alphacoronavirus 1, which was detected in both oropharyngeal and rectal swabs albeit with differential pathogenicity. Further analyses showed that some viruses, like alphacoronavirus 1, harbored multiple lineages exhibiting distinct pathogenicity, tissue, or host preferences. Ultimately, a systematic evolutionary screening identified 27 potential zoonotic pathogens in this sample set, with far more bacterial than viral species, implying potential health threats to humans. Overall, our meta-transcriptomic analysis reveals a landscape of actively transcribing microorganisms in major companion animals, highlighting key pathogens, those with the potential for cross-species transmission, and possible zoonotic threats. IMPORTANCE: This study provides a comprehensive characterization of the entire community of infectious microbes (viruses, bacteria, and fungi) in companion animals like cats and dogs, termed the "infectome." By analyzing hundreds of samples from across China, the researchers identified numerous known and novel pathogens, including 27 potential zoonotic agents that could pose health risks to both animals and humans. Notably, some of these zoonotic pathogens were detected even in apparently healthy pets, highlighting the importance of surveillance. The study also revealed key microbial factors associated with respiratory and gastrointestinal diseases in pets, as well as potential cross-species transmission events between cats and dogs. Overall, this work sheds light on the complex microbial landscapes of companion animals and their potential impacts on animal and human health, underscoring the need for monitoring and management of these infectious agents.

Metagenomic analysis of individual mosquito viromes reveals the geographical patterns and drivers of viral diversity.

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Here, using a meta-transcriptomic approach, we determined the viromes of 2,438 individual mosquitoes (81 species), spanning ~4,000 km along latitudes and longitudes in China. From these data we identified 393 viral species associated with mosquitoes, including 7 (putative) species of arthropod-borne viruses (that is, arboviruses). We identified potential mosquito species and geographic hotspots of viral diversity and arbovirus occurrence, and demonstrated that the composition of individual mosquito viromes was strongly associated with host phylogeny. Our data revealed a large number of viruses shared among mosquito species or genera, enhancing our understanding of the host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, perhaps reflecting long-distance mosquito dispersal. Together, these results greatly expand the known mosquito virome, linked viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the biogeography and diversity of viruses in insect vectors.

Effects of vinpocetine on random skin flap survival in rats.

The effect of vinpocetine on flap survival, vascular endothelial growth factor (VEGF) expression, and superoxide dismutase (SOD) and malondialdehyde (MDA) contents were evaluated in this study. The McFarlane flap model was established in 20 rats and evaluated within two groups. Postoperative celiac injection was given for 7 days in the two groups: vinpocetine was applied in Group 1, and the same volume of saline was applied in Group 2. Flap necrosis was measured on day 7 by cellophane in all groups. VEGF expression was determined using immunohistochemical methods on tissue samples taken after 7 days of injections. SOD and MDA contents were examined according to the Kit (reagent instructions). Vinpocetine significantly reduced necrosis area in Group 1 (p < 0.05). VEGF expression and SOD contents were significantly increased in Group 1 compared with Group 2 (p < 0.01), whereas MDA level was reduced (p < 0.05). This experimental study demonstrates that vinpocetine improves survival of random skin flaps, promotes neovascularization, and increases VEGF expression. Meanwhile, vinpocetine has a protective effect against ischemia-reperfusion injury by improving SOD vitality and decreasing MDA value.

Research on digital twin modeling and monitoring technology for smoke alarm calibration system.

Aiming at the problems of backward calibration method of smoke alarm, low production efficiency and difficult real-time monitoring, a digital twin system modeling and monitoring method of smoke alarm calibration is proposed. First, through the analysis of smoke alarm calibration requirements, the overall framework design of the digital twin calibration system for smoke alarm is proposed, and then the twin model of smoke box is constructed by running the digital twin five-dimensional model. The physical smoke box, geometric model, physical model, rule model and behavior model are introduced in detail; Then the communication system architecture, data acquisition and data mapping are used to construct the twin data model; Finally, the feasibility was verified by the calibration system of an enterprise. Through the system, the qualified rate of smoke alarm calibration was increased from 98 to 99.6%, and the repair rate of defective products was reduced by 1.6%.

Forming Analysis and Heat Treatment of TC31 Titanium Alloy Component with High Ribs and Thin Webs.

TC31 is a new type of high-temperature titanium alloy, but few researchers have studied the combination of forming and heat treatment of a component using this material. The component with high ribs and thin webs was studied by numerical simulation and trail production. Based on the establishment of the finite element model, the forming process was analyzed by simulation software, and the maximum forming load of the component was 1920 kN. Ultimately, there were no folding defects of the component during the forming process. The material flow law was revealed by selecting the typical section of the component, and then the forming process was verified and the fully filled component was obtained. After that, the component was subjected to post-processing, and three heat treatment methods were designed to conduct heat treatment experiments on it (heat treatment: solution treatment and aging treatment). By analyzing the influence of three heat treatment methods on mechanical properties, the optimal heat treatment method was obtained, namely a solution treatment at 960 °C for 2.5 h and aging treatment at 610 °C for 7 h. The ultimate tensile strength, yield strength, elongation, and section shrinkage of the component through forging forming and heat treatment are higher than those of original material; meanwhile, it also indicates that the designed heat treatment has a better effect on the high-temperature mechanical properties of this titanium alloy at 650 °C than that at 450 °C. The research on the combination of the forming and heat treatment of this component provides a reference for the engineering application of high-temperature titanium alloys.

Synthesis and evaluation of potent (iso)ellipticine-based inhibitors of MYLK4 accessed via expeditious synthesis from isoquinolin-5-ol.

The K2S2O8-mediated generation of p-iminoquinone contributed to the regioselective substitution of isoquinolin-5,8-dione. This hydroxyl group-guided substitution was also applied to selected heterocycles and addressed the regioselectivity issue of quinones. This study has provided an expeditious pathway from isoquinolin-5-ol (5) to ellipticine (1) and isoellipticine (2), which benefits the comprehensive comparison of their activity. Compounds 1 and 2 displayed marked MYLK4 inhibitory activity with IC50 values of 7.1 and 6.1 nM, respectively. In the cellular activity of AML cells (MV-4-11 and MOLM-13), compound 1 showed better AML activity than compound 2.

Metagenomic analysis of individual mosquitos reveals the ecology of insect viruses.

Mosquito transmitted viruses are responsible for an increasing burden of human disease. Despite this, little is known about the diversity and ecology of viruses within individual mosquito hosts. Using a meta-transcriptomic approach, we analysed the virome of 2,438 individual mosquitos (79 species), spanning ~4000 km along latitudes and longitudes in China. From these data we identified 393 core viral species associated with mosquitos, including seven (putative) arbovirus species. We identified potential species and geographic hotspots of viral richness and arbovirus occurrence, and demonstrated that host phylogeny had a strong impact on the composition of individual mosquito viromes. Our data revealed a large number of viruses shared among mosquito species or genera, expanding our knowledge of host specificity of insect-associated viruses. We also detected multiple virus species that were widespread throughout the country, possibly facilitated by long-distance mosquito migrations. Together, our results greatly expand the known mosquito virome, linked the viral diversity at the scale of individual insects to that at a country-wide scale, and offered unique insights into the ecology of viruses of insect vectors.

Signaling pathways in the regulation of cancer stem cells and associated targeted therapy.

Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.

Bispectrum-based Cross-frequency Functional Connectivity: Classification of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease known to affect brain functional connectivity (FC). Linear FC measures have been applied to study the differences in AD by splitting neurophysiological signals such as electroencephalography (EEG) recordings into discrete frequency bands and analysing them in isolation. We address this limitation by quantifying cross-frequency FC in addition to the traditional within-band approach. Cross-bispectrum, a higher-order spectral analysis, is used to measure the nonlinear FC and is compared with the cross-spectrum, which only measures the linear FC within bands. Each frequency coupling is then used to construct an FC network, which is in turn vectorised and used to train a classifier. We show that fusing features from networks improves classification accuracy. Although both within-frequency and cross-frequency networks can be used to predict AD with high accuracy, our results show that bispectrum-based FC outperforms cross-spectrum suggesting an important role of cross-frequency FC. Clinical relevance-This establishes diagnostic relevance of cross-frequency coupling in Alzheimer's disease.