Circulation of COVID-19-Related Medicines on Japanese Websites during the COVID-19 Pandemic and Their Quality and Authenticity.

Substandard and falsified medical products for treating COVID-19 have spread worldwide. These medicines have entered Japan through personal importation of products purchased via the Internet. In this study, we investigated the circulation of 19 COVID-19-related medicines on the Internet in Japan and evaluated the pharmaceutical quality and authenticity of 2 medicines (dexamethasone tablets and ivermectin tablets) obtained online. We purchased 23 samples of 0.5-mg dexamethasone tablets and 13 samples of 3-mg ivermectin tablets from the Internet in December 2020 and July 2022. We investigated the quality and authenticity of the obtained samples through visual observation and tested their authenticity. We conducted pharmacopoeia compliance testing (quantitative assay, content uniformity tests, and dissolution tests) using the high-performance liquid chromatography-photodiode array detector method. No prescription was ever required at the time of purchase. Visual observation revealed that most samples lacked a package insert and some samples had packaging deficiencies. In terms of authenticity, eight ivermectin samples were genuine; the authenticity of the other samples remained uncertain. Four dexamethasone samples and three ivermectin samples failed quality testing based on pharmacopeia validation standards. Our findings illustrate that dexamethasone and ivermectin tablets of poor quality are available online. It is important to increase consumer awareness and provide information about these medicines to prevent the purchase of substandard medicines via the Internet.

Microbes and metabolites in immunity.

The immune system has a vital, albeit complex, relationship with the microbes residing within us, one that we are only beginning to understand. We asked investigators what they felt were the fundamental challenges we currently face in unraveling the impacts of microbes and their metabolites on host immunity and to discuss key opportunities toward achieving future insights and innovation.

Taurolithocholic acid protects against viral haemorrhagic fever via inhibition of ferroptosis.

Bile acids are microbial metabolites that can impact infection of enteric and hepatitis viruses, but their functions during systemic viral infection remain unclear. Here we show that elevated levels of the secondary bile acid taurolithocholic acid (TLCA) are associated with reduced fatality rates and suppressed viraemia in patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne haemorrhagic fever virus. TLCA inhibits viral replication and mitigates host inflammation during SFTSV infection in vitro, and indirectly suppresses SFTSV-mediated induction of ferroptosis by upregulating fatty acid desaturase 2 via the TGR5-PI3K/AKT-SREBP2 axis. High iron and ferritin serum levels during early infection were correlated with decreased TLCA levels and fatal outcomes in SFTSV-infected patients, indicating potential biomarkers. Furthermore, treatment with either ferroptosis inhibitors or TLCA protected mice from lethal SFTSV infection. Our findings highlight the therapeutic potential of bile acids to treat haemorrhagic fever viral infection.

Unveiling the synergetic benefits of the tunneling technique using stapler tractor in precise resection of lung segments: a retrospective cohort study.

Background: Tunneling technique has shown preliminary promise in lung segmentectomy which requires the use of staplers in specific procedures. However, the obstacle when staples pass is the most obvious factor hindering the implementation and development of this technique. This study investigated whether the obstacle of the technology could be addressed by using an innovative self-designed stapler tractor and analyzed the combined and respective advantages of them. Methods: The clinical data of patients with lung nodules located near anatomical sites with potential tunnel creation treated by segmentectomy were analyzed in this retrospective case-control study. The data were divided into four groups according to four distinct surgical strategies: In Group A, the tunneling technique was performed with a stapler tractor; in Group B, the tunneling technique was performed without a stapler tractor; in Group C, didn't perform the tunneling technique but using stapler tractor in a normal approach; and in Group D, neither performed the technique nor used the stapler tractor. The general linear data, operation times, intraoperative adverse events, postoperative recovery and complications were compared. Results: Compared with other groups, Group A exhibited the best surgical outcomes in comprehensive aspects. Separately, the tunnel groups (Group A&B) had better outcomes in the macro implementation of operation, including resection margin, the number of sampled intrapulmonary lymph nodes and resected subsegments, while the staple tractor groups (Group A&C) performed better on details of the procedure, including operation time, conversion to thoracotomy, and intraoperative bleeding (p < 0.05). Both of them were beneficial for shorter hospital stay, and the tunnel group was more advantageous. Conclusion: The tunneling technique is an advanced and beneficial surgical strategy for performing precise resection of lung segments while a stapler tractor can promote and facilitate it as a supplementary instrument. They show more combined benefits in effectively minimizing the occurrence of erroneous injuries and enhancing the operational efficacy.

Secondhand smoke exposure and asthma status among adolescents: Findings from the 2019-2020 California Student Tobacco Survey.

Background and objectives: Secondhand tobacco smoke is associated with worsening asthma symptoms among children. However, the relationship between secondhand marijuana smoke and asthma symptoms among youth has not been examined. This study compares the prevalence of secondhand tobacco and marijuana smoke exposure, overall and by asthma status, among middle and high school students. Methods: The study assessed participants of the 2019-2020 California Student Tobacco Survey: a large, cross-sectional random sample of 8th, 10th, and 12th graders (N = 158,937). Descriptive analyses examined exposure to combustible tobacco and marijuana secondhand smoke by students' asthma status and sociodemographic characteristics. Results: More students with asthma were exposed to combustible tobacco secondhand smoke (13.4 %) and marijuana secondhand smoke (12.0 %) than students without asthma (10.9 % and 9.3 %, respectively). The prevalence of secondhand marijuana smoke exposure was higher among 12th grade students (12.2 %) while the prevalence of secondhand tobacco smoke exposure was higher among 8th grade students (13.4 %) and those who lived in rural locations (15.4 %). Conclusions: California students are exposed to marijuana secondhand smoke at similar proportions to combustible tobacco secondhand smoke and more students with asthma are exposed to marijuana secondhand smoke. These results expand the public health issue of secondhand smoke exposure among children with asthma by highlighting the need to examine marijuana secondhand smoke. Given the rapid shift in marijuana laws across the US, exposure to secondhand marijuana smoke is likely to increase. Therefore, vulnerable populations, such as children with asthma, should be prioritized for interventions that aim to alleviate secondhand marijuana exposure.

Engineering the nanozyme hydrogel beads by polyvinyl alcohol/chitosan encapsulation with recyclable and sustainable catalytic activity for visual analysis of hydrogen peroxide.

BACKGROUND: Hydrogen peroxide (H2O2) plays a vital role in human health and have been regarded as a crucial analyte in metabolic processes, redox transformations, foods research and medical fields. Especially, the long-time and excessive digestion of H2O2 may even cause severe diseases. Although conventional instrumental methods and nanozymes-based colorimetric methods have been developed to accomplish the quantitative analysis of H2O2, the drawbacks of instrument dependence, cost-effectiveness, short lifespan, non-portable and unsustainable detection efficacies will limit their applications in different detection scenarios. RESULTS: Herein, to address these challenges, we have proposed a novel strategy for nanozyme (RuO2) hydrogel preparation by the solid support from cross-linked polyvinyl alcohol (PVA) and chitosan (CS) to both inherit the dominant peroxidase-like (POD) activity and protect the RuO2 from losing efficacies. Taking advantages from the hydrogel, the encapsulated RuO2 were further prepared as the regularly spherical beads (PCRO) to exhibit the sustainable, recyclable, and robust catalysis. Moreover, the intrinsic color interferences which originated from RuO2 can be avoided by the encapsulation strategy to promote the detection accuracy. Meanwhile, the high mechanical strength of PCRO shows the high stability, reproducibility, and cyclic catalysis to achieve the recyclable detection performance and long lifetime storage (40 days), which enables the sensitively detection of H2O2 with the detection limit as lower to 15 µM and the wide detection linear range from 0.025 to 1.0 mM. SIGNIFICANCE: On the basis of the unique properties, PCRO has been further adopted to construct a smartphone detection platform to realize the instrument-free and visual analysis of H2O2 in multi-types of milk and real water samples through capturing, processing, and analyzing the RGB values from the colorimetric photographs. Therefore, PCRO with the advanced detection efficacies holds the great potential in achieving the portable and on-site analysis of targets-of-interest.

cGAS-activated endothelial cell-T cell cross-talk initiates tertiary lymphoid structure formation.

Aberrant activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway causes autoimmunity in humans and mice; however, the exact mechanism by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology is still not fully understood. Here, we used a cGAS knockin (KI) mouse model that develops systemic autoimmunity. In the lungs of cGAS-KI mice, blood vessels were enclosed by organized lymphoid tissues that resemble tertiary lymphoid structures (TLSs). Cell-intrinsic cGAS induction promoted up-regulation of CCR5 in CD8+ T cells and led to CCL5 production in vascular endothelial cells. Peripheral CD8+ T cells were recruited to the lungs and produced CXCL13 and interferon-γ. The latter triggered endothelial cell death, potentiated CCL5 production, and was essential for TLS establishment. Blocking CCL5 or CCR5, or depleting CD8+ T cells, impaired TLS formation. cGAS-mediated TLS formation also enhanced humoral and antitumor responses. These data demonstrate that cGAS signaling drives a specialized lymphoid structure that underlies autoimmune tissue pathology.

Liquid Biopsy Instrument for Ultra-Fast and Label-Free Detection of Circulating Tumor Cells.

Rapid diagnosis and real-time monitoring are of great important in the fight against cancer. However, most available diagnostic technologies are time-consuming and labor-intensive and are commonly invasive. Here, we describe CytoExam, an automatic liquid biopsy instrument designed based on inertial microfluidics and impedance cytometry, which uses a deep learning algorithm for the analysis of circulating tumor cells (CTCs). In silico and in vitro experiments demonstrated that CytoExam could achieve label-free detection of CTCs in the peripheral blood of cancer patients within 15 min. The clinical applicability of CytoExam was also verified using peripheral blood samples from 10 healthy donors and >50 patients with breast, colorectal, or lung cancer. Significant differences in the number of collected cells and predicted CTCs were observed between the 2 groups, with variations in the dielectric properties of the collected cells from cancer patients also being observed. The ultra-fast and minimally invasive features of CytoExam may pave the way for new paths for cancer diagnosis and scientific research.

Discovery of sesquiterpene lactones with anti-inflammatory effect from Youngia japonica.

The preliminary study revealed that the ethyl acetate eluate of Youngia japonica (YJ-E) could inhibit the expression of key proteins of p-p65, p-IκBα, p-IKKα/ß, and p-AKT in LPS stimulated BV2 cell. Further phytochemical study led to the isolation of eight compounds from YJ-E, including one new sesquiterpene lactone. Their structures were elucidated by several spectroscopic data, and comparing the NMR data of known compound. In addition, all of the isolates were evaluated for the anti-inflammatory effect. As a result, compounds 3 and 4 distinctly attenuated the expressions of p-IκBα, p-p65, and p-AKT in LPS stimulated BV2 cell, respectively.

Astrocytes modulate brain phosphate homeostasis via polarized distribution of phosphate uptake transporter PiT2 and exporter XPR1.

Aberrant inorganic phosphate (Pi) homeostasis causes brain calcification and aggravates neurodegeneration, but the underlying mechanism remains unclear. Here, we found that primary familial brain calcification (PFBC)-associated Pi transporter genes Pit2 and Xpr1 were highly expressed in astrocytes, with importer PiT2 distributed over the entire astrocyte processes and exporter XPR1 localized to astrocyte end-feet on blood vessels. This polarized PiT2 and XPR1 distribution endowed astrocyte with Pi transport capacity competent for brain Pi homeostasis, which was disrupted in mice with astrocyte-specific knockout (KO) of either Pit2 or Xpr1. Moreover, we found that Pi uptake by PiT2, and its facilitation by PFBC-associated galactosidase MYORG, were required for the high Pi transport capacity of astrocytes. Finally, brain calcification was suppressed by astrocyte-specific PiT2 re-expression in Pit2-KO mice. Thus, astrocyte-mediated Pi transport is pivotal for brain Pi homeostasis, and elevating astrocytic Pi transporter function represents a potential therapeutic strategy for reducing brain calcification.

Electrically Driven Deterministic Plasmon Light Sources Based on Arrays of Molecular Tunnel Junctions.

Surface plasmons excited via inelastic tunnelling have led to plasmon light sources with small footprints and ultrafast response speeds, which are favored by integrated optical circuits. Self-assembled monolayers of organic molecules function as highly tunable tunnel barriers with novel functions. However, limited by the low effective contact between the liquid metal electrode and the self-assembled monolayers, it is quite challenging to obtain molecular plasmon light sources with high density and uniform emission. Here, by combining lithographic patterning with a solvent treatment method, we have demonstrated electrically driven deterministic plasmon emission from arrays of molecular tunnel junctions. The solvent treatment could largely improve the effective contact from 9.6% to 48% and simultaneously allow the liquid metal to fill into lithographically patterned micropore structures toward deterministic plasmon emission with desired patterns. Our findings open up new possibilities for tunnel junction-based plasmon light sources, laying the foundation for electrically driven light-emitting metasurfaces.

Source identification and migration fate of heavy metals of soil-groundwater system in a thousand-year cultivation region.

Pollution of farmland by heavy metals threatens food security and human health. In addition, heavy metals in soil could infiltrate into groundwater to influence the water quality and safety of drinking water. However, the relationship between heavy metal pollution in soil and groundwater is still not clear. In this study, we investigated the soil and groundwater in the Guanzhong Plain region, which is a significant grain production base in China, and determined the spatial distributions, ecological risk, sources, and migration fates of heavy metals (As, Cd, Cr, Cu, Ni, Pb, and Zn). The results showed that the mean values (0-20 cm) in the soil were 19.57 mg kg-1 for As, 0.71 mg kg-1 for Cd, 69.65 mg kg-1 for Cr, 21.97 mg kg-1 for Cu, 28.67 mg kg-1 for Ni, 17.54 mg kg-1 for Pb, and 73.77 mg kg-1 for Zn, and the corresponding mean values in groundwater were 1.2, 0.04, 4.69, 0.15, 0.07, 0.3, and 3.6 µg L-1, respectively. The mean values for As, Cd, Cr, Pb, and Zn in soil exceeded the background values, and the mean values for As, Cd and Pb exceeded those in groundwater. Positive matrix factorization models identified five sources (fertilizers and organic fertilizers, natural sources, pesticides and herbicides, industrial activities, and sedimentation caused by transportation) for heavy metal pollution in soil and four sources (industry activity, atmospheric sedimentation caused by transportation, natural sources, and agriculture) for heavy metal pollution in groundwater. The soil particle composition and soil organic carbon content were important factors that affected the vertical distribution of heavy metals in the soil. The migration modes (convection and diffusion) were not found for all heavy metals. These results help to understand the relationships between heavy metals in soil and groundwater in farmland ecosystems regionally.

Physiological occlusal force attenuates replacement root resorption of replanted teeth: an experimental animal study.

BACKGROUND: Tooth avulsion represents the most severe form of dental trauma, necessitating tooth replantation as the primary treatment. However, the risk of replacement root resorption (RRR) poses a significant threat to tooth retention following replantation. This study preliminarily aimed to investigate the effect of physiological occlusal force on RRR after the replantation of avulsed teeth and to explore the potential underlying mechanisms. METHODS: Thirty-six 4-week-old male Sprague-Dawley rats underwent extraction and immediate replantation of their left maxillary molars. The rats were randomly divided into two major groups: the occluded (n = 18) group, where the opposite mandibular teeth were preserved; non-occluded (n = 18) group, where the opposite mandibular teeth were extracted. Within each major group, there were three subgroups corresponding to 7 days, 14 days, and 2 months, resulting in a total of six subgroups, (n = 6 per subgroup). The right maxillary first molars served as the normal control. Various periodontal characteristics were assessed using haematoxylin-eosin (H&E), tartrate-resistant acid phosphatase (TRAP) staining, and micro-computed tomography (micro-CT). RESULTS: Histological staining revealed that under occlusal force, the early stage (day 7) after tooth replantation mainly manifested as root surface resorption, especially in the non-occluded group, which gradually diminished over time. Cementum and periodontal ligament (PDL) repair was observed on day 14. Micro-CT analysis indicated a significant decrease in PDL width in the non-occluded group two months after replantation, consistent with the histological findings, signifying severe RRR in the non-occluded group. CONCLUSIONS: This study provides preliminary evidence that physiological occlusal force may attenuate osteoclastogenesis during the early stage of tooth replantation, thereby reducing the occurrence of RRR and promoting periodontal healing.

Discovery of Sesquiterpene Lactones with Cytotoxicity from the Herb of Youngia japonica.

In the process of searching for anti-breast cancer agents, five sesquiterpene lactones (1-5), including two previously undescribed ones, yjaponica B-C (1-2), were isolated from the herb of Youngia japonica. Their structures were elucidated by spectroscopic data analyses and Marfey's method. Cytotoxic activities of all compounds against A549, U87, and 4T1 cell lines were tested using the CCK8 assay. The result showed that compound 3 possessed the highest cytotoxic activity against 4T1 cells with an IC50 value of 10.60 µM. Furthermore, compound 3 distinctly induced apoptosis, inhibited immigration, and blocked the cell cycle of 4T1 cells. In addition, compound 3 induced the production of reactive oxygen species. Further anticancer mechanism studies showed that compound 3 significantly upregulated expression of the cleaved caspase 3 and PARP, whereas it downregulated the expression of Bcl-2, cyclin D1, cyclin A2, CDK4, and CDK2. Taken together, our results demonstrate that compound 3 has a high potential of being used as a leading compound for the discovery of new anti-breast cancer agent.

Polyethyleneimine-mediated assembly of DNA nanotubes for KRAS siRNA delivery in lung adenocarcinoma therapy.

Self-assembled DNA nanostructures hold great promise in biosensing, drug delivery and nanomedicine. Nevertheless, challenges like instability and inefficiency in cellular uptake of DNA nanostructures under physiological conditions limit their practical use. To tackle these obstacles, this study proposes a novel approach that integrates the cationic polymer polyethyleneimine (PEI) with DNA self-assembly. The hypothesis is that the positively charged linear PEI can facilitate the self-assembly of DNA nanostructures, safeguard them against harsh conditions and impart them with the cellular penetration characteristic of PEI. As a demonstration, a DNA nanotube (PNT) was successfully synthesized through PEI mediation, and it exhibited significantly enhanced stability and cellular uptake efficiency compared to conventional Mg2+-assembled DNA nanotubes. The internalization mechanism was further found to be both clathrin-mediated and caveolin-mediated endocytosis, influenced by both PEI and DNA. To showcase the applicability of this hybrid nanostructure for biomedical settings, the KRAS siRNA-loaded PNT was efficiently delivered into lung adenocarcinoma cells, leading to excellent anticancer effects in vitro. These findings suggest that the PEI-mediated DNA assembly could become a valuable tool for future biomedical applications.

Multiparameter Mechanical Phenotyping for Accurate Cell Identification Using High-Throughput Microfluidic Deformability Cytometry.

Mechanical phenotyping has been widely employed for single-cell analysis over recent years. However, most previous works on characterizing the cellular mechanical properties measured only a single parameter from one image. In this paper, the quasi-real-time multiparameter analysis of cell mechanical properties was realized using high-throughput adjustable deformability cytometry. We first extracted 12 deformability parameters from the cell contours. Then, the machine learning for cell identification was performed to preliminarily verify the rationality of multiparameter mechanical phenotyping. The experiments on characterizing cells after cytoskeletal modification verified that multiple parameters extracted from the cell contours contributed to an identification accuracy of over 80%. Through continuous frame analysis of the cell deformation process, we found that temporal variation and an average level of parameters were correlated with cell type. To achieve quasi-real-time and high-precision multiplex-type cell detection, we constructed a back propagation (BP) neural network model to complete the fast identification of four cell lines. The multiparameter detection method based on time series achieved cell detection with an accuracy of over 90%. To solve the challenges of cell rarity and data lacking for clinical samples, based on the developed BP neural network model, the transfer learning method was used for the identification of three different clinical samples, and finally, a high identification accuracy of approximately 95% was achieved.

Sharp needle reconstructs peripheral outflow for patients with malfunctional arteriovenous fistula.

OBJECTIVE: To investigate the feasibility and efficacy of combining ultrasound-guided sharp needle technique with percutaneous transluminal angioplasty (PTA) for treating outflow stenosis or dysfunction in arteriovenous fistula (AVF) among hemodialysis patients. METHODS: From October 2021 to March 2023, patients with occluded or malfunctional fistula veins not amenable to regularly angioplasty were retrospectively enrolled in the study. They underwent ultrasound-guided sharp needle intervention followed by PTA. Data on the location and length between the two veins, technical success, clinical outcomes, and complications were collected. Patency rates post-angioplasty were calculated through Kaplan-Meier analysis. RESULTS: A total of 23 patients were included. The mean length of the reconstructed extraluminal segment was 3.18 cm. The sharp needle opening was performed on the basilic vein (60.9%), brachial vein (26.1%), or upper arm cephalic vein (13%) to create outflow channels. Postoperatively, all cases presented with mild subcutaneous hematomas around the tunneling site and minor diffuse bleeding. The immediate patency rate for the internal fistulas was 100%, with 3-month, 6-month, and 12-month patency rates at 91.3%, 78.3%, and 43.5%, respectively. CONCLUSION: Sharp needle technology merged with PTA presents an effective and secure minimally invasive method for reconstructing the outflow tract, offering a new solution for recanalizing high-pressure or occluded fistulas.

Enterococcus-derived tyramine hijacks α2A-adrenergic receptor in intestinal stem cells to exacerbate colitis.

Inflammatory bowel disease (IBD) is characterized by dysbiosis of the gut microbiota and dysfunction of intestinal stem cells (ISCs). However, the direct interactions between IBD microbial factors and ISCs are undescribed. Here, we identify α2A-adrenergic receptor (ADRA2A) as a highly expressed GPCR in ISCs. Through PRESTO-Tango screening, we demonstrate that tyramine, primarily produced by Enterococcus via tyrosine decarboxylase (tyrDC), serves as a microbial ligand for ADRA2A. Using an engineered tyrDC-deficient Enterococcus faecalis strain and intestinal epithelial cell-specific Adra2a knockout mice, we show that Enterococcus-derived tyramine suppresses ISC proliferation, thereby impairing epithelial regeneration and exacerbating DSS-induced colitis through ADRA2A. Importantly, blocking the axis with an ADRA2A antagonist, yohimbine, disrupts tyramine-mediated suppression on ISCs and alleviates colitis. Our findings highlight a microbial ligand-GPCR pair in ISCs, revealing a causal link between microbial regulation of ISCs and colitis exacerbation and yielding a targeted therapeutic approach to restore ISC function in colitis.

Microbial metabolite steers intestinal stem cell fate under stress.

Recently in Cell Metabolism, Wei et al.1 unveiled a brain-to-gut pathway that conveys psychological stress to intestinal epithelial cells, leading to their dysfunction. This gut-brain axis involves a microbial metabolite, indole-3-acetate (IAA), as a niche signal that hampers mitochondrial respiration to skew intestinal stem cell (ISC) fate.

Construction of Prediction Model of Foodborne Disease Outbreaks and Its Trend Prediction - Guizhou Province, China, 2023-2025.

Objective: Foodborne diseases pose a significant public health concern globally. This study aims to analyze the correlation between disease prevalence and climatic conditions, forecast the pattern of foodborne disease outbreaks, and offer insights for effective prevention and control strategies and optimizing health resource allocation policies in Guizhou Province. Methods: This study utilized the χ2 test and four comprehensive prediction models to analyze foodborne disease outbreaks recorded in the Guizhou Foodborne Disease Outbreak system between 2012 and 2022. The best-performing model was chosen to forecast the trend of foodborne disease outbreaks in Guizhou Province, 2023-2025. Results: Significant variations were observed in the incidence of foodborne disease outbreaks in Guizhou Province concerning various meteorological factors (all P≤0.05). Among all models, the SARIMA-ARIMAX combined model demonstrated the most accurate predictive performance (RMSE: Prophet model=67.645, SARIMA model=3.953, ARIMAX model=26.544, SARIMA-ARIMAX model=26.196; MAPE: Prophet model=42.357%, SARIMA model=37.740%, ARIMAX model=15.289%, SARIMA-ARIMAX model=13.961%). Conclusion: The analysis indicates that foodborne disease outbreaks in Guizhou Province demonstrate distinct seasonal patterns. It is recommended to concentrate prevention efforts during peak periods. The SARIMA-ARIMAX hybrid model enhances the precision of monthly forecasts for foodborne disease outbreaks, offering valuable insights for future prevention and control strategies.