Human noroviruses (HuNVs) are the leading cause of gastroenteritis worldwide. NS1.2 is critical for HuNV pathogenesis, but the function is still unclear. The GII NS1.2 of HuNVs, unlike GI NS1.2, was ...localized to the endoplasmic reticulum (ER) and lipid droplets (LDs) and is accompanied by a distorted-filamentous ER morphology and aggregated-enlarged LDs. LC3 was recruited to the NS1.2-localized membrane through an autophagy-independent pathway. NS1.2, expressed from a cDNA clone of GII.4 norovirus, formed complexes with NTPase and NS4, which exhibited aggregated vesicle-like structures that were also colocalized with LC3 and LDs. NS1.2 is structurally divided into three domains from the N terminus: an inherently disordered region (IDR), a region that contains a putative hydrolase with the H-box/NC catalytic center (H-box/NC), and a C-terminal 251-330 a.a. region containing membrane-targeting domain. All three functional domains of NS1.2 were required for the induction of the filamentous ER. The IDR was essential for LC3 recruitment by NS1.2. Both the H-Box/NC and membrane-targeting domains are required for the induction of aggregated-enlarged LDs, NS1.2 self-assembly, and interaction with NTPase. The membrane-targeting domain was sufficient to interact with NS4. The study characterized the NS1.2 domain required for membrane targeting and protein-protein interactions, which are crucial for forming a viral replication complex.
Certain bacteria demonstrate the ability to target and colonize the tumor microenvironment, a characteristic that positions them as innovative carriers for delivering various therapeutic agents in ...cancer therapy. Nevertheless, our understanding of how bacteria adapt their physiological condition to the tumor microenvironment remains elusive. In this work, we employed liquid chromatography-tandem mass spectrometry to examine the proteome of
colonized in murine tumors. Compared to
cultivated in the rich medium, we found that
colonized in tumors notably upregulated the processes related to ferric ions, including the enterobactin biosynthesis and iron homeostasis. This finding indicated that the tumor is an iron-deficient environment to
. We also found that the colonization of
in the tumor led to an increased expression of lipocalin 2 (LCN2), a host protein that can sequester the enterobactin. We therefore engineered
in order to evade the nutritional immunity provided by LCN2. By introducing the IroA cluster, the
synthesizes the glycosylated enterobactin, which creates steric hindrance to avoid the LCN2 sequestration. The IroA-
showed enhanced resistance to LCN2 and significantly improved the anti-tumor activity in mice. Moreover, the mice cured by the IroA-
treatment became resistant to the tumor re-challenge, indicating the establishment of immunological memory. Overall, our study underscores the crucial role of bacteria's ability to acquire ferric ions within the tumor microenvironment for effective cancer therapy.
Functional engineering of musculoskeletal tissues generally involves the use of differentiated or progenitor cells seeded with specific growth factors in biomaterial scaffolds. Ideally, the scaffold ...should be a functional and structural biomimetic of the native extracellular matrix and support multiple tissue morphogenesis. We have previously shown that electrospun, three-dimensional nanofibrous scaffolds that morphologically resemble collagen fibrils are capable of promoting favorable biological responses from seeded cells, indicative of their potential application for tissue engineering. In this study, we tested a three-dimensional nanofibrous scaffold fabricated from poly(
ε
-caprolactone) (PCL) for its ability to support and maintain multilineage differentiation of bone marrow-derived human mesenchymal stem cells (hMSCs) in
vitro. hMSCs were seeded onto pre-fabricated nanofibrous scaffolds, and were induced to differentiate along adipogenic, chondrogenic, or osteogenic lineages by culturing in specific differentiation media. Histological and scanning electron microscopy observations, gene expression analysis, and immunohistochemical detection of lineage-specific marker molecules confirmed the formation of three-dimensional constructs containing cells differentiated into the specified cell types. These results suggest that the PCL-based nanofibrous scaffold is a promising candidate scaffold for cell-based, multiphasic tissue engineering.
ObjectivesStudies concerning the association between shift work and drinking problems showed inconsistent results. We used data from a large occupational cohort to examine the association between ...shift work and different types of drinking behaviour.MethodsA total of 93 121 non-abstinent workers from the Finnish Public Sector Study were enrolled in the study. Six waves of survey data were collected between 2000 and 2017. Work schedules were categorised as regular day, non-night shift and night shift work, and shift intensities were calculated from registered working hour data. Two indicators of adverse drinking behaviour were measured: at-risk drinking (>7 and >14 drinks per week in women and men, respectively) and high-intensity drinking (measured as pass-out experience). Intraindividual analysis was conducted using fixed-effects regression to examine the association between shift work and drinking behaviours.ResultsCompared with regular day work, night shift work was associated with an increased risk of high-intensity drinking (OR 1.28, 95% CI 1.07 to 1.52) but a lower risk of at-risk drinking (OR 0.85, 95% CI 0.74 to 0.99). Shift workers who worked long shifts had a lower risk of at-risk drinking compared with those who rarely worked long shifts (OR 0.58, 95% CI 0.37 to 0.93).ConclusionsAssociations between shift work and alcohol use vary according to drinking patterns. Workers engaged in high-intensity drinking more often during night shift schedules compared with day work, but did not drink averagely higher volume.
Exosomal microRNAs (miRNAs) from cancer cells play a key role in mediating the oral squamous cell carcinoma (OSCC) microenvironment. The objective of this study was to investigate how the long ...non-coding RNA (lncRNA) MEG3 affects OSCC angiogenesis through exosomal miR-421. Global miRNA microarray analysis and quantitative real-time PCR (qRT-PCR) were performed to determine the level of miRNAs in OSCC cell-derived exosomes. Cell migration, invasion, tube formation, immunohistochemistry, and hemoglobin concentrations were used to study the effects of exosomal miR-421 in angiogenesis. Western blotting was used to determine the expression level of HS2ST1 and VEGFR2-related downstream proteins. MiRNA array and qRT-PCR identified the upregulation of miR-421 in OSCC cell-derived exosomes. Furthermore, exosomal miR-421 can be taken up by human umbilical vein endothelial cells (HUVECs) and then target HS2ST1 through VEGF-mediated ERK and AKT phosphorylation, thereby promoting HUVEC migration, invasion, and tube formation. Additionally, forced expression of the lncRNA MEG3 in OSCC cells reduced exosomal miR-421 levels and then increased HS2ST1 expression, thereby reducing the VEGF/VEGFR2 pathway in HUVECs. Our results demonstrate a novel mechanism by which lncRNA MEG3 can act as a tumor suppressor and regulate endothelial angiogenesis through the exosomal miR-421/HS2ST1 axis, which provides a potential therapeutic strategy for OSCC angiogenesis.
Zero-valent iron nanoparticles (ZVI NPs) have been used extensively for the remediation of contaminated soil and groundwater. Owing to their large active surface area, they serve as strong and ...effective reductants. However, the ecotoxicity and bioavailability of ZVI NPs in diverse ecological media have not been evaluated in detail and most studies have focused on non-nano ZVI or Fe
. In addition, the antimicrobial properties of ZVI NPs have rarely been investigated, and the underlying mechanism of their toxicity remains unknown.
In the present study, we demonstrate that ZVI NPs exhibited significant toxicity at 1000 ppm against two distinct gram-positive bacterial strains (Bacillus subtilis 3610 and Bacillus thuringiensis 407) but not against two gram-negative strains (Escherichia coli K12 and ATCC11634). Specifically, ZVI NPs caused at least a 4-log and 1-log reductions in cell numbers, respectively, in the two Bacillus strains, whereas no change was detected in the two E. coli strains. X-ray photoelectron spectroscopy, X-ray absorption near-edge, and extended X-ray absorption fine structure spectra confirmed that Bacillus cells exposed to ZVI NPs contained mostly Fe
O
with some detectable FeS. This finding indicated that Fe
nanoparticles penetrated the bacterial cells, where they were subsequently oxidized to Fe
O
and FeS. RedoxSensor analysis and propidium iodide (PI) staining showed decreased reductase activity and increased PI in both Bacillus strains treated with a high (1000 ppm) concentration of ZVI NPs.
Taken together, these data show that the toxicity of ZVI NPs was derived from their oxidative properties, which may increase the levels of reactive oxygen species and lead to cell death.
Background
Pancreatic cancer is often diagnosed at a late stage with a poor prognosis due to insidious symptoms and lack of evidence‐based screening in general population. Palliative care's ...acceptance in Asian cultures is hindered by misconceptions and ineffective communication about management that improve quality of life other than cancer directed treatment. Our study aimed to determine the effect of the Shared decision‐making with Oncologists and Palliative care specialists (SOP) model developed from the traditional shared decision‐making (SDM) model on the palliative care acceptance rate and medical resource utilization.
Methods
This is a prospective cohort study implementing the SOP model at the National Taiwan University Hospital from January 2018 to December 2019 for patients with advanced pancreatic cancer. Medical resource utilization was defined and recorded as the rate of hospitalization, emergency room (ER), and intensive care unit admissions. We compared the results between two groups: patients who received the SOP model in 2019 and patients who did not receive it in 2018.
Results
137 patients with advanced pancreatic cancer were included in our study. The result showed that the acceptance rate of palliative care significantly increased from 50% to 78.69% after the SOP model (p = 0.01). The hospitalization rate did not show a significant difference between 2018 (93.42%, 95% CI: 0.88–0.99) and 2019 (93.44%, 95% CI: 0.87–1.00). 83.61% (95% CI: 0.74–0.93) of our patients in 2019 had at least one ER visit; the rate was 81.5% (95% CI: 0.73–0.91) in 2018 (p = 0.28). The percentage of patients admitted to the ICU increased from 3.95% in 2018 to 8.2% (95% CI: −0.05–0.08) in 2019 (95% CI: 0.11–0.15) (p = 0.00). The hospitalization and ER visit showed no statistically difference between 2 years.
Conclusions
The modified SOP model markedly augmented palliative care's acceptance of patients with advanced pancreatic cancer. Adoption of the SOP model would provide these patients a more proactive and systematic approach to deliver needed healthcare.
Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, and it is mainly treated through lifestyle modifications. The very low-carbohydrate diet (VLCD) can help lose weight ...rapidly but the possible effects of extreme dietary patterns on lipid metabolism and inflammatory responses in individuals with NAFLD remain debatable. Moreover, VLCD protein content may affect its effectiveness in weight loss, steatosis, and inflammatory responses. Therefore, we investigated the effects of VLCDs with different protein contents in NAFLD rats and the mechanisms underlying these effects. After a 16-week inducing period, the rats received an isocaloric normal diet (NC group) or a VLCD with high or low protein content (NVLH vs. NVLL group, energy ratio:protein/carbohydrate/lipid=20/1/79 vs. 6/1/93) for the next 8 weeks experimental period. We noted that the body weight decreased in both the NVLH and NVLL groups; nevertheless, the NVLH group demonstrated improvements in ketosis. The NVLL group led to hepatic lipid accumulation, possibly by increasing very-low-density lipoprotein receptor (VLDLR) expression and elevating liver oxidative stress, subsequently activating the expression of Nrf2, and inflammation through the TLR4/TRIF/NLRP3 and TLR4/MyD88/NF-κB pathway. The NVLH was noted to prevent the changes in VLDLR and the TLR4-inflammasome pathway partially. The VLCD also reduced the diversity of gut microbiota and changed their composition. In conclusion, although low-protein VLCD consumption reduces BW, it may also lead to metabolic disorders and changes in microbiota composition; nevertheless, a VLCD with high protein content may partially alleviate these limitations.
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Pancreatic ductal adenocarcinoma (PDAC) is a malignant cancer and chemotherapy ineffectively treats PDAC, leading to the requirement for alternative tumor-targeted treatment. Human amniotic fluid ...mesenchymal stem cells (hAFMSCs) have been revealed to suppress tumor growth in various cancers and they are a strong candidate for treating PDAC.
To evaluate the effects of hAFMSCs on human pancreatic carcinoma cells (PANC1, AsPC1 and BxPC3 cell lines) and the possible mechanism involved, an in vitro cell coculture system was used. A PANC1 orthotopic xenograft mouse model was established and hAFMSCs were injected intravenously at 4 weeks post-xenograft.
An in vitro coculture assay showed that hAFMSCs inhibited PANC1 cell proliferation by inducing S phase cell cycle arrest and increased cell apoptosis in a time-dependent manner. In PANC1 cells, hAFMSCs caused the downregulation of Cyclin A and Cyclin B1 as well as the upregulation of p21 (CDKN1A) at 24 h post coculture. The upregulation of pro-apoptotic factors Caspase-3/-8 and Bax at 24 h post coculture reduced the migration and invasion ability of PANC1 cells through inhibiting the epithelial-mesenchymal transition (EMT) process. In a PANC1 orthotopic xenograft mouse model, a single injection of hAFMSCs showed significant tumor growth inhibition with evidence of the modulation of cell cycle and pro-apoptotic regulatory genes and various genes involved in matrix metallopeptidase 7 (MMP7) signaling-triggered EMT process. Histopathological staining showed lower Ki67 levels in tumors from hAFMSCs-treated mice.
Our data demonstrated that hAFMSCs strongly inhibit PDAC cell proliferation, tumor growth and invasion, possibly by altering cell cycle arrest and MMP7 signaling-triggered EMT.
Amphiphilic comb-like random copolymers synthesized from poly(ethylene glycol) methyl ether methacrylate (PEGMMA) and stearyl methacrylate (SMA) with PEGMMA contents ranging between 30 wt% and 25 wt% ...were demonstrated to self-assemble into various well-defined nanostructures, including spherical micelles, wormlike micelles, and vesicle-like nanodomains, in anhydride-cured epoxy thermosets. In addition, the polymer blends of the comb-like random copolymer and poly(stearyl methacrylate) were prepared and incorporated into epoxy thermosets to form irregularly shaped nanodomains. Our research findings indicate that both the comb-like random copolymers and polymer blends are suitable as toughening modifiers for epoxy. When added at a concentration of 5 wt%, both types of modifiers lead to substantial improvements in the tensile toughness (>289%) and fracture toughness of epoxy thermosets, with minor reductions in their elastic modulus (<16%) and glass transition temperature (<6.1 °C). The fracture toughness evaluated in terms of the critical stress intensity factor (
K
IC
) and the strain energy release rate (
G
IC
) increased by more than 67% and 131% for the modified epoxy thermosets containing comb-like random copolymers.
Amphiphilic comb-like random copolymers bearing epoxy-philic PEGMMA and epoxy-phobic alkyl pendants can self-assemble into well-defined nanostructures in anhydride-cured epoxy thermosets.
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