Locoregional control is a significant prognostic factor for hepatocellular carcinoma (HCC). Historically, the use of radiotherapy (RT) for HCC was limited owing to the low radiotolerance of the liver ...and the need for high RT doses for disease control. We aimed to examine if 1α,25‐dihydroxyvitamin D3 (calcitriol) has a role in the tumor inhibition and the radiation response of HCC in vitro and in vivo, and explore the underlying mechanisms. The human and murine liver cancer cell lines were selected for cellular and animal experiments to investigate the changes in tumor characteristics and the radiation response after calcitriol supplementation. The effects induced by calcitriol supplementation on interleukin‐6 (IL‐6) signaling and the tumor immune microenvironment following RT were also examined. Our data revealed that calcitriol supplementation attenuated tumor aggressive behavior, decrease IL‐6 expression, and augmented radiation‐induced tumor inhibition. The biological changes following calcitriol treatment included suppressed epithelial‐mesenchymal transition, attenuated cancer stem cell‐like properties and increased radiation‐induced reactive oxygen species and cell death in vitro. Regarding immune microenvironment, calcitriol attenuated the recruitment of myeloid‐derived suppressor cell (MDSC) recruitment and increased the infiltration of cytotoxic T cells in tumor following RT. Furthermore, When the primary liver tumor was irradiated with larger dose per fraction, calcitriol induced a smaller size of synchronous unirradiated tumor in mice, which linked with attenuated IL‐6 signaling and MDSC recruitment. In conclusion, calcitriol treatment reduced tumor aggressiveness and enhanced the radiation response. The inhibited IL‐6 signaling and subsequently enhanced antitumor immunity might be responsible to augment radiation‐induced tumoricidal effect induced by calcitriol. Based on our results, we suggest that calcitriol could exert the antitumor and radiosensitization effects for HCC, especially for multifocal tumors.
Adverse maternal outcomes and perinatal complications are closely associated with overt maternal hypothyroidism, but whether these complications occur in women with subclinical hypothyroidism (SCH) ...during pregnancy remains controversial. The aim of this study was to evaluate the effects of SCH on maternal and perinatal outcomes during pregnancy.
A prospective study of data from 8012 pregnant women (371 women with SCH, 7641 euthyroid women) was performed. Maternal serum samples were collected in different trimesters to examine thyroid hormone concentrations. SCH was defined as a thyroid stimulating hormone concentration exceeding the trimester-specific reference value with a normal free thyroxine concentration. The occurrence of maternal outcomes, including gestational hypertension (GH), gestational diabetes mellitus, placenta previa, placental abruption, prelabor rupture of membranes (PROM), and premature delivery; and perinatal outcomes, including intrauterine growth restriction (IUGR), fetal distress, low birth weight (LBW; live birth weight ≤ 2500 g), stillbirth, and malformation, was recorded. Logistic regression with adjustment for confounding demographic and medical factors was used to determine the risks of adverse outcomes in patients with SCH.
Compared with euthyroid status, SCH was associated with higher rates of GH (1.819% vs. 3.504%, P = 0.020; χ2 = 7.345; odds ratio (OR), 2.243; 95% confidence interval (CI), 1.251-4.024), PROM (4.973% vs. 8.625%, P = 0.002; χ2 = 72.102; adjusted OR, 6.014; 95% CI, 3.975-9.099), IUGR (1.008% vs. 2.965%, <0.001; χ2 = 13.272; adjusted OR, 3.336; 95% CI, 1.745-6.377), and LBW (1.885% vs. 4.582%, P<0.001; χ2 = 13.558; adjusted OR, 2.919; 95% CI, 1.650-5.163).
The results of this study indicate that pregnant women with SCH had increased risks of GH and PROM, and their fetuses and infants had increased risks of IUGR and LBW. Thus, routine maternal thyroid function testing is necessary to improve maternal and perinatal outcomes.
Summary
Background
Liver fibrosis is the strongest histological risk factor for liver‐related complications and mortality in metabolic dysfunction‐associated fatty liver disease (MAFLD). Second ...harmonic generation/two‐photon excitation fluorescence (SHG/TPEF) is a powerful tool for label‐free two‐dimensional and three‐dimensional tissue visualisation that shows promise in liver fibrosis assessment.
Aim
To investigate combining multi‐photon microscopy (MPM) and deep learning techniques to develop and validate a new automated quantitative histological classification tool, named AutoFibroNet (Automated Liver Fibrosis Grading Network), for accurately staging liver fibrosis in MAFLD.
Methods
AutoFibroNet was developed in a training cohort that consisted of 203 Chinese adults with biopsy‐confirmed MAFLD. Three deep learning models (VGG16, ResNet34, and MobileNet V3) were used to train pre‐processed images and test data sets. Multi‐layer perceptrons were used to fuse data (deep learning features, clinical features, and manual features) to build a joint model. This model was then validated in two further independent cohorts.
Results
AutoFibroNet showed good discrimination in the training set. For F0, F1, F2 and F3‐4 fibrosis stages, the area under the receiver operating characteristic curves (AUROC) of AutoFibroNet were 1.00, 0.99, 0.98 and 0.98. The AUROCs of F0, F1, F2 and F3‐4 fibrosis stages for AutoFibroNet in the two validation cohorts were 0.99, 0.83, 0.80 and 0.90 and 1.00, 0.83, 0.80 and 0.94, respectively, showing a good discriminatory ability in different cohorts.
Conclusion
AutoFibroNet is an automated quantitative tool that accurately identifies histological stages of liver fibrosis in Chinese individuals with MAFLD.
Deep learning (DL) model and joint model (AutoFibroNet). Both deep learning models are used for automated classification and quantification of liver fibrosis stages, in which the AutoFibroNet uses multi‐layer perceptron (MLP) to integrate clinical features, manual features and DL features before classification.
The use of social media is incomparably on the rise among students, influenced by the globalized forms of communication and the post-pandemic rush to use multiple social media platforms for education ...in different fields of study. Though social media has created tremendous chances for sharing ideas and emotions, the kind of social support it provides might fail to meet students’ emotional needs, or the alleged positive effects might be short-lasting. In recent years, several studies have been conducted to explore the potential effects of social media on students’ affective traits, such as stress, anxiety, depression, and so on. The present paper reviews the findings of the exemplary published works of research to shed light on the positive and negative potential effects of the massive use of social media on students’ emotional well-being. This review can be insightful for teachers who tend to take the potential psychological effects of social media for granted. They may want to know more about the actual effects of the over-reliance on and the excessive (and actually obsessive) use of social media on students’ developing certain images of self and certain emotions which are not necessarily positive. There will be implications for pre- and in-service teacher training and professional development programs and all those involved in student affairs.
Lignin is a complex biopolymer derived primarily from the condensation of three monomeric precursors, the monolignols. The synthesis of monolignols occurs in the cytoplasm. To reach the cell wall ...where they are oxidized and polymerized, they must be transported across the cell membrane. However, the molecular mechanisms underlying the transport process are unclear. There are conflicting views about whether the transport of these precursors occurs by passive diffusion or is an energized active process; further, we know little about what chemical forms are required. Using isolated plasma and vacuolar membrane vesicles prepared from Arabidopsis, together with applying different transporter inhibitors in the assays, we examined the uptake of monolignols and their derivatives by these native membrane vesicles. We demonstrate that the transport of lignin precursors across plasmalemma and their sequestration into vacuoles are ATP-dependent primary-transport processes, involving ATP-binding cassette-like transporters. Moreover, we show that both plasma and vacuolar membrane vesicles selectively transport different forms of lignin precursors. In the presence of ATP, the inverted plasma membrane vesicles preferentially take up monolignol aglycones, whereas the vacuolar vesicles are more specific for glucoconjugates, suggesting that the different ATP-binding cassette-like transporters recognize different chemical forms in conveying them to distinct sites, and that glucosylation of monolignols is necessary for their vacuolar storage but not required for direct transport into the cell wall in Arabidopsis.
ATP-sensitive potassium (K-ATP) channels, coupling cell metabolism to cell membrane potential, are involved in brain diseases including stroke. Emerging evidence shows that astrocytes play important ...roles in the pathophysiology of cerebral ischemia. Kir6.1, a pore-forming subunit of K-ATP channel, is prominently expressed in astrocytes and participates in regulating its function. However, the exact role of astrocytic Kir6.1-containg K-ATP channel (Kir6.1/K-ATP) in ischemic stroke remains unclear. Here, we found that astrocytic Kir6.1 knockout (KO) mice exhibited larger infarct areas and more severe brain edema and neurological deficits in middle cerebral artery occlusion stroke model. Both activated gliosis and neuronal loss were aggravated in astrocytic Kir6.1 KO mice. Furthermore, the protein levels of pro-apoptotic protein Bcl-2 associated X (Bax) and active caspase-3 were up-regulated and the expression of anti-apoptotic protein Bcl-2 was down-regulated in astrocytic Kir6.1 KO mice. This is accompanied by enhanced endoplasmic reticulum stress (ER stress) responses in brain tissues and in astrocytes during ischemia/reperfusion (I/R) injury. Finally, inhibition of ER stress rescued astrocyte apoptosis induced by Kir6.1 deletion during I/R injury. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel protects brain from cerebral ischemia/reperfusion injury through inhibiting ER stress and suggest that astrocytic Kir6.1/K-ATP channel is a promising therapeutic target for ischemic stroke.
•Astrocytic Kir6.1 knockout aggravates cerebral ischemia/reperfusion injury in mice.•Astrocytic Kir6.1 deletion promotes ischemia-induced astrocyte apoptosis.•Astrocytic Kir6.1 knockout enhances endoplasmic reticulum stress in astrocytes.•Inhibition of ER stress reverses Kir6.1 knockout-induced astrocyte apoptosis.
Highlights•IL-6 significantly predicted the prognosis for HNSCC. •Increased PD-L1 and MDSCs are responsible to IL-6-induce immunosuppressive microenvironment in HNSCC. •IL-6 is positively linked with ...the PD-L1 expression in HNSCC after irradiation. •NLR was relevant to IL-6 and PD-L1 levels for HNSCC patients to make informed decisions regarding treatment options.
Background: DNA methylation is an epigenetic mechanism central to development and maintenance of complex mammalian tissues, but our understanding of its role in intestinal development is limited. ...Results: We use whole genome bisulfite sequencing, and find that differentiation of mouse colonic intestinal stem cells to intestinal epithelium is not associated with major changes in DNA methylation. However, we detect extensive dynamic epigenetic changes in intestinal stem cells and their progeny during the suckling period, suggesting postnatal epigenetic development in this stem cell population. We find that postnatal DNA methylation increases at 3' CpG islands (CGIs) correlate with transcriptional activation of glycosylation genes responsible for intestinal maturation. To directly test whether 3' CGI methylation regulates transcription, we conditionally disrupted two major DNA methyltransferases, Dnmt1 or Dnmt3a, in fetal and adult intestine. Deficiency of Dnmt1 causes severe intestinal abnormalities in neonates and disrupts crypt homeostasis in adults, whereas Dnmt3a loss was compatible with intestinal development. These studies reveal that 3' CGI methylation is functionally involved in the regulation of transcriptional activation in vivo, and that Dnmt1 is a critical regulator of postnatal epigenetic changes in intestinal stem cells. Finally, we show that postnatal 3' CGI methylation and associated gene activation in intestinal epithelial cells are significantly altered by germ-free conditions. Conclusions: Our results demonstrate that the suckling period is critical for epigenetic development of intestinal stem cells, with potential important implications for lifelong gut health, and that the gut microbiome guides and/or facilitates these postnatal epigenetic processes.
Ginger is a widespread source of herbal medicine and traditional spices. Among its various bioactive components, ginger polysaccharides (GPs) have attracted the attention of researchers worldwide ...because of their significant bioactivity. Recent studies have demonstrated the antioxidant, antitumour, anti-inflammatory, immunomodulatory, hypoglycaemic, cough suppressant and thrombotic anticoagulant effects of GPs. However, the structure-bioactivity relationship of GPs has yet to be comprehensively investigated. This review aims to explore all the current published studies on GPs. It further examines various aspects, including the extraction and purification methods, structure, bioactivity, application and structure-bioactivity relationship of GPs. Thus, this review intends to provide a reference for future GP-related research and development.
Ginger is a widespread source of herbal medicine and traditional spices.
This paper presents a new class of dual-, tri- and quad-band BPF by using proposed open stub-loaded shorted stepped-impedance resonator (OSLSSIR). The OSLSSIR consists of a two-end-shorted ...three-section stepped-impedance resistor (SIR) with two identical open stubs loaded at its impedance junctions. Two 50- Ω tapped lines are directly connected to two shorted sections of the SIR to serve as I/O ports. As the electrical lengths of two identical open stubs increase, many more transmission poles (TPs) and transmission zeros (TZs) can be shifted or excited within the interested frequency range. The TZs introduced by open stubs divide the TPs into multiple groups, which can be applied to design a multiple-band bandpass filter (BPF). In order to increase many more design freedoms for tuning filter performance, a high-impedance open stub and the narrow/broad side coupling are introduced as perturbations in all filters design, which can tune the even- and odd-mode TPs separately. In addition, two branches of I/O coupling and open stub-loaded shorted microstrip line are employed in tri- and quad-band BPF design. As examples, two dual-wideband BPFs, one tri-band BPF, and one quad-band BPF have been successfully developed. The fabricated four BPFs have merits of compact sizes, low insertion losses, and high band-to-band isolations. The measured results are in good agreement with the full-wave simulated results.
PDF
