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Background: Triple-negative breast cancer is a breast cancer subtype characterized by its challenging prognosis, and establishing prognostic models aids its clinical treatment. PANoptosis, a recently identified type of programmed cell death, influences tumor growth and patient outcomes. Nonetheless, the precise impact of PANoptosis-related genes on the prognosis of triple-negative breast cancer has yet to be determined. Methods: Clinical information for the triple-negative breast cancer samples was collected from the Gene Expression Omnibus and The Cancer Genome Atlas databases, while 19 PANoptosis-related genes were sourced from previous studies. We first categorized PANoptosis-related subtypes and determined the differentially expressed genes between them. Subsequently, we developed and validated a PANoptosis-associated predictive model using LASSO and Cox multivariate regression analyses. Statistical evaluations were conducted using R software, and the mRNA expression levels of the genes were quantified using real-time PCR. Results: Using consensus clustering analysis, we divided triple-negative breast cancer patients into two clusters based on PANoptosis-related genes and identified 1054 differentially expressed genes between these clusters. Prognostic-related genes were subsequently selected to re-cluster patients, validating their predictive ability. A prognostic model was then constructed based on four genes: BTN2A2, CACNA1H, PIGR, and S100B. The expression and enriched cell types of these genes were examined and the expression levels were validated in vitro. Furthermore, the model was validated, and a nomogram was created to enhance personalized risk assessment. The risk score, proven to be an independent prognostic indicator for triple-negative breast cancer, showed a positive correlation with both age and disease stage. Immune infiltration and drug sensitivity analyses suggested appropriate therapies for different risk groups. Mutation profiles and pathway enrichment were analyzed, providing insights into potential therapeutic targets. Conclusion: A PANoptosis-related prognostic model was successfully developed for triple-negative breast cancer, offering a novel approach for predicting patient prognosis and guiding treatment strategies.

Abstract Endoplasmic reticulum (ER) stress can trigger various cell death mechanisms beyond apoptosis, providing promise in cancer treatment. Oncosis, characterized by cellular swelling and increased membrane permeability, represents a non-apoptotic form of cell death. In our study, we discovered that Arnicolide D (AD), a natural sesquiterpene lactone compound, induces ER stress-mediated oncosis in hepatocellular carcinoma (HCC) cells, and this process is reactive oxygen species (ROS)-dependent. Furthermore, we identified the activation of the PERK-eIF2α-ATF4-CHOP pathway during ER stress as a pivotal factor in AD-induced oncosis. Notably, the protein synthesis inhibitor cycloheximide (CHX) was found to effectively reverse AD-induced oncosis, suggesting ATF4 and CHOP may hold crucial roles in the induction of oncosis by AD. These proteins play a vital part in promoting protein synthesis during ER stress, ultimately leading to cell death. Subsequent studies, in where we individually or simultaneously knocked down ATF4 and CHOP in HCC cells, provided further confirmation of their indispensable roles in AD-induced oncosis. Moreover, additional animal experiments not only substantiated AD’s ability to inhibit HCC tumor growth but also solidified the essential role of ER stress-mediated and ROS-dependent oncosis in AD’s therapeutic potential. In summary, our research findings strongly indicate that AD holds promise as a therapeutic agent for HCC by its ability to induce oncosis.

Abstract Peptide-based therapeutics have gained attention as promising therapeutic modalities, however, their prevalent drawback is poor circulation half-life in vivo. In this paper, we report the selection of albumin-binding macrocyclic peptides from genetically encoded libraries of peptides modified by perfluoroaryl-cysteine SNAr chemistry, with decafluoro-diphenylsulfone (DFS). Testing of the binding of the selected peptides to albumin identified SICRFFC as the lead sequence. We replaced DFS with isosteric pentafluorophenyl sulfide (PFS) and the PFS-SICRFFCGG exhibited K D = 4–6 µM towards human serum albumin. When injected in mice, the concentration of the PFS-SICRFFCGG in plasma was indistinguishable from the reference peptide, SA-21. More importantly, a conjugate of PFS-SICRFFCGG and peptide apelin-17 analogue (N3-PEG6-NMe17A2) showed retention in circulation similar to SA-21; in contrast, apelin-17 analogue was cleared from the circulation after 2 min. The PFS-SICRFFC is the smallest known peptide macrocycle with a significant affinity for human albumin and substantial in vivo circulation half-life. It is a productive starting point for future development of compact macrocycles with extended half-life in vivo.

Background: Out-hospital cardiac arrest (OHCA) is a major cause of mortality and morbidity worldwide. The magnitude of the post-resuscitation inflammatory response is closely related to the severity of the circulatory dysfunction. Currently, targeted temperature management (TTM) has become an essential part of the post-resuscitation care for unconscious OHCA survivors. Some novel prognostic inflammatory markers may help predict outcomes of OHCA patients after TTM. Methods: A retrospective observational cohort study of 65 OHCA patients treated with TTM was conducted in a tertiary hospital in Taiwan. The primary outcome measure was in-hospital mortality. Baseline and post-TTM neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte (PLR), and the systemic immune inflammation index (SII) were identified as potential predictors. Results: These patients had a mean age of 62.2 ± 17.0 years. Among the total sample, 53.8% had an initial shockable rhythm and 61.5% had a presumed cardiac etiology. The median resuscitation duration was 20 min (IQR 13.5–28.5) and 60% received subsequent percutaneous coronary intervention. The mean baseline NLR, PLR and SII were 7.5 ± 16.7, 118 ± 207, 1395 ± 3004, and the mean post-TTM NLR, PLR and SII were 15.0 ± 11.6, 206 ± 124, 2369 ± 2569, respectively. Using multiple logistic regression analysis, post-TTM NLR was one of the independent factors which predicted in-hospital mortality (adjusted odds ratio (aOR): 1.249, 95% confidence interval (CI): 1.040–1.501, p = 0.017). Conclusion: Post-TTM NLR is a predictor of in-hospital mortality in OHCA patients who underwent TTM.

Tumor-associated macrophages (TAMs) are pivotal in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC), influencing various stages from initiation to metastasis. Understanding the role of TAMs in HCC is crucial for developing novel therapeutic strategies. Macrophages exhibit plasticity, resulting in M1 and M2 phenotypes, with M1 macrophages displaying antitumor properties and M2 macrophages promoting tumor progression. Targeting TAMs to alter their polarization could offer new avenues for HCC treatment. β,β-dimethylacrylalkannin (DMAKN), a natural naphthoquinone, has gained attention for its antitumor properties. However, its impact on TAMs modulation remains unclear. This study investigates DMAKN’s modulation of TAMs and its anti-HCC activity. Using an in vitro model with THP-1 cells, we induced M1 macrophages with LPS/IFN-γ and M2 macrophages with IL-4/IL-13, confirming polarization with specific markers. Co-culturing these macrophages with HCC cells showed that M1 cells inhibited HCC growth, while M2 cells promoted it. Screening for non-toxic DMAKN concentrations revealed its ability to induce M1 polarization and enhance LPS/IFN-γ-induced M1 macrophages, both showing anti-HCC effects. Conversely, DMAKN suppressed IL-4/IL-13-induced M2 polarization, inhibiting M2 macrophages’ promotion of HCC cell viability. In summary, DMAKN induces and enhances M1 polarization while inhibiting M2 polarization of macrophages, thereby inhibiting HCC cell growth. These findings suggest that DMAKN has the potential to regulate TAMs in HCC, offering promise for future therapeutic development.

Objective: To evaluate the regression rate of endometrial polyps (EPs) in a cohort of asymmetric women after conservative follow-up. Materials and methods: In this retrospective cohort study, a total of 1006 women with asymptomatic EPs were treated with expectant management or hormonal drugs between June 1999 and May 2018. Four hundred forty-eight women (44.5%) were administered with hormonal medications and 558 women were managed expectantly (55.5%). Office hysteroscopy was performed to confirm the diagnosis and regression of EPs. Hormonal administration included oral contraceptives, progestin and cyclic estrogen/progestin regimen according to physicians' preferences. Clinical characteristics, including the patient's age, body mass index, parity, and type of conservative management were collected. Results: The mean observation time was 14.1 ± 18.5 months (range, 1–162 months). The overall regression rate of EPs in this cohort was 33.5%, 24.6% occurred after medication and 8.9% after expectant management. Patient age (

Elephantopus scaber, globally acknowledged for its edible and medicinal uses, remains underexplored despite the identification of active compounds. This research explores Elephantopus scaber extract's therapeutic capabilities in hepatocellular carcinoma (HCC). Initial in vitro screenings using the MTT assay revealed that ethanol extract (EEES) inhibited HCC cell proliferation while exhibiting low toxicity to normal cells. Further explorations showed EEES induced cell cycle arrest, apoptosis, and inhibited cell metastasis. A bioinformatics analysis using a network pharmacology approach identified the PI3K/Akt pathway as a key modulation for EEES's anti-HCC activities, validated through western blot analysis. In animal studies, EEES demonstrated the ability to inhibit HCC tumor growth in vivo with a high level of safety. In summary, our research positions Elephantopus scaber as a potent herb with anti-HCC activities and remarkable safety, offering promising prospects for the prevention and treatment of liver diseases, including HCC.

Objective: To evaluate the anticancer activity of the natural diterpenoid lasiokaurin (LAS) against nasopharyngeal carcinoma (NPC) both in vitro and in vivo, along with investigating its underlying mechanism. Methods: MTT and colony formation assays were used to assess cell viability. Flow cytometry was utilized for the analysis of cell cycle arrest and apoptosis. Additionally, wound healing and transwell invasion assays were conducted separately to investigate cell migration and invasion. To uncover potential targets and pathways of LAS within NPC, a network pharmacological study based on RNA-sequencing (RNA-seq) was performed. Immunoblotting was subsequently used to determine protein levels. Furthermore, the anti-NPC activity of LAS was evaluated in vivo using a xenograft mouse model. Results: Based on in vitro investigations, it is evident that LAS exerted substantial inhibitory effects on NPC cells. Notably, LAS demonstrated significant reductions in cell viability, migration, and invasion capabilities, while simultaneously inducing apoptosis and G2/M cell cycle arrest. Furthermore, LAS suppressed the activation of MAPK, mTOR, STAT3, and NF-κB pathways within NPC cells. Additionally, in vivo experiments underscored LAS's capacity to attenuate NPC tumor growth without eliciting any discernible impact on body weight. Conclusion: Our data clearly demonstrate the anticancer activity of LAS against NPC, both in vitro and in vivo. These findings firmly position LAS as a potential candidate for the treatment of NPC.

This study involved direct doping of In2O3 into silicon carbide (SiC) powder, resulting in 8.0 at% In-doped SiC powder. Subsequently, heating at 500 °C was performed to form a target, followed by the utilization of electron beam (e-beam) technology to deposit the In-doped SiC thin films with the thickness of approximately 189.8 nm. The first breakthrough of this research was the successful deposition of using e-beam technology. The second breakthrough involved utilizing various tools to analyze the physical and electrical properties of In-doped SiC thin films. Hall effect measurement was used to measure the resistivity, mobility, and carrier concentration and confirm its n-type semiconductor nature. The uniform dispersion of In ions in SiC was as confirmed by electron microscopy energy-dispersive spectroscopy and secondary ion mass spectrometry analyses. The Tauc Plot method was employed to determine the Eg values of pure SiC and In-doped SiC thin films. Semiconductor parameter analyzer was used to measure the conductivity and the I-V characteristics of devices in In-doped SiC thin films. Furthermore, the third finding demonstrated that In2O3-doped SiC thin films exhibited remarkable current density. X-ray photoelectron spectroscopy and Gaussian-resolved spectra further confirmed a significant relationship between conductivity and oxygen vacancy concentration. Lastly, depositing these In-doped SiC thin films onto p-type silicon substrates etched with buffered oxide etchant resulted in the formation of heterojunction p-n junction. This junction exhibited the rectifying characteristics of a diode, with sample current values in the vicinity of 102 mA, breakdown voltage at approximately −5.23 V, and open-circuit voltage around 1.56 V. This underscores the potential of In-doped SiC thin films for various semiconductor devices.

Alanine substitution in peptides is crucial for studying peptide-based inhibitors of protein–protein interactions, but limited information is obtained from single alanine substitution. Here, the authors develop a label-free combinatorial alanine affinity selection platform to establish multi-alanine mutational tolerance and provide structure-activity relationships.

Due to its intricate heterogeneity, high invasiveness, and poor prognosis, triple-negative breast cancer (TNBC) stands out as the most formidable subtype of breast cancer. At present, chemotherapy remains the prevailing treatment modality for TNBC, primarily due to its lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth receptor 2 (HER2). However, clinical chemotherapy for TNBC is marked by its limited efficacy and a pronounced incidence of adverse effects. Consequently, there is a pressing need for novel drugs to treat TNBC. Given the rich repository of diverse natural compounds in traditional Chinese medicine, identifying potential anti-TNBC agents is a viable strategy. This study investigated lasiokaurin (LAS), a natural diterpenoid abundantly present in Isodon plants, revealing its significant anti-TNBC activity both in vitro and in vivo. Notably, LAS treatment induced cell cycle arrest, apoptosis, and DNA damage in TNBC cells, while concurrently inhibiting cell metastasis. In addition, LAS effectively inhibited the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and signal transducer and activator of transcription 3 (STAT3), thus establishing its potential for multitarget therapy against TNBC. Furthermore, LAS demonstrated its ability to reduce tumor growth in a xenograft mouse model without exerting detrimental effects on the body weight or vital organs, confirming its safe applicability for TNBC treatment. Overall, this study shows that LAS is a potent candidate for treating TNBC.

The cause of trigger fingers remains uncertain. High lipid levels in the blood may reduce blood supply to the distal fingers and promote inflammation. We aimed to explore the association between hyperlipidemia and trigger finger. A nationwide population-based cohort study using longitudinal data from 2000 to 2013, 41,421 patients were included in the hyperlipidemia cohort and 82,842 age- and sex-matched patients were included in the control cohort. The mean age was 49.90 ± 14.73 years in the hyperlipidemia cohort and 49.79 ± 14.71 years in the control cohort. After adjusting for possible comorbidities, the hazard ratio of trigger finger in the hyperlipidemia cohort was 4.03 (95% confidence interval [CI], 3.57-4.55), with values of 4.59 (95% CI, 3.67-5.73) and 3.77 (95% CI, 3.26-4.36) among male and female patients, respectively. This large-scale population-based study demonstrated that hyperlipidemia is correlated to trigger finger.

Objective: To evaluate the safety, potential benefits and possible mechanisms of the extract of Si Ben Cao (SBC), a traditional Chinese medicine formula composed of four herbs, for skin whitening. Methods: The reflux method was performed to prepare the extract of SBC. MTT assay was used to evaluate the cytotoxic of SBC extract in vitro. Skin irritation test and skin allergy test on rats were performed to evaluate the safety of SBC extract in vivo. Intercellular melanin production was analyzed to assess the function of SBC extract for whitening. Afterwards, we analyzed the activity of intracellular tyrosinase, Ultraviolet (UV) absorption, and anti-oxidant activity, which were related to melanin production. Results: The aqueous extract and ethanol extract of SBC were prepared separately. MTT assay results showed aqueous extract of SBC at a concentration of 100 μg/mL had no inhibitory effect on the proliferation of B16F10 cells even after treatment for 96 h, indicating that aqueous extract of SBC was not cytotoxic. Thus, we conducted subsequent experiments using aqueous extract of SBC. The results on rats showed SBC extract was safe to apply on the skin without causing irritation and allergies. Analysis of melanin content showed SBC extract had inhibitory effect on cellular melanin generation and secretion. Moreover, we found that SBC extract was able to reduce cellular tyrosinase activity, as well as absorb UV light and scavenge DPPH radicals for anti-oxidants. Conclusion: Our data clearly demonstrated that SBC extract is safe and effective for skincare, and it is suitable for use with the purpose of skin whitening and health benefits.

The pathogenic influences of uterine bacteria on endometrial carcinogenesis remain unclear. The aim of this pilot study was to compare the microbiota composition of endometrial lavage samples obtained from women with either endometrial hyperplasia (EH) or endometrial cancer (EC) versus those with benign uterine conditions. We hypothesized that specific microbiota signatures would distinguish between the two groups, possibly leading to the identification of bacterial species associated with endometrial tumorigenesis. A total of 35 endometrial lavage specimens (EH, n = 18; EC, n = 7; metastatic EC, n = 2; benign endometrial lesions, n = 8) were collected from 32 women who had undergone office hysteroscopy. Microbiota composition was determined by sequencing the V3−V4 region of 16S rRNA genes and results were validated by real-time qPCR in 46 patients with EC/EH and 13 control women. Surprisingly, we found that Bacillus pseudofirmus and Stenotrophomonas rhizophila – two plastic-degrading bacterial species – were over-represented in endometrial lavage specimens collected from patients with EC/EH. Using computational analysis, we found that the functional profile of endometrial microbiota in EC/EH was associated with fatty acid and amino acid metabolism. In summary, our hypothesis-generating data indicate that the plastic-degrading bacteria Bacillus pseudofirmus and Stenotrophomonas rhizophila are over-represented within the endometrial lavage microbiota of women with EC/EH living in Taiwan. Whether this may be related to plastic pollution deserves further investigation.

In the context of ZnO nanorods (NRs) grown on Si and indium tin oxide (ITO) substrates, this study aimed to compare their degradation effect on methylene blue (MB) at different concentrations. The synthesis process was carried out at a temperature of 100 °C for 3 h. After the synthesis of ZnO NRs, their crystallization was analyzed using X-ray diffraction (XRD) patterns. The XRD patterns and top-view SEM observations demonstrate variations in synthesized ZnO NRs when different substrates were used. Furthermore, cross-sectional observations reveal that ZnO NRs synthesized on an ITO substrate exhibited a slower growth rate compared to those synthesized on a Si substrate. The as-grown ZnO NRs synthesized on the Si and ITO substrates exhibited average diameters of 110 ± 40 nm and 120 ± 32 nm and average lengths of 1210 ± 55 nm and 960 ± 58 nm, respectively. The reasons behind this discrepancy are investigated and discussed. Finally, synthesized ZnO NRs on both substrates were utilized to assess their degradation effect on methylene blue (MB). Photoluminescence spectra and X-ray photoelectron spectroscopy were employed to analyze the quantities of various defects of synthesized ZnO NRs. The effect of MB degradation after 325 nm UV irradiation for different durations can be evaluated using the Beer–Lambert law, specifically by analyzing the 665 nm peak in the transmittance spectrum of MB solutions with different concentrations. Our findings reveal that ZnO NRs synthesized on an ITO substrate exhibited a higher degradation effect on MB, with a rate of 59.5%, compared to NRs synthesized on a Si substrate, which had a rate of 73.7%. The reasons behind this outcome, elucidating the factors contributing to the enhanced degradation effect are discussed and proposed.

Indium oxide (In2O3) is a widely used n-type semiconductor for detection of pollutant gases; however, its gas selectivity and sensitivity have been suboptimal in previous studies. In this work, zinc-doped indium oxide nanowires with appropriate morphologies and high crystallinity were synthesized using chemical vapor deposition (CVD). An accurate method for electrical measurement was attained using a single nanowire microdevice, showing that electrical resistivity increased after doping with zinc. This is attributed to the lower valence of the dopant, which acts as an acceptor, leading to the decrease in electrical conductivity. X-ray photoelectron spectroscopy (XPS) analysis confirms the increased oxygen vacancies due to doping a suitable number of atoms, which altered oxygen adsorption on the nanowires and contributed to improved gas sensing performance. The sensing performance was evaluated using reducing gases, including carbon monoxide, acetone, and ethanol. Overall, the response of the doped nanowires was found to be higher than that of undoped nanowires at a low concentration (5 ppm) and low operating temperatures. At 300 °C, the gas sensing response of zinc-doped In2O3 nanowires was 13 times higher than that of undoped In2O3 nanowires. The study concludes that higher zinc doping concentration in In2O3 nanowires improves gas sensing properties by increasing oxygen vacancies after doping and enhancing gas molecule adsorption. With better response to reducing gases, zinc-doped In2O3 nanowires will be applicable in environmental detection and life science.

Abstract Background To evaluate the use of a human fibrin glue (Tisseel) for minor bleeding control and approximation of ovarian defect during transvaginal natural orifice ovarian cystectomy (TNOOC) of benign and non-endometriotic ovarian tumors. Methods A total of 125 women with benign and non-endometriotic ovarian tumors who underwent TNOOC between May 2011 and January 2020: 54 with the aid of Tisseel and 71 with traditional suture for hemostasis and approximation of ovarian defect. Surgical outcomes such as length of surgery, operative blood loss, postoperative pain score, and postoperative hospital stay were recorded. Before and immediately (10 days) and at 6 months after the procedure, serum anti-Müllerian hormone (AMH) levels were also determined. Results Complete hemostasis and approximation of ovarian defect were achieved in all cases. No significant difference was noted in the operating time, operative blood loss, postoperative pain scores after 12, 24 and 48 h, length of postoperative stay, and baseline AMH levels between the two groups. The operation did not have a negative effect on the immediate and 6-month postoperative AMH levels in the suture group. However, the decline in the AMH levels was significant immediately after surgery in the Tisseel group, nevertheless, no significant difference was noted in the AMH levels at 6 months (3.3 vs. 1.7 mg/mL; p = 0.042, adjusted p = 0.210). Conclusion The use of Tisseel in TNOOC of benign and non-endometriotic ovarian tumors without suturing the ovarian tissue is clinically safe and feasible.

Pulmonary fibrosis is a major public health problem with unclear mechanism and limited therapeutic options. Here the authors show that a fibroblast-enriched endoplasmic reticulum protein, TXNDC5, promotes pulmonary fibrosis by stabilizing TGFBR1 and show the potential of TXNDC5 as a therapeutic target against pulmonary fibrosis.

The sequence space accessible to evolving proteins can be enhanced by cellular chaperones that assist biophysically defective clients in navigating complex folding landscapes. It is also possible, at least in theory, for proteostasis mechanisms that promote strict quality control to greatly constrain accessible protein sequence space. Unfortunately, most efforts to understand how proteostasis mechanisms influence evolution rely on artificial inhibition or genetic knockdown of specific chaperones. The few experiments that perturb quality control pathways also generally modulate the levels of only individual quality control factors. Here, we use chemical genetic strategies to tune proteostasis networks via natural stress response pathways that regulate the levels of entire suites of chaperones and quality control mechanisms. Specifically, we upregulate the unfolded protein response (UPR) to test the hypothesis that the host endoplasmic reticulum (ER) proteostasis network shapes the sequence space accessible to human immunodeficiency virus-1 (HIV-1) envelope (Env) protein. Elucidating factors that enhance or constrain Env sequence space is critical because Env evolves extremely rapidly, yielding HIV strains with antibody- and drug-escape mutations. We find that UPR-mediated upregulation of ER proteostasis factors, particularly those controlled by the IRE1-XBP1s UPR arm, globally reduces Env mutational tolerance. Conserved, functionally important Env regions exhibit the largest decreases in mutational tolerance upon XBP1s induction. Our data indicate that this phenomenon likely reflects strict quality control endowed by XBP1s-mediated remodeling of the ER proteostasis environment. Intriguingly, and in contrast, specific regions of Env, including regions targeted by broadly neutralizing antibodies, display enhanced mutational tolerance when XBP1s is induced, hinting at a role for host proteostasis network hijacking in potentiating antibody escape. These observations reveal a key function for proteostasis networks in decreasing instead of expanding the sequence space accessible to client proteins, while also demonstrating that the host ER proteostasis network profoundly shapes the mutational tolerance of Env in ways that could have important consequences for HIV adaptation.

In recent years, the learning efficacy of online to offline (O2O) teaching methods seems to outperform traditional teaching methods in the field of education. Students can use a small private online course (SPOC) teaching platform to preview class-related materials, learn basic knowledge, and enhance the practical experience of system development in offline courses. The research team applied an artificial intelligence (AI) precision education strategy to design a teaching experiment that evaluated whether this approach may lead to better learning outcomes. In addition to questionnaire surveys to ascertain students' attitudes toward and their satisfaction with learning, this study employed in-depth interviews to understand a potential influence on changes in teachers' curriculum design and teaching approaches when SPOCs was integrated into the traditional university classroom, as well as the impact of the AI precision education model. The results showed that the AI precision education model may facilitate students' learning experience and enhance student achievement.

This work performs fundamental electrical measurements and a positive bias temperature instability (PBTI) test on an N-type metal oxide semiconductor capacitor (MOSCAP) and a La2O3 dipole-doped N-type MOSCAP. Experimental results show that the dipole-doped N-type MOSCAP has a lower threshold voltage and gate current leakage than do the N-type MOSCAP. After positive bias stress, an abnormal gate current leakage decrease appears in both dipole-doped and normal N-type MOSCAPs under short term stress. Analysis of capacitance and gate current measurements indicate that electron trapping and defect generation cause the change in gate current after positive bias stress. Generally, devices with higher gate leakage have more severe degradation after PBTI. However, in this work, the dipole sample shows a lower initial gate current leakage but higher gate current degradation than those found in the control sample after PBTI. Based on the electrical measurement results and the energy band simulation, a conduction model was proposed to explain the abnormal PBTI of the dipole-doped N-type MOSCAP.

Background: We present two patients who suffered from endometritis as a result of a foreign body reaction to an anti-adhesive barrier positioned during hysteroscopic surgery. Case: The first case—who had previously undergone hysteroscopic lysis of intrauterine adhesions—presented with persistent abdominal pain and vaginal discharge. Ultrasound revealed an irregularly shaped strip of hyperechoic lesion. On diagnostic hysteroscopy, a foreign body presenting as a flattened bundle was observed and identified as the anti-adhesive barrier positioned during her previous surgery. The second patient—who had previously undergone laparoscopic surgery and hysteroscopic polypectomy—presented with abdominal pain in the left lower quadrant. Ultrasound revealed an intrauterine hyperechoic avascular lesion, while hysteroscopy identified a piece of crumpled plastic wrap. Both patients showed clinical improvement after removal of the extraneous material. Conclusion: Intrauterine positioning of anti-adhesive barriers during hysteroscopic surgery can give rise to endometritis as a result of foreign body reactions.

Given the widespread acceptance of computational thinking (CT) in educational systems around the world, primary and higher education has begun thinking about how to cultivate students' CT competences. The artificial intelligence of things (AIoT) combines artificial intelligence (AI) and the Internet of things (IoT) and involves integrating sensing technologies at the lowest level with relevant algorithms in order to solve real-world problems. Thus, it has now become a popular technological application for CT training. In this study, a novel AIoT learning with Augmented Reality (AR) technology was proposed and explored the effect of CT skills. The students used AR applications to understand AIoT applications in practice, attempted the placement of different AR sensors in actual scenarios, and further generalized and designed algorithms. Based on the results of the experimental course, we explored the influence of prior knowledge and usage intention on students' CT competence training. The results show that proposed AIoT learning can increase students' learning intention and that they had a positive impact on problem solving and comprehension with AR technology, as well as application planning and design.

In order to solve the problem of geological disasters caused by karst collapse in the K1379+300-K1471+920 section of the Quannan Expressway reconstruction and expansion, the evaluation of karst collapse susceptibility in the study area was carried out, and the corresponding prevention measures are put forward. Firstly, by identifying and determining the susceptible factors of karst collapse in the study area, three criterion layers, including the basic geological conditions, karst collapse impact, and human activities were selected, with a total of seven susceptible factors. The analytic hierarchy process (AHP) was used to assign values to each factor, and the evaluation model of karst collapse susceptibility in the study area was established. Then, using the spatial analysis function of ArcGIS, the seven susceptible factor partition maps were superimposed according to the evaluation model, and the evaluation map of the karst collapse susceptibility was obtained. The study area was divided into five levels of susceptibility: extremely susceptible areas (2.64–2.81), susceptible areas (2.43–2.64), somewhat susceptible areas (1.88–2.43), non-susceptible areas (1.04–1.88), and non-karst areas (0.51–1.04). The length of the extremely susceptible area is 11.90 km, 12.85% of the total length of the route, and the susceptible area, somewhat susceptible area, non-susceptible area, and non-karst area account for 25.05%, 39.54%, 11.01%, and 11.55% of the total length, respectively. The research results of the karst collapse susceptibility in the area are consistent with the actual situation. Finally, combined with the research results, prevention measures for karst collapse are put forward, which provide a reference for the prevention and mitigation of disaster in engineering construction.

In this study, the head-mounted virtual reality (VR) technology is adpoted for computational thinking teaching in the AIoT Maker course teaching. The earthquake relief situation is designed in the VR in the course scenario, because in the context of situational thinking, pre-emptive training in the face of emergency disasters has been conducted through observation meetings or training courses. Through listening to lecturers or experienced personnel to share experiences, students often have a harder time thinking about real scenes and it is harder to think creatively how to design with the emergency disaster response. In view of this, this research will combine the development and evaluation of earthquake relief training courses for head-mounted VR and computational thinking experiments to explore the use of VR and computational thinking experiments to drive students to create ideas for real disaster relief scenarios. Through computational thinking, students think about different script situations and discuss in each scene to find a suitable maker design of the AIoT project. Finally, this study combined with its modular space program training to develop students’ programming skills. According to the experiment, this study is able to strength students’ practical learning motivation, and follow-up employ ability training for course learning.

The dysregulation of store-operated Ca2+ entry (SOCE) promotes cancer progression by changing Ca2+ levels in the cytosol or endoplasmic reticulum. Stromal interaction molecule 1 (STIM1), a component of SOCE, is upregulated in several types of cancer and responsible for cancer cell migration, invasion, and metastasis. To explore the impact of STIM1-mediated SOCE on the turnover of focal adhesion (FA) and cell migration, we overexpressed the wild-type and constitutively active or dominant negative variants of STIM1 in an osteosarcoma cell line. In this study, we hypothesized that STIM1-mediated Ca2+ elevation may increase cell migration. We found that constitutively active STIM1 dramatically increased the Ca2+ influx, calpain activity, and turnover of FA proteins, such as the focal adhesion kinase (FAK), paxillin, and vinculin, which impede the cell migration ability. In contrast, dominant negative STIM1 decreased the turnover of FA proteins as its wild-type variant compared to the cells without STIM1 overexpression while promoting cell migration. These unexpected results suggest that cancer cells need an appropriate amount of Ca2+ to control the assembly and disassembly of focal adhesions by regulating calpain activity. On the other hand, overloaded Ca2+ results in excessive calpain activity, which is not beneficial for cancer metastasis.

Single molecular machines are capable of a variety of functions, but methods to couple motion between them are still lacking. Here, Wasioet al. report the emergent behaviour of spontaneously formed two-dimensional crystals, which display correlated switching of their sub-molecular rotor units.

In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (IK1 and IKACh) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking IK1 and IKACh with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC50 of IK1 and IKACh block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of IK1 and IKACh. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC50 of IK1 block by chloroquine was similar to that of IKACh. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of IK1 and IKACh can be a targeted therapeutic strategy for persistent atrial fibrillation.

The threat of viral pandemics demands a comprehensive understanding of evolution at the host-pathogen interface. Here, we show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that the Pro283 nucleoprotein variant, which (1) is conserved across human influenza strains, (2) confers resistance to the Myxovirus resistance protein A (MxA) restriction factor, and (3) critically contributed to adaptation to humans in the 1918 pandemic influenza strain, is rendered unfit by heat shock factor 1 inhibition-mediated host chaperone depletion at febrile temperatures. This fitness loss is due to biophysical defects that chaperones are unavailable to address when heat shock factor 1 is inhibited. Thus, influenza subverts host chaperones to uncouple the biophysically deleterious consequences of viral protein variants from the benefits of immune escape. In summary, host proteostasis plays a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host switching, and for antiviral drug development.

We systematically and quantitatively evaluate whether endoplasmic reticulum (ER) proteostasis factors impact the mutational tolerance of secretory pathway proteins. We focus on influenza hemaggluttinin (HA), a viral membrane protein that folds in the host’s ER via a complex pathway. By integrating chemical methods to modulate ER proteostasis with deep mutational scanning to assess mutational tolerance, we discover that upregulation of ER proteostasis factors broadly enhances HA mutational tolerance across diverse structural elements. Remarkably, this proteostasis network-enhanced mutational tolerance occurs at the same sites where mutational tolerance is most reduced by propagation at fever-like temperature. These findings have important implications for influenza evolution, because influenza immune escape is contingent on HA possessing sufficient mutational tolerance to evade antibodies while maintaining the capacity to fold and function. More broadly, this work provides the first experimental evidence that ER proteostasis mechanisms define the mutational tolerance and, therefore, the evolution of secretory pathway proteins.

As reported by the Taiwan Cancer Registry in 2013 squamous cell carcinoma of head and neck cancer (HNSCC) was the sixth most frequently diagnosed cancer and the 5th most common cause of cancer related death and its incidence and mortality rate is still rising. The co-occurrence of HNSCC and secondary primary cancer (SPC) and the chemopreventive effect of aspirin on certain malignancies had been reported. Therefore we conducted this national study to investigate the use of aspirin associated with risk reduction of secondary primary cancer for patients with head and neck cancer in Taiwan. We searched the Registry for Catastrophic Illness in the National Health Insurance Research Database (NHIRD) for 18,234 patients (3,576 aspirin users and 14,667 non-aspirin users) diagnosed with HNSCC during 2000-2005. The SPC incidence density during follow-up in 2000-2011 was compared between the groups. For HNSCC patients, aspirin use after diagnosis was significantly associated with SPC risk reduction by 25% (adjusted HR, 0.75; 95% CI, 0.63-0.89; p = 0.001) after multivariate analysis. In the subgroup analysis, we found that esophageal cancer and stomach cancer incidence were significantly reduced after aspirin use (adjusted HR, 0.60; 95% CI, 0.41-0.90; p = 0.01 for esophageal cancer; adjusted HR, 0.27; 95% CI, 0.08-0.87; p = 0.03 for stomach cancer). Aspirin use for 1-3 years was associated with SPC risk reduction by 35% (adjusted HR, 0.65; 95% CI, 0.49-0.87; p = 0.003). SPC risk reduction extended continuously for more than 3 years of follow up (adjusted HR, 0.72; 95% CI, 0.53-0.98; p = 0.030). Our data shows aspirin use was associated with reduced SPC incidence for HNSCC patients, attributed mainly to reduced risk of esophageal and stomach cancer.

Summary:. A new type of needle system combines 2 parts, an inner needle and an outer needle. The inner needle is used for filler injection and the outer needle acts as a guiding needle that can observe blood reflow when inserting into the vessel lumen during injection process. This new needle system can be used for all kinds of filler, providing real time monitoring for physician and preventing intravascular injection of any filler.

Predicting and constraining RNA virus evolution require understanding the molecular factors that define the mutational landscape accessible to these pathogens. RNA viruses typically have high mutation rates, resulting in frequent production of protein variants with compromised biophysical properties. Their evolution is necessarily constrained by the consequent challenge to protein folding and function. We hypothesized that host proteostasis mechanisms may be significant determinants of the fitness of viral protein variants, serving as a critical force shaping viral evolution. Here, we test that hypothesis by propagating influenza in host cells displaying chemically-controlled, divergent proteostasis environments. We find that both the nature of selection on the influenza genome and the accessibility of specific mutational trajectories are significantly impacted by host proteostasis. These findings provide new insights into features of host–pathogen interactions that shape viral evolution, and into the potential design of host proteostasis-targeted antiviral therapeutics that are refractory to resistance.

Phostensin is encoded by KIAA1949. 5'-RACEanalysis has been used to identify the translation start site of phostensin mRNA, indicating that it encodes 165 amino acids with an apparent molecular weight of 26 kDa on SDS-PAGE. This low-molecular-weight phostensin is present in human peripheral blood mononuclear cells and many leukemic cell lines. Phostensin is a protein phosphatase-1(PP1) binding protein. It also contains one actin-binding motif at its C-terminal region and binds to the pointed ends of actin filaments, modulating actin dynamics. In the current study, a high-molecular-weight phostensin is identified by using immunoprecipitationin combination with a proteomic approach. This new species of phostensin is also encoded by KIAA1949 and consists of 613 amino acids with an apparent molecular weight of 110 kDa on SDS-PAGE. The low-molecular-weight and high-molecular-weight phostensins were named as phostensin-α and phostensin-β, respectively. Although phostensin-α is the C-terminal region of phostensin-β, it is not degraded from phostensin-β. Phostensin-β is capable of associating with PP1 and actin filaments, and is present in many cell lines.

Phostensin, a protein phosphatase 1 F-actin cytoskeleton-targeting subunit encoded by KIAA1949, consists of 165 amino acids and caps the pointed ends of actin filaments. Sequence alignment analyses suggest that the C-terminal region of phostensin, spanning residues 129 to 155, contains a consensus actin-binding motif. Here, we have verified the existence of an actin-binding motif in the C-terminal domain of phostensin using colocalization, F-actin co-sedimentation and single filament binding assays. Our data indicate that the N-terminal region of phostensin (1–129) cannot bind to actin filaments and cannot retard the pointed end elongation of gelsolin-actin seeds. Furthermore, the C-terminal region of phostensin (125–165) multiply bind to the sides of actin filaments and lacks the ability to block the pointed end elongation, suggesting that the actin-binding motif is located in the C-terminal region of the phostensin. Further analyses indicate that phostensin binding to the pointed end of actin filament requires N-terminal residues 35 to 51. These results suggest that phostensin might fold into a rigid structure, allowing the N-terminus to sterically hinder the binding of C-terminus to the sides of actin filament, thus rendering phostensin binding to the pointed ends of actin filaments.

Human dihydroorotate dehydrogenase (hDHODH) is a class-2 dihydroorotate dehydrogenase. Because it is extensively used by proliferating cells, its inhibition in autoimmune and inflammatory diseases, cancers, and multiple sclerosis is of substantial clinical importance. In this study, we had two aims. The first was to develop an hDHODH pharma-similarity index approach (PhSIA) using integrated molecular dynamics calculations, pharmacophore hypothesis, and comparative molecular similarity index analysis (CoMSIA) contour information techniques. The approach, for the discovery and design of novel inhibitors, was based on 25 diverse known hDHODH inhibitors. Three statistical methods were used to verify the performance of hDHODH PhSIA. Fischer's cross-validation test provided a 98% confidence level and the goodness of hit (GH) test score was 0.61. The q(2), r(2), and predictive r(2) values were 0.55, 0.97, and 0.92, respectively, for a partial least squares validation method. In our approach, each diverse inhibitor structure could easily be aligned with contour information, and common substructures were unnecessary. For our second aim, we used the proposed approach to design 13 novel hDHODH inhibitors using a scaffold-hopping strategy. Chemical features of the approach were divided into two groups, and the Vitas-M Laboratory fragment was used to create de novo inhibitors. This approach provides a useful tool for the discovery and design of potential inhibitors of hDHODH, and does not require docking analysis; thus, our method can assist medicinal chemists in their efforts to identify novel inhibitors.