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The novel coronavirus disease 2019 (COVID-19) has affected a large number of countries. Informing the public and decision makers of the COVID-19′s economic burdens is essential for understanding the real pandemic impact. COVID-19 premature mortality and disability impact in Taiwan was analyzed using the Taiwan National Infectious Disease Statistics System (TNIDSS) by estimating the sex/age-specific years of life lost through death (YLLs), the number of years lived with disability (YLDs), and the disability-adjusted life years (DALYs) from January 2020 to November 2021. Taiwan recorded 1004.13 DALYs (95% CI: 1002.75–1005.61) per 100,000 population for COVID-19, with YLLs accounting for 99.5% (95% CI: 99.3% 99.6%) of all DALYs, with males suffering more from the disease than females. For population aged ≥ 70 years, the disease burdens of YLDs and YLLs were 0.1% and 99.9%, respectively. Furthermore, we found that duration of disease in critical state contributed 63.9% of the variance in DALY estimations. The nationwide estimation of DALYs in Taiwan provides insights into the demographic distributions and key epidemiological parameter for DALYs. The essentiality of enforcing protective precautions when needed is also implicated. The higher YLLs percentage in DALYs also revealed the fact of high confirmed death rates in Taiwan. To reduce infection risks and disease, it is crucial to maintain moderate social distancing, border control, hygiene measures, and increase vaccine coverage levels. [ABSTRACT FROM AUTHOR]

Public messages on the Internet political inquiry platform rely on manual classification, which has the problems of heavy workload, low efficiency, and high error rate. A Bi-directional long short-term memory (Bi-LSTM) network model based on attention mechanism was proposed in this paper to realize the automatic classification of public messages. Considering the network political inquiry data set provided by the BdRace platform as samples, the Bi-LSTM algorithm is used to strengthen the correlation between the messages before and after the training process, and the semantic attention to important text features is strengthened in combination with the characteristics of attention mechanism. Feature weights are integrated through the full connection layer to carry out classification calculations. The experimental results show that the F1 value of the message classification model proposed here reaches 0.886 and 0.862, respectively, in the data set of long text and short text. Compared with three algorithms of long short-term memory (LSTM), logistic regression, and naive Bayesian, the Bi-LSTM model can achieve better results in the automatic classification of public message subjects. [ABSTRACT FROM AUTHOR]

Objective: To explore the role of Internet addiction in the development of self-harm/suicidal behavior among adolescents after 1-year of follow-up.Study Design: We conducted this 1-year, prospective cohort study of 1861 adolescents (mean age 15.93 years) attending a senior high school in Taiwan; 1735 respondents (93.2%) were classified as having no history of self-harm/suicidal attempts in the initial assessment and were referred to as the "noncase" cohort. The Chen Internet Addiction Scale was used to identify individuals with Internet addiction. The participants were evaluated for self-harm/suicidal behavior again 1 year later and the "noncase" cohort was selected for statistical analysis. To examine the relationship between Internet addiction and self-harm/suicidal behavior, multivariate logistic regression analysis was performed using Internet addiction at baseline as the predictor for newly developed self-harm/suicidal behavior in the next year, after adjustment for potential confounding variables.Results: The prevalence rate of Internet addiction at baseline was 23.0%. There were 59 students (3.9%) who were identified as having developed new self-harm/suicidal behaviors on follow-up assessments. After controlling for the effects of potential confounders, the relative risk of newly emerging self-harm/suicidal behavior for participants who were classified as Internet addicted was 2.41 (95% CI 1.16-4.99, P = .018) when compared with those without Internet addiction.Conclusions: Our findings indicate that Internet addiction is prospectively associated with the incidence of self-harm/suicidal behavior in adolescents. [ABSTRACT FROM AUTHOR]

Free-standing and binder-free electrodes of carbon cloth uniformly covered with Cu 2 NiSnS 4 nanospheres are synthesized via a facile surfactant-assisted hydrothermal method combined with post annealing treatment. The flexible composites are directly applied as electrodes for lithium ion batteries (LIBs) and sodium ion batteries (SIBs). The as-prepared electrodes display outstanding electrochemical performance. They deliver high reversible capacities of 1537 and 329 mAh g −1 after 150 cycles at a current density of 0.1 A g −1 for LIBs and SIBs, respectively. Even when the current density increases to 2 A g −1 , the specific capacity remains at 1200 mAh g −1 for LIBs. Benefiting from the intrinsic nature of materials, structure features, and good electrochemical performance, the as-prepared flexible electrode can be utilized for flexible energy storage devices. [ABSTRACT FROM AUTHOR]

Radiotherapy is adopted to obliterate multiple malignant tumors clinically, which might also induce antitumor immune response. However, traditional radiotherapy is not enough to ablate tumors and activate long-term immunological response. Here, we developed a hybrid nanoplatform (MGTe) composed of GTe (glutathione (GSH) decorated Te nanoparticles) and fusing tumor cell membranes (TM) and bacterial outer membranes (BM). In this nanoplatform, GTe was designed for radiotherapy sensitization, concurrently the fusion of TM and BM was expected for amplifying antitumor immune. With a high-Z element, MGTe could enhance radiosensitivity by reactive oxygen species (ROS) production and cancer cell immunogenic death (ICD) under X-ray irradiation, which would also trigger antitumor immune. At meanwhile, TM and BM would further enlarge the immunological effects through antigen presenting cells (APCs) maturation and cytotoxic T lymphocytes (CTLs) stimulation. In this synergistic strategy, the combination of MGTe and X-ray showed significant tumor inhibition by radiation-driven immunotherapy, which will find great potential as an attractive clinical alternative to fight against tumor with reduced side effects. [ABSTRACT FROM AUTHOR]

Although cancer vaccines exhibit great advances in the field of immunotherapy, developing an efficient vaccine platform for personalized tumor immunotherapy is still a major challenge. Here we demonstrate that a bioactive vaccine platform (HMP@Ag) fabricated with hybrid M13 phage and personal tumor antigens can facilitate delivery of antigens into lymph nodes and activate antigen-presenting cells (APCs) through the Toll-like receptor 9 (TLR9) signaling pathway, which boosts both innate and adaptive immune response. As an adjuvant platform, hybrid M13 phages can deliver various tumor-specific antigens through simple adsorption to support the current development of personalized vaccines for cancers. Notably, the HMP@Ag vaccine not only prevented the tumors, but also delayed the tumor growth in established (subcutaneous and orthotopic) and metastatic tumor-bearing models while synergy with immune checkpoint blockade (ICB) therapy. Moreover, HMP@Ag triggered a robust neoantigen-based specific immune response in tumor-specific mutation models. In a clinically relevant surgery model, using autologous cell membrane from primary tumors-based HMP@Ag cooperation with ICB dramatically inhibited the post-operation recurrence, and elicited a long-term immune memory effect simultaneously. These findings imply that the M13 phage represents a powerful tool to develop a bio-activated hybrid platform for personalized therapy. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) therapy has exhibited great clinical benefits in multiple cancers types. However, most cancer patients such as colorectal cancers (CRC) show poor response to ICB. Here, we develop a magnetic nanoparticle (MNP)-mediated delivery of CRISPR/Cas9 system (LMPM) to target the DNA repair pathway and inactivate endogenous DNA mismatch repair (MMR)-related Mlh1 gene as a new strategy of immunotherapy. The genetically knockout of Mlh1 can be effectively realized by CRISPR/Cas9 edition with external magnetic field control. As a consequence, the inactivation of Mlh1 lead to an increased tumor mutation burden and enhancement of tumor immunogenicity in situ , which can elicit strong antitumor immunity. Both in vitro and in vivo studies demonstrate that deploying such a strategy of targeting inactivation of Mlh1 shows high inhibition efficacy in the established tumors. In this way, tumor infiltration of CD8+ T cells and ICB response are significantly improved compared with α-PD1 monotherapy. In short, it is certified that precision targeting of DNA MMR pathway can boost specific anti-tumor immune response and display the potent potential in versatile tumor immunotherapy therapeutic exploitation. Magnetic nanoparticle-mediated delivery of CRISPR/Cas9 system in vivo was reported for down-regulating DNA mismatch repair gene Mlh1 to increase tumor mutation burden and boost anti-tumor immune response. [Display omitted] • Magnetic nanoparticle-mediated delivery of Cas9/sgMlh1 system effectively down-regulated Mlh1 both in vitro and in vivo. • The inactivation of Mlh1 could increase the tumor mutation burden to enhance the tumor immunogenicity in situ. • LMPM significantly facilitated the tumor-infiltrating of CD8+ T cells and potentiated ICB response. [ABSTRACT FROM AUTHOR]

Purpose Early-onset bipolar disorder is associated with a more severe illness course and poorer outcome. Its identification in adolescents may provide the opportunity for adequate intervention to improve global functioning and long-term prognosis. Thus, this study aimed to screen mood disturbance in a sample of high school students using Mood Disorder Questionnaire (MDQ) and follow up their adaptive functioning 1 year later. Methods In the first year, adolescents aged 15–17 years old from a Taiwanese senior high school (N = 1,151) completed the Chinese version of MDQ, the Impulsiveness Scale, and a set of questions about risky behaviors. A subgroup of respondents (N = 184) picked randomly were interviewed to validate the diagnosis of bipolar disorder. In the second year, the Social Adjustment Inventory for Children and Adolescents was applied for the same sample of subjects for the measurement of their adaptive functions. Results The intraclass correlation coefficient and the Cronbach α coefficient of the MDQ were .68 and .61, respectively. MDQ score of at least 7 showed modest sensitivity (.57) and specificity (.64) for bipolar disorder. Higher MDQ score predicted risky behaviors in adolescents at baseline measurement. MDQ score was found significantly correlated with Impulsiveness Scale total score. In follow-up evaluation, participants with an MDQ score of ≥7 had poorer social adjustment. Conclusions Our findings suggest that untreated mood disturbance among adolescents leads to impaired social adaptive functioning in the next year. The application of MDQ in adolescents may help clinicians in early intervention for their emotional disturbance. [ABSTRACT FROM AUTHOR]

Background/Purpose: Traditionally, tooth germ is observed by histological investigation with hematoxylin and eosin stain and information may loss during the process. The purpose of this study is to use multiphoton laser fluorescence microscopy to observe the developing tooth germs of mice for building up the database of the images of tooth germs and compare with those from conventional histological analysis. Methods: Tooth germs were isolated from embryonic and newborn mice with age of Embryonic Day 14.5 and Postnatal Days 1, 3, 5, and 7. Results: Comparison of the images of tooth germ sections in multiphoton microscopy with the images of histology was performed for investigating the molar tooth germs. It was found that various signals arose from different structures of tooth germs. Pre-dentin and dentin have strong second-harmonic generation signals, while ameloblasts and enamel tissues were shown with strong autofluorescence signals. Conclusion: In this study, a novel multiphoton microscopy database of images from developing tooth germs in mice was set up. We confirmed that multiphoton laser microscopy is a powerful tool for investigating the development of tooth germ and is worthy for further application in the study of tooth regeneration. [ABSTRACT FROM AUTHOR]

Abstract: Aims of the study: Kanglaite (KLT) is a useful antitumor drug with proven effects when combined with chemotherapy, radiotherapy or surgery. We hypothesize that KLT has antitumor activity and immunomodulatory effects in Lewis lung carcinoma. Materials and methods: C57BL/6 mice with Lewis lung carcinoma were divided into four groups: the control group (C), cisplatin group (1mg/kg, DDP), low KLT group (6.25ml/kg body weight [L]), and high KLT group (12.5ml/kg body weight [H]). T cell proliferation was determined by the MTT assay. Nuclear factor-kappa B (NF-κB), inhibitor kappa B alpha (IκBα), IκB kinase (IKK) and epidermal growth factor receptor (EGFR) levels were measured by western blotting. An enzyme-linked immunosorbent assay was used to analyze the expression of interleukin-2 (IL-2). Results: Intraperitoneal KLT significantly inhibited the growth of Lewis lung carcinoma, and the spleen index was significantly higher in the L and H groups than in the C group. KLT stimulated T cell proliferation in a dose-dependent manner. Treatment with KLT at either 6.25 or 12.5ml/kg decreased the level of NF-κB in the nucleus in a dose-dependent manner, and KLT markedly decreased the expression of IκBα, IKK and EGFR in the cytoplasm of tumor cells and overall. IL-2 was significantly increased in the supernatant of splenocytes in the H group. Conclusions: These results demonstrate that KLT has pronounced antitumor and immunostimulatory activities in C57BL/6 mice with Lewis lung carcinoma. These may affect the regulation of NF-κB/IκB expression, in addition to cytokines such as IL-2 and EGFR. Further work needs to investigate the relevant signaling pathway effects, but our findings suggest that KLT may be a promising antitumor drug for clinical use. [Copyright &y& Elsevier]

Aims of the study: Sodium houttuyfonate (SH) is an addition compound of sodium bisulfite and houttuynin. Houttuynin is one of the main ingredients in the volatile oil of Houttuynia cordata Thunb, which has been widely used in traditional Chinese medicines. In this study, we investigated the effect of SH in membranous glomerulonephritis (MGN) induced by cationic Bovine Serum Albumin (C-BSA) in BALB/c mice. Materials and methods: Mice were divided into four groups, including normal vehicle-treated controls (N group), model (M group), low SH of 60mg/kg body weight (L group), or high SH of 120mg/kg body weight (H group). Urine protein quantification was detected by the urine protein strip test. Morphological assessment in kidneys was observed by light microscope and electron microscopy. The level of nuclear factor-kappaB (NF-κB) in the nuclear was evaluated by Western blot. Immunohistochemical was used to analyze the expression of MCP-1. Results: SH was shown to reverse C-BSA induced increases in urinary protein, and changes in morphology. Treatment with SH at 60–120mg/kg (L and H groups, respectively) dose-dependently decreased the level of nuclear NF-κB and MCP-1 expression compared to that of the M group. Conclusions: This study reveals that SH could treat C-BSA induced MGN in BALB/c mice by suppressing NF-κB activation and MCP-1 expression. Therefore, the most likely mechanism underlying the biological effects of SH is inhibition of an NF-κB mediated-cytokine pathway. [Copyright &y& Elsevier]

Gut microbiota is closely related to the tumorigenesis and progression of colorectal cancer (CRC), especially Fusobacterium nucleatum (Fn) could promote colorectal tumor growth and cause chemoresistance. Here, we developed a tumor-triggered release drug delivery gel to inhibit CRC cell growth in situ by intestinal perfusion. Antibiotic metronidazole (MTZ) and 5-fluorouracil (5-FU), the first-line chemotherapy drug of CRC, are individually incorporated into metal polyphenol network-coated mesoporous silica nanoparticle (MSN), and then blended with carboxymethyl cellulose (CMC) to obtain an anti-CRC gel, AB-Gel. In vivo studies showed that AB-Gel could efficiently inhibit the growth and metastasis of CRC in an orthotopic mouse model attributing to the MTZ-induced modulation in the CRC-related microbiota. Chemotherapy efficacy against orthotopic CRC was significantly enhanced by the elimination of Fn. This strategy based on the combination of gut microbiota modulation and chemotherapy would be considered as an enhanced strategy for CRC treatment with potential use in the clinic. A colonic perfusion gel with tumor-triggered drug release ability was designed for colorectal cancer therapy using combination of gut microbiota modulation and chemotherapy. [Display omitted] • Developing a drug delivery gel (AB-Gel) to inhibit colorectal cancer (CRC) in situ by intestinal perfusion. • AB-Gel can inhibit CRC in orthotopic mouse model due to the combined effect of antibacterial and anticancer. • AB-Gel can form a sticky layer on colonic mucosa and prolong drug release time. [ABSTRACT FROM AUTHOR]

Abstract: Developing a photocatalyst system for the conversion of solar energy to electric energy or chemical energy is a topic of great interest with fundamental and practical importance. The semiconductor catalysts, such as InTaO4, have been extensively used for water splitting under visible light irradiation. However, it has not been used for photoreduction of carbon dioxide with water. InTaO4 was synthesized by solid-state reaction. NiO was added by incipient-wetness impregnation method as the cocatalysts. The catalysts were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), ultraviolet–visible spectroscopy (UV–Vis) and X-ray photoelectron spectroscopy (XPS). The photocatalytic reduction was carried out in a Pyrex reactor under visible light illumination using 500W halogen light as the light source. The band gap of InTaO4 was estimated, from UV–Vis spectrum, to be 2.6eV, showing that these catalysts have ability to reduce CO2 into methanol. The effects of the NiO cocatalyst and pretreatment process on the photocatalytic reduction of the catalyst to methanol were investigated. The methanol yield increased with the amount of NiO cocatalyst. The reduction–oxidation pretreatment had a positive effect on the catalyst. [Copyright &y& Elsevier]

We report the design, synthesis and evaluation of a class of phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates and show that conjugate 16b elicits immune cell infiltration and remodels the "cold" hepatic tumor microenvironment to the inflamed "hot" tumor. Structure-property relationship study via linker modifications and subsequent pharmacokinetics profiling were carried out to improve the solubility and stability of the conjugates in vivo. In a spontaneous hepatocellular carcinoma mouse model, we showed that conjugate 16b exhibited better antitumor efficacy than sorafenib. In particular, significant increase of CD8+ T cell infiltration and granzyme B level was observed, providing insights in sensitizing tumors from intrinsic immune suppressive microenvironment. Evaluation of tumor inflammation-related mRNA expression profile revealed that conjugate 16b, through inductions of key gene expressions including STAT1, CXCL9, CCL5, and PD-L1, rejuvenated tumor microenvironment with enhancement in T cell-, macrophage-, NK cell-, chemokines and cytokines'- functions. Our study establishes that an apoptosis-targeting theranostic enables enrichment of multifaceted immune cells into the tumor mass, which provides potential therapeutic strategies in the combination with immune checkpoint blockade treatment. [Display omitted] • Designing phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates. • Reducing hepatic tumor burden and increasing immune cells infiltration. • Remodeling of hepatic tumor microenvironment to inflamed "hot" tumor. [ABSTRACT FROM AUTHOR]

Abstract: Carbonic anhydrases (CAs) comprise a family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. CAs contribute to a myriad of physiological processes, including pH regulation, anion transport and water balance. To date, 16 known members of the mammalian alpha-CA family have been identified. Given that the catalytic family members share identical reaction chemistry, their physiologic roles are influenced greatly by their tissue and sub-cellular locations. CAVI is the lone secreted CA and exists in both saliva and the gastrointestinal mucosa. An alternative, stress-inducible isoform of CAVI (CAVI-b) has been shown to be expressed from a cryptic promoter that is activated by the CCAAT/Enhancer-Binding Protein Homologous Protein (CHOP). The CAVI-b isoform is not secreted and is currently of unknown physiological function. Here we use neuronal models, including a model derived using Car6 and CHOP gene ablations, to delineate a role for CAVI-b in ischemic protection. Our results demonstrate that CAVI-b expression, which is increased through CHOP-signaling in response to unfolded protein stress, is also increased by oxygen–glucose deprivation (OGD). While enforced expression of CAVI-b is not sufficient to protect against ischemia, CHOP regulation of CAVI-b is necessary for adaptive changes mediated by BDNF that reduce subsequent ischemic damage. These results suggest that CAVI-b comprises a necessary component of a larger adaptive signaling pathway downstream of CHOP. [Copyright &y& Elsevier]

Abstract: Carbonic anhydrase VI (CA VI), encoded by type A transcripts of the gene Car6, is a secretory product of salivary glands and is found in the enamel pellicle. Because higher caries prevalence is associated with lower salivary concentrations of CA VI in humans, we tested whether CA VI protects enamel surfaces from caries induced by Streptococcus mutans, using Car6 −/− mice, in which salivary CA VI expression is absent. We detected aberrant Car6 type A transcripts in Car6 −/− mice, likely targets for nonsense-mediated mRNA decay. Expression of the intracellular stress-induced isoform of CA VI encoded by type B transcripts was restricted to parotid and submandibular glands of wild type mice. The salivary function of Car6 −/− mice was normal as assessed by the histology and protein/glycoprotein profiles of glands, salivary flow rates and protein/glycoprotein compositions of saliva. Surprisingly, total smooth surface caries and sulcal caries in Car6 −/− mice were more than 6-fold and 2-fold lower than in wild type mice after infection with S. mutans strain UA159. Recoveries of S. mutans and total microbiota from molars were also lower in Car6 −/− mice. To explore possible mechanisms for increased caries susceptibility, we found no differences in S. mutans adherence to salivary pellicles, in vitro. Interestingly, higher levels of Lactobacillus murinus and an unidentified Streptococcus species were cultivated from the oral microbiota of Car6 −/− mice. Collective results suggest salivary CA VI may promote caries by modulating the oral microbiota to favor S. mutans colonization and/or by the enzymatic production of acid within plaque. [Copyright &y& Elsevier]

[Display omitted] Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are currently used therapy for non-small cell lung cancer (NSCLC) patients; however, drug resistance during cancer treatment is a critical problem. Survivin is an anti-apoptosis protein, which promotes cell proliferation and tumor growth that highly expressed in various human cancers. Here, we show a novel synthetic compound derived from gefitinib, do-decyl-4-(4-(3-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)propyl) piper-azin-1-yl)-4-oxobutanoate, which is named as SP101 that inhibits survivin expression and tumor growth in both the EGFR-wild type and -T790M of NSCLC. SP101 blocked EGFR kinase activity and induced apoptosis in the A549 (EGFR-wild type) and H1975 (EGFR-T790M) lung cancer cells. SP101 reduced survivin proteins and increased active caspase 3 for inducing apoptosis. Ectopic expression of survivin by a survivin-expressed vector attenuated the SP101-induced cell death in lung cancer cells. Moreover, SP101 inhibited the gefitinib-resistant tumor growth in the xenograft human H1975 lung tumors of nude mice. SP101 substantially reduced survivin proteins but conversely elicited active caspase 3 proteins in tumor tissues. Besides, SP101 exerted anticancer abilities in the gefitinib resistant cancer cells separated from pleural effusion of a clinical lung cancer patient. Consistently, SP101 decreased the survivin proteins and the patient-derived xenografted lung tumor growth in nude mice. Anti-tumor ability of SP101 was also confirmed in the murine lung cancer model harboring EGFR T790M-L858R. Together, SP101 is a new EGFR inhibitor with inhibiting survivin that can be developed for treating EGFR wild-type and EGFR-mutational gefitinib-resistance in human lung cancers. [ABSTRACT FROM AUTHOR]