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Hsuan Huang,1 Hsiao-Ling Su,2 Chih-Hsung Huang,2 Yi-Hsin Lin2 1Division of Pediatric Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan; 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Taiwan Adventist Hospital, Taipei, TaiwanCorrespondence: Yi-Hsin Lin, Division of Endocrinology and Metabolism, Department of Internal Medicine, Taiwan Adventist Hospital, Taipei, Taiwan, Tel +886-2-2771-8151, Email slimesin0709@gmail.comBackground: During the COVID-19 pandemic, the national lockdown had a significant impact on healthcare systems and diabetes management. The results of relevant studies were inconsistent. The aim of the study was to investigate the impact of lockdown on glycemic control among patients with type 2 diabetes mellitus(T2D) in Taiwan.Methods: This was a retrospective study conducted in a single regional hospital in Northern Taiwan. The clinic characteristics of the patients were summarized. Anthropometric and biochemical data before and after the lockdown were collected and analyzed. Stepwise multiple regression analysis was performed to identify the independent determinants of variables, including baseline characteristics and laboratory parameters, for the changes in glycated hemoglobin(HbA1c).Results: A total of 943 (females 48.5%) patients with T2D were enrolled. The mean age of the patients was 60.6± 12.3years, with a mean HbA1c of 7.0± 1.0%, a mean diabetes duration of 7.3± 4.6years, and a mean body mass index(BMI) of 26.5± 4.5kg/m2. The overall means of HbA1c and fasting blood glucose were significantly improved after the lockdown compared to before (7.0± 1.0 vs 6.8± 0.9, p< 0.001 and 132.2± 33.3 vs 124.4± 30.0, p< 0.001, respectively). The proportion of patients achieving HbA1c target (≤ 7%) was higher after the lockdown compared to before (61.5% vs 68.9%, p< 0.001). Stepwise multiple regression analysis revealed that baseline HbA1c before the lockdown was a positive contributor to the change in HbA1c after the lockdown, whereas BMI and co-morbidity with dyslipidemia were negative contributors (standardized coefficient +0.16, p< 0.001; − 0.07, p=0.025; − 0.12, p=0.001, respectively).Conclusion: Our study highlights the benefits of lockdown measures on diabetic control in Northern Taiwan as a single-center experience with the improvement of HbA1c and fasting blood glucose. Understanding these consequences of national lockdown can help healthcare providers to improve diabetes care during the pandemic.Keywords: COVID-19 lockdown, type 2 diabetes mellitus, glycemic control

Shu-Her Chiao,1* Siou-Hong Lin,1* Ching-I Shen,2* Jiunn-Wang Liao,3 I-Jiuan Bau,1 Jiun-Chiou Wei,4 Li-Ping Tseng,1 Shan-hui Hsu,4 Ping-Shan Lai,2 Shinn-Zong Lin,5–7 Jiang-Jen Lin,4 Hong-Lin Su,1,8 1Department of Life Sciences, Agricultural Biotechnology Center, National Chung Hsing University, 2Department of Chemistry, Agricultural Biotechnology Center, National Chung Hsing University, 3Graduate Institute of Veterinary Pathobiology, Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan; 4Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan; 5Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan; 6Department of Neurosurgery, China Medical University Beigan Hospital, Yunlin, Taiwan; 7Graduate Institute of Immunology, China Medical University, Taichung, Taiwan; 8Department of Physical Therapy, China Medical University, Taichung, Taiwan*These three authors contributed equallyAbstract: Developing effective and safe drugs is imperative for replacing antibiotics and controlling multidrug-resistant microbes. Nanoscale silicate platelet (NSP) and its nanohybrid, silver nanoparticle/NSP (AgNP/NSP), have been developed, and the nanohybrids show a strong and general antibacterial activity in vitro. Here, their efficacy for protecting Salmonella-infected chicks from fatality and septicemia was evaluated. Both orally administrated NSP and AgNP/NSP, but not AgNPs alone, effectively reduced the systemic Salmonella infection and mortality. In addition, quantitative Ag analyses demonstrated that Ag deposition from AgNP/NSP in the intestines was less than that from conventional AgNPs, indicating that the presence of NSP for immobilizing AgNPs reduced Ag accumulation in tissue and improved the safety of AgNPs. These in vivo results illustrated that both NSP and AgNP/NSP nanohybrid represent potential agents for controlling enteric bacterial infections.Keywords: silver, nanoparticle, biocompatibility, infection, cytotoxicity

Background: The family Lauraceae is subdivided into six main lineages: Caryodaphnopsideae, Cassytheae, Cryptocaryeae, Hypodaphnideae, Laureae, and Neocinnamomeae. However, phylogenetic relationships among these lineages have been debatable due to incongruence between trees constructed using nuclear ribosomal DNA (nrDNA) sequences and chloroplast (cp) genomes. As with cp DNA, the mitochondrial (mt) DNA of most flowering plants is maternally inherited, so the phylogenetic relationships recovered with mt genomes are expected to be consistent with that from cp genomes, rather than nrDNA sequences., Results: The mitogenome of Machilus yunnanensis, with a length of 735,392 bp, has a very different genome size and gene linear order from previously published magnoliid mitogenomes. Phylogenomic reconstructions based on 41 mt genes from 92 Lauraceae mitogenomes resulted in highly supported relationships: sisterhood of the Laureae and a group containing Neocinnamomeae and Caryodaphnopsideae, with Cassytheae being the next sister group, followed by Cryptocaryeae. However, we found significant incongruence among the mitochondrial, chloroplast, and nuclear phylogenies, especially for the species within the Caryodaphnopsideae and Neocinnamomeae lineages. Time-calibrated phylogenetic analyses showed that the split between Caryodaphnopsideae and Neocinnamomeae dated to the later Eocene, around 38.5 Ma, Laureae originated in the Late Cretaceous, around 84.9 Ma, Cassytheae originated in the mid-Cretaceous around 102 Ma, and Cryptocaryeae originated in the Early Cretaceous around 116 Ma. From the Late Cretaceous to the Paleocene, net diversification rates significantly increased across extant clades of major lineages, and both speciation rates and net diversification rates continued steady growth towards the present., Conclusions: The topology obtained here for the first time shows that mt genes can be used to support relationships among lineages of Lauraceae. Our results highlight that both Caryodaphnopsideae and Neocinnamomeae lineages are younger than previously thought, likely first diversifying in the Eocene, and species in the other extant lineages of Lauraceae dates in a long-time span from the Early Cretaceous to the Eocene, and the climate of a period of about 90 million years was relatively warm, while the extant species of Lauraceae then continuously diversified with global cooling from the Eocene to the present day., (© 2024. The Author(s).)

Background: Neoadjuvant immunotherapy with chemotherapy improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Given its immunomodulating effect, we investigated whether stereotactic body radiotherapy (SBRT) enhances the effect of immunochemotherapy., Methods: The SACTION01 study was a single-arm, open-label, phase 2 trial that recruited patients who were 18 years or older and had resectable stage IIA-IIIB NSCLC from the Sun Yat-sen University Cancer Center, Guangzhou, China. Eligible patients received SBRT (24 Gy in three fractions) to the primary tumour followed by two cycles of 200 mg intravenous PD-1 inhibitor, tislelizumab, plus platinum-based chemotherapy. Surgical resection was performed 4-6 weeks after neoadjuvant treatment. The primary endpoint was major pathological response (MPR), defined as no more than 10% residual viable tumour in the resected tumour. All analyses were conducted on an intention-to-treat basis, including all patients who were scheduled for neoadjuvant treatment. The trial was registered with ClinicalTrials.gov (NCT05319574) and is ongoing but closed to recruitment., Findings: Between May 18, 2022, and June 20, 2023, 46 patients (42 men and four women) were enrolled and scheduled for neoadjuvant treatment. MPR was observed in 35 (76%, 95% CI 61-87) of 46 patients. The second cycle of immunochemotherapy was withheld in four (9%) patients due to pneumonia (n=2), colitis (n=1), and increased creatinine (n=1). Grade 3 or worse adverse events related to neoadjuvant treatment occurred in 12 (26%, 95% CI 14-41) patients. The most frequent treatment-related adverse event (TRAE) was alopecia (16 [35%] patients), and the most frequent grade 3 or worse TRAE was neutropenia (six [13%]). There was one treatment-related death, caused by neutropenia. No deaths within 90 days of surgery were reported., Interpretation: Preoperative SBRT followed by immunochemotherapy is well tolerated, feasible, and leads to a clinically significant MPR rate. Future randomised trials are warranted to support these findings., Funding: BeiGene., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Functional recovery following the surgical fixation of acetabular posterior wall fractures remains a challenge. This study compares outcomes of posterior wall fracture reconstruction using an anatomical posterior acetabular plate (APAP) versus conventional reconstruction plates. Methods: Forty patients with acetabular fractures involving the posterior wall or column underwent surgery, with 20 treated using APAPs (APAP group) and 20 with conventional pelvic reconstruction plates (control group). Baseline patient characteristics, intraoperative blood loss and time, reduction quality, postoperative function, and postoperative complications were compared using appropriate non-parametric statistical tests. A general linear model for repeated measures analysis of variance was employed to analyze trends in functional recovery. Results: No significant differences were observed in baseline characteristics. APAP significantly reduced surgical time by 40 min (186.5 ± 51.0 versus 225.0 ± 47.7, p =0.004) and blood loss (695 ± 393 versus 930 ± 609, p = 0.049) compared to conventional plates. At 3 and 6 months following surgery, the APAP group exhibited higher functional scores (modified Merle d'Aubigné scores 10 ± 1.8 versus 7.8 ± 1.4, p < 0.001; 13.4 ± 2.8 versus 10.1 ± 2.1, p = 0.001), converging with the control group by 12 months (modified Merle d'Aubigné scores 14.2 ± 2.6 versus 12.7 ± 2.6, p = 0.072; OHS 31.6 ± 12.3 versus 30.3 ± 10.1, p = 0.398). Radiologically, the APAP group demonstrated superior outcomes ( p = 0.047). Complication and conversion rates to hip arthroplasty did not significantly differ between groups (10% versus 15%, p = 0.633). Conclusions : The use of an APAP in reconstructing the posterior acetabulum significantly reduces surgical time, decreases intraoperative blood loss, and leads to earlier functional recovery compared to conventional reconstruction plates. The APAP provides stable fixation of the posterior wall and ensures the durable maintenance of reduction, ultimately yielding favorable surgical outcomes.

Background: This study aimed to explore the expression level and transcriptional regulation mechanism of Extra Spindle Pole Bodies Like 1 (ESPL1) in bladder cancer (BC)., Methods: A multicentre database of samples (n = 1391) was assayed for ESPL1 mRNA expression in BC and validated at the protein level by immunohistochemical (IHC) staining of in-house samples (n = 202). Single-cell sequencing (scRNA-seq) analysis and enrichment analysis explored ESPL1 distribution and their accompanying molecular mechanisms. ATAC-seq, ChIP-seq and Hi-C data from multiple platforms were used to investigate ESPL1 upstream transcription factors (TFs) and potential epigenetic regulatory mechanisms. Immune-related analysis, drug sensitivity and molecular docking of ESPL1 were also calculated. Furthermore, upstream microRNAs and the binding sites of ESPL1 were predicted. The expression level and early screening efficacy of miR-299-5p in blood (n = 6625) and tissues (n = 537) were examined., Results: ESPL1 was significantly overexpressed at the mRNA level (p < 0.05, SMD = 0.75; 95 % CI = 0.09, 1.40), and IHC staining of in-house samples verified this finding ( p  < 0.0001). ESPL1 was predominantly distributed in BC epithelial cells. Coexpressed genes of ESPL1 were enriched in cell cycle-related signalling pathways, and ESPL1 might be involved in the communication between epithelial and residual cells in the Hippo, ErbB, PI3K-Akt and Ras signalling pathways. Three TFs (H2AZ, IRF5 and HIF1A) were detected upstream of ESPL1 and presence of promoter-super enhancer and promoter-typical enhancer loops. ESPL1 expression was correlated with various immune cell infiltration levels. ESPL1 expression might promote BC growth and affect the sensitivity and therapeutic efficacy of paclitaxel and gemcitabine in BC patients. As an upstream regulator of ESPL1, miR-299-5p expression was downregulated in both the blood and tissues, possessing great potential for early screening., Conclusions: ESPL1 expression was upregulated in BC and was mainly distributed in epithelial cells. Elevated ESPL1 expression was associated with TFs at the upstream transcription start site (TSS) and distant chromatin loops of regulatory elements. ESPL1 might be an immune-related predictive and diagnostic marker for BC, and the overexpression of ESPL1 played a cancer-promoting role and affected BC patients' sensitivity to drug therapy. miR-299-5p was downregulated in BC blood and tissues and was also expected to be a novel marker for early screening., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Background: Esculentin-1, initially discovered in the skin secretions of pool frogs (Pelophylax lessonae), has demonstrated broad-spectrum antimicrobial activity; however, its immunomodulatory properties have received little attention., Results: In the present study, esculentin-1 cDNA was identified by analysing the skin transcriptome of the dark-spotted frog (Pelophylax nigromaculatus). Esculentin-1 from this species (esculentin-1PN) encompasses a signal peptide, an acidic spacer peptide, and a mature peptide. Sequence alignments with other amphibian esculentins-1 demonstrated conservation of the peptide, and phylogenetic tree analysis revealed its closest genetic affinity to esculentin-1P, derived from the Fukien gold-striped pond frog (Pelophylax fukienensis). Esculentin-1PN transcripts were observed in various tissues, with the skin exhibiting the highest mRNA levels. Synthetic esculentin-1PN demonstrated antibacterial activity against various pathogens, and esculentin-1PN exhibited bactericidal activity by disrupting cell membrane integrity and hydrolyzing genomic DNA. Esculentin-1PN did not stimulate chemotaxis in RAW264.7, a murine leukemic monocyte/macrophage cell line. However, it amplified the respiratory burst and augmented the pro-inflammatory cytokine gene (TNF-α and IL-1β) expression in RAW264.7 cells., Conclusions: This novel finding highlights the immunomodulatory activity of esculentin-1PN on immune cells., (© 2024. The Author(s).)

Mycobacteria are causative agents of tuberculosis (TB), which is a global health concern. Drug-resistant TB strains are rapidly emerging, thereby necessitating the urgent development of new drugs. Two-component signal transduction systems (TCSs) are signaling pathways involved in the regulation of various bacterial behaviors and responses to environmental stimuli. Applying specific inhibitors of TCSs can disrupt bacterial signaling, growth, and virulence, and can help combat drug-resistant TB. We conducted a comprehensive pharmacophore-based inhibitor screening and biochemical and biophysical examinations to identify, characterize, and validate potential inhibitors targeting the response regulators PhoP and MtrA of mycobacteria. The constructed pharmacophore model Phar-PR-n4 identified effective inhibitors of formation of the PhoP-DNA complex: ST132 (IC 50 = 29 ± 1.6 µM) and ST166 (IC 50 = 18 ± 1.3 µM). ST166 (KD = 18.4 ± 4.3 μM) and ST132 (KD = 14.5 ± 0.1 μM) strongly targeted PhoP in a slow-on, slow-off manner. The inhibitory potency and binding affinity of ST166 and ST132 for MtrAC were comparable to those of PhoP. Structural analyses and molecular dynamics simulations revealed that ST166 and ST132 mainly interact with the α8-helix and C-terminal β-hairpin of PhoP, with functionally essential residue hotspots for structure-based inhibitor optimization. Moreover, ST166 has in vitro antibacterial activity against Macrobacterium marinum . Thus, ST166, with its characteristic 1,2,5,6-tetrathiocane and terminal sulphonic groups, has excellent potential as a candidate for the development of novel antimicrobial agents to combat pathogenic mycobacteria., Competing Interests: There are no conflicts of interest to declare., (© 2024 The Authors.)

Low back pain (LBP) is a leading cause of long-term disability globally. Intervertebral disk degeneration (IVDD) is mainly responsible for discogenic pain in LBP-affected young patients. There is no effective therapy to reverse disease severity and IVDD progression. This study investigates the effect of human peripheral blood-derived mononuclear cells (PBMCs) on pain relief and life quality improvement in IVDD patients. The enriched monocytes of the PBMCs could differentiate into CD14 and CD206 double-positive M2 macrophages in vitro . Preclinical evidence in rats showed that the transplanted PBMCs exhibited anti-inflammatory and moderate tissue-repair effects on controlling IVDD progress in the rat model. The PBMCs significantly steered the aggrecan and type II collagen expressions and attenuated the pro-inflammatory cytokines in the affected disk. Based on the animal results, 36 patients with chronic low back pain (CLBP) were included in clinical trials. The control group was conservative care only, and the experimental group was platelet-rich plasma (PRP) and PBMCs intradiscal injections. We first confirmed the single lumbar disk causing the discogenic pain by provocative discography or magnetic resonance imaging (MRI). Discogenic LBP participants received one intradiscal injection of autologous PBMCs and followed for 6 months. Our clinical trial showed that patients' LBP and disability were significantly ameliorated after the PBMCs transplantation rather than PRP. These preclinical and pilot clinical studies indicate that intradiscal injection of the enriched PBMCs might be a feasible and potential cell therapy to control pain and disability in IVDD patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors have the following competing interests. The technology transfer office of National Chung Hsing University has received consultancy, speaker fees, and research grants on behalf of H-LS from Duogenic StemCells Corporation and Hualien Tzu Chi Medical Center. F-HW, C-YH, and C-IS are employees of Duogenic StemCells Corporation. F-HW, C-YH, C-IS, H-LS, and C-LL are shareholders of Duogenic StemCells Corporation. Y-HC, M-HH, S-CK, Y-HK, C-HC, and D-WCC have no conflict of interest with respect to the research, authorship, and publication of this article. Patents, products in development, and marketing products are associated with this research.

Extensive research has been conducted on the spectral properties of chromeno[4,3-b]pyridine derivatives, owing to their potential applications in sensing, optoelectronic devices, and drug discovery. This study presents a comprehensive investigation into the fluorosolvatochromism of selected chromeno[4,3-b]pyridine derivatives, with a particular emphasis on the impact of methoxy substitution. Three derivatives were synthesized and subjected to spectral analysis: chromeno[4,3-b]pyridine-3-carboxylate (I) as the parent compound, and its 7-methoxy (II) and 8-methoxy (III) substituted derivatives.The UV-Vis absorption spectra of all derivatives exhibited a broad band with a maximum absorption wavelength that remained unaffected by the surrounding medium. However, distinct fluorescence properties were observed among them. Specifically, derivative II displayed notable fluorescence, while derivatives I and III exhibited no fluorescence properties. Furthermore, derivative II exhibited a fluorescence spectrum that is significantly influenced by the polarity of the medium. To investigate the fluorosolvatochromic behavior in depth, we conducted a comprehensive analysis using various neat solvents with different polarities and hydrogen bonding capabilities. The results obtained revealed a significant positive fluorosolvatochromism, with a bathochromic shift in the fluorescence spectrum as the solvent polarity increased. To understand how specific and non-specific interactions between the solute and the solvent affected the fluorosolvatochromism of II, we employed the four empirical scales model of Catalán. The obtained results demonstrated that intramolecular charge transfer played a crucial role in the fluorescence behavior of II. To provide a molecular-level explanation for the experimental spectral properties, we utilized the DFT and TD-DFT/B3LYP/6-31 + G(d) computational methods with the IEFPCM implicit solvation approach. The spectral differences between II and III were rationalized in terms of the frontier molecular orbitals (FMOs: the HOMO and LUMO), where distinct natures were observed among the examined derivatives. This study offers valuable insights into the impact of methoxy substitution on the physical and chemical properties of chromeno[4,3-b]pyridine derivatives, specifically concerning their spectral properties as elucidated by their fluorosolvatochromic behavior., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The multidimensional mixture data structure exists in many test (or inventory) conditions. Heterogeneity also relatively exists in populations. Still, some researchers are interested in deciding to which subpopulation a participant belongs according to the participant's factor pattern. Thus, in this study, we proposed three analysis procedures based on the factor mixture model to analyze data in the multidimensional mixture context. Simulations were manipulated with different levels of factor numbers, factor correlations, numbers of latent classes, and class separation. Issues with regard to model selection were discussed at first. The results showed that in the two-class situations the procedures of "factor structure first then class number" (Procedure 1) and "factor structure and class number considered simultaneously" (Procedure 3) performed better than the "class number first then factor structure" (Procedure 2) and yielded precise parameter estimation and classification accuracy. It would be appropriate to choose Procedures 1 and 3 when strong measurement invariance is assumed while using an information criterion, but Procedure 1 saved more time than Procedure 3. In the three-class situations, the performance of all three procedures was limited. Implementations and suggestions have been addressed in this research., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

A novel bis-phenylurea-based aliphatic amine (BPUA) was prepared via a facile synthetic route, and evaluated as a potential green organic corrosion inhibitor for carbon steel in 1.0 M HCl solutions. NMR spectroscopy experiments confirmed the preparation of the targeted structure. The corrosion inhibitory behavior of the prospective green compound was explored experimentally by electrochemical methods and theoretically by DFT-based quantum chemical calculations. Obtained results revealed an outstanding performance of BPUA, with efficiency of 95.1% at the inhibitor concentration of 50 mg L -1  at 25 °C. The novel compound has improved the steel resistivity and noticeably reduced the corrosion rate from 33 to 1.7 mils per year. Furthermore, the adsorption study elucidates that the mechanism of the corrosion inhibition activity obeys Langmuir isotherm with mixed physisorption/chemisorption modes for BPUA derivatives on the steel surface. Calculated Gibb's free energy of the adsorption process ranges from -35 to -37 kJ mol -1 . The SEM morphology analysis validates the electrochemical measurements and substantiates the corrosion-inhibiting properties of BPUA. Additionally, the eco-toxicity assessment on human epithelial MCF-10A cells proved the environmental friendliness of the BPUA derivatives. Density functional theory (DFT) calculations correlated the inhibitor's chemical structure with the corresponding inhibitory behavior. Quantum descriptors disclosed the potentiality of BPUA adsorption onto the surface through the heteroatom-based functional groups and aromatic rings., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Objective: To use the spatiotemporal distribution model and INLA algorithm to study the spatiotemporal characteristics and influencing factors of tuberculosis in Shanghai and to provide a theoretical basis for formulating regional tuberculosis epidemic prevention and control measures. Methods: Based on the data of registered pulmonary tuberculosis cases in Shanghai during 2013-2020 derived from the tuberculosis management information system of China Disease Control and Prevention Information System, the hierarchical Bayesian model was adopted to fit the tuberculosis case data, identify the spatiotemporal variation characteristics of tuberculosis, and explore the potential socioeconomic characteristics and other factors related to health services and spatiotemporal characteristics. Results: From 2013 to 2020, 29 281 registered tuberculosis cases were reported in Shanghai, with an average annual incidence of 25.224/100 000. From 2013 to 2020, the incidence trend increased first and then decreased, the highest incidence was reported in 2014 (27.991/100 000). The incidence of tuberculosis in Shanghai is characterized by spatial clustering. Through the spatial characteristics and risk analysis of the reported incidence of tuberculosis, it is found that the high-risk area of tuberculosis in Shanghai is the suburban communities, whereas downtown communities are the low-risk areas. The incidence risk of pulmonary tuberculosis is associated with the gross domestic product per capita ( RR =0.48), the number of beds per 10 000 persons ( RR =0.56), the normalized vegetation index ( RR =0.50), and the night light index ( RR =0.80). Conclusions: With the steady progress of tuberculosis prevention and control in the central urban area of Shanghai, special attention should be paid to the prevention and control in the suburbs further to improve the social and economic level in the suburbs and increase the coverage rate of urban green space, to reduce the incidence of tuberculosis and reduce the disease burden of tuberculosis in Shanghai.

The hard-shelled mussel ( Mytilus coruscus ) has been used as a traditional Chinese medicine and health food in China for centuries. Polysaccharides from mussel has been reported to have multiple biological functions, however, it remains unclear whether mussel polysaccharide (MP) exerts protective effects in intestinal functions, and the underlying mechanisms of action remain unclear. The aim of this study was to investigate the protective effects and mechanism of MP on intestinal oxidative injury in mice. In this study, 40 male BALB/C mice were used, with 30 utilized to produce an animal model of intestinal oxidative injury with intraperitoneal injection of cyclophosphamide (Cy) for four consecutive days. The protective effects of two different doses of MP (300 and 600 mg/kg) were assessed by investigating the change in body weight, visceral index, and observing colon histomorphology. Moreover, the underlying molecular mechanisms were investigated by measuring the antioxidant enzymes and related signaling molecules through ELISA, real-time PCR, and western blot methods. The results showed that MP pretreatment effectively protected the intestinal from Cy-induced injury: improved the colon tissue morphology and villus structure, increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, and reduced malondialdehyde (MDA) content in serum and colon tissues. Meanwhile, MP also significantly increased the expression levels of SOD, GSH-Px, heme oxygenase-1 (HO-1), and nuclear factor E2-related factor 2 (Nrf2) mRNA in colon tissues. Further, western blot results showed that the expression of Nrf2 protein was significantly upregulated while kelch-like ECH-associated protein 1 (Keap1) was significantly downregulated by MP in the colonic tissues. This study indicates that MP can ameliorate Cy-induced oxidative stress injury in mice, and Nrf2-Keap1 signaling pathway may mediate these protective effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Background: Lymph node dissection (LND) is crucial procedure during radical resection of non-small cell lung cancer (NSCLC), but the prognostic value of L4 LND remains elusive. To investigate the prognostic value of L4 LND in patients with left-side NSCLC who underwent video-assisted thoracoscopic surgery (VATS)., Methods: Three hundred twelve patients who underwent VATS between Jan. 2007 and Dec. 2016 were reviewed. Of those, 119 underwent L4 LND (L4 D+ ), whereas the other 193 patients did not (L4 D- ). The inclusion criteria were as follows: patients diagnosed with primary left-sided NSCLC who underwent VATS lobectomy combined with LND; patients subjected to R0 resection and tumor pathological stage T 1-4 N 0-2 M0. The primary endpoint was overall survival (OS). OS was calculated from the operation date to the date of death. The chi-square test was used for categorical variables, and a t test was used for continuous variables., Results: A total of 119 patients underwent L4 LND, and the procedure was more likely to be performed on upper lobe tumors (P=0.019). Patient distributions with respect to age, gender, smoking history, clinical stage, adjuvant therapy, tumor differentiation and tumor size were well balanced between two groups. More lymph nodes (LNs) were dissected in the L4 D+ group than in the L4 D- group (P<0.001). The rate of metastasis to L4 lymph nodes was 9.2%, which was comparable between patients with upper and lower lobe tumors (8.9% vs. 10.0%, P=1.000). The L4 D+ group exhibited a significantly better OS than the L4 D- group (median OS: undefined vs. 130 months, HR 0.47; 95% CI: 0.31-0.72; P=0.002). Multivariate analysis showed that L4 LND was an independent factor for OS. However, OS did not significantly differ between the two groups of cT1aN0 and cT1bN0 patients (OS: HR 0.44; 95% CI: 0.18-1.06; P=0.12)., Conclusions: L4 LND is recommended for patients with left-sided NSCLC as an essential component of radical resection. The role of L4 LND in cT1a-bN0 disease warrants further study., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-18/coif). The authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Cell expansion of human pluripotent stem cells (hPSCs) commonly depends on Matrigel as a coating matrix on two-dimensional (2D) culture plates and 3D microcarriers. However, the xenogenic Matrigel requires sophisticated quality-assurance processes to meet clinical requirements. In this study, we develop an innovative coating-free medium for expanding hPSCs. The xenofree medium supports the weekend-free culture and competitive growth of hPSCs on several cell culture plastics without an additional pre-coating process. The pluripotent stemness of the expanded cells is stably sustained for more than 10 passages, featured with high pluripotent marker expressions, normal karyotyping, and differentiating capacity for three germ layers. The expression levels of some integrins are reduced, compared with those of the hPSCs on Matrigel. This medium also successfully supports the clonal expansion and induced pluripotent stem cell establishment from mitochondrial-defective MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) patient's peripheral blood mononuclear cells. This innovative hPSC medium provides a straightforward scale-up process for producing clinical-orientated hPSCs by excluding the conventional coating procedure.

Osteoarthritis (OA) is a common chronic skeletal disease in the elderly. There is no effective therapy to reverse disease severity and knee OA (KOA) progression, particularly at the late stage. This study aims to examine the effect of peripheral blood-derived mononuclear cells (PBMNCs) on pain and motor function rescue in patients with Kellgren-Lawrence (KL) grade II to IV KOA. Participants received one intra-articular (IA) injection of autologous PBMNCs. The mononuclear cells were isolated from peripheral blood, enriched by a specialized medium (MoFi medium), and separated by Ficoll-Paque solution. The isolated and enriched PBMNCs could differentiate into M1 and M2 macrophages in vitro . The in vivo anti-inflammatory effect of the PBMNCs was similar to that of bone marrow mesenchymal stem cells, evaluated by complete Freund's adjuvant-induced arthritis in rodents. A single-arm and open-label pilot study showed that patients' knee pain and motor dysfunction were significantly attenuated after the cell transplantation, assessed by visual analogue scale (VAS) and Knee injury and Osteoarthritis Outcome Score (KOOS) at 6 and 12 months post-treatment. Notably, the therapeutic effect of the PBMNCs treatment can be stably maintained for 24 months, as revealed by the KOOS scores. These preclinical and pilot clinical data suggest that IA injection of MoFi-PBMNCs might serve as a novel medical technology to control the pain and the progress of KOA.

The human type II collagen (Col II), specifically expressed in chondrocytes, is a crucial component of the adult hyaline cartilage. We examine the potential of artificial induction of Col II in human peripheral blood mononuclear cells (PBMNCs) as a novel Col II provider. Human PBMNCs were purified and were treated with high doses of macrophage-colony stimulating factor (M-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), or granulocyte-colony stimulating factor (G-CSF) and examined the Col II expression at indicated days. Quantitative Col II expression was validated by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), immunocytochemistry, and flow cytometry. We demonstrate that monocytes in PBMNCs can be artificially induced to express both Col II proteins and M2 macrophage markers by the high concentration of colony-stimulating factors, especially M-CSF and GM-CSF. The Col II proteins were detected on the cell membrane and in the cytoplasm by flow cytometry and immunocytostaining. Combination with IL-4 provided a synergistic effect with M-CSF/GM-CSF to trigger Col II expression in M2 macrophages. These CD206 and Col II double-expressing cells, named modified macrophages, share M2 macrophages' anti-inflammatory potency. We demonstrated that the modified macrophages could significantly attenuate the inflammatory progress of Complete Freund's adjuvant (CFA)-induced arthritis and collagen-induced arthritis in rodents. Here, we provide the first evidence that a modified macrophage population could ectopically express Col II and control the progress of arthritis in animals., (© 2022. The Author(s).)

Retinal pigmented epithelial (RPE) cells possess high mitochondria content for energy production, which is required for phagocytosis and vision cycle metabolism. The mitochondrial integrity in RPE cells helps the homeostasis of photoreceptor turnover and prevents retina aging and degeneration. Mitochondrial transplantation benefits the recovery of several acute inflammatory diseases, leading us to investigate the effects of mitochondrial transplantation on retina degeneration. Allogeneic mitochondria were isolated and delivered into the vitreous chamber in the Royal College of Surgeons (RCS) rats, which exhibit inherited and early-onset retina degeneration. The progress of retina degeneration was examined with optical coherence tomography (OCT) and visual evoked potential (VEP) to determine the retina thickness and integrity of afferent electrical signals from affected eyes, respectively. We found that mitochondria engraftment moderately attenuated the degeneration of retinal layers in RCS rats by histological examination. This result was consistent with the OCT measurement of retina thickness around the optic disc. The VEP analysis revealed that the peak one (N1) latency, representing the arriving time of electrical impulse from the retina to cortex, was substantially maintained as the normal value after the mitochondrial transplantation. This result suggests that the intra-vitreous transplanted mitochondria ameliorate the degeneration of photoreceptors in RCS rats and might be potential for clinical application.

Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant tumor of the central nervous system. GBM has a very low 5-year survival rate and reaching merely a median of ~15 months even with aggressive treatments. PPARγ (Peroxisome proliferator- activated receptor gamma) agonists (ciglitazone), while being widely used on patients of type 2 diabetes mellitus, also have approved anticancer effects. Their action mechanisms on malignant glioma are not fully understood. The aim of this study is to investigate the potential therapeutic effect of PPARγ agonists on maligant glioma. Glioma cell line and in-vivo/ex-vivo animal model intervened by ciglitazone were used to assess the associated mechanism and therapeutic effect. Our results from in vivo and ex vivo experiments showed that ciglitazone not only inhibited tumor growth and its associated angiogenesis, but it also reduced colony formation and migration of tumors. Ciglitazone inhibited the phosphorylation of STAT3 (signal transducer and activator of transcription 3) (at the point of tyrosine 705 by increasing both the amount and activity of SHP-2 (Src homology region 2-containing protein tyrosine phosphatase 2) proteins, based on evidence obtained from immunoprecipitation and immunohistochemistry. Furthermore, ciglitazone activated proteasomes and lysosomes to degrade cell-cycle-related proteins like Cyclin D1, Cyclin E, CDK2 (Cyclin-dependent kinase 2), and CDK4 (Cyclin-dependent kinase 4). Ciglitazone triggered expressions of LC3 (Microtubule-associated protein 1A/1B-light chain 3) and formation of acidic vesicular organelles (AVOs), both of which were implicated in the autophagy pathway. In conclusion, ciglitazone showed the multiple actions to regulate the growth of glioma, which appeared to be a potential candidate for treating malignant glioma.

Human pluripotent stem cell (hPSC)-derived motor neurons (MNs) act as models for motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy. However, the MN differentiation efficiency and viability following cryopreservation require further development for application in large-scale studies and drug screening. Here, we developed a robust protocol to convert hPSCs into MN cryopreservation stocks (hPSCs were converted into >92% motor neural progenitors and >91% MNs). Near-mature MNs were cryopreserved at a high thawing survival rate and 89% MN marker expression on day 32. Moreover, these MNs exhibited classical electrophysiological properties and neuromuscular junction (NMJ) formation ability within only 4−6 days after thawing. To apply this platform as an MND model, MN stocks were generated from SOD1G85R, SOD1G85G isogenic control, and sporadic ALS hPSC lines. The thawed ALS MNs expressed ALS-specific cytopathies, including SOD1 protein aggregation and TDP-43 redistribution. Thus, a stable and robust protocol was developed to generate ready-to-use cryopreserved MNs without further neuronal maturation processes for application in MND mechanistic studies, NMJ model establishment, and large-scale drug screening.

Flotation is an attractive method for separating the different components of waste printed circuit boards (WPCBs) due to its cleanliness and efficiency. Non-metallic particles (NMPs) with good floatability usually need to be floated, however, it is difficult to achieve complete removal. The effect of particle size on the flotation behavior of NMPs, which is usually ignored in previous studies, is concerned in this paper. Flotation tests and kinetic analysis were carried out to reveal the effect of reagent dosage on flotation characteristics of particles in narrow size fractions. As the fineness decreases, the particles are more likely to be floated. Equally, the finer the particle size, the lower the reagent dosage required to achieve the maximum recovery. For 1-0.5 mm and -0.045 mm, the maximum recovery increased from 42.16% (1500 g/t MIBC) to 97.31% (100 g/t MIBC). Therefore, the feasibility of reducing particle size by grinding to improve floatability was verified. The results show that the reduction of particle size can significantly promote its efficiency of being floated. After grinding treatment, -0.045 mm yields in each size fraction (1-0.5, 0.5-0.25, 0.25-0.125, 0.125-0.074, 0.074-0.045 mm) increased by 22.10%, 28.42%, 30.90%, 64.56%, 89.32%, resulting in an increase of 37.71%, 13.12%, 2.82%, 7.82% and 2.00% in maximum recovery, respectively. It is also proved that the particle size, rather than the resin content, has a more significant effect on the floatability of NMPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To analyze the spatiotemporal characteristics of hand,foot and mouth disease (HFMD) in China, explore the association of socioeconomic, population and health services factors with the incidence of HFMD in China, and provide information for the prevention and control of HFMD. Methods: Bayesian spatiotemporal model was used to fit the data of HFMD, evaluate the spatiotemporal variation of HFMD, and identify the potential association between the risk of HFMD and social, economic, population and health services. Results: From 2011 to 2018, a total of 17 118 050 HFMD cases, including 2 283 deaths, were reported in China. The reported incidence showed a fluctuating increase trend from 2011 to 2014, and a fluctuating decrease trend from 2014 to 2018. Meanwhile, there was a fluctuating decrease trend of mortality rate. The incidence of HFMD had spatial clustering, with the highest incidence in southern China with hot spot and high risk areas, and the lowest incidence in northwestern China where cold spot and low risk areas were found. The risk for HFMD was associated with GDP per capita ( RR =3.54), number of industrial enterprises above designated size of 10 000 people ( RR =1.61), urbanization rate ( RR =3.00), birth rate ( RR =2.36), number of beds in medical institutions per 10 000 people ( RR =3.40), and green area in parks per capita ( RR =0.57). Conclusions: The hotspot area for HFMD prevention and control in China was in the southeast coastal provinces from 2011 to 2018. In order to reduce the incidence of HFMD, it is necessary to increase the green area in parks per capita while accelerating urbanization process.

Karstic landscapes play an important role in biodiversity formation and often contain high levels of endemism. However, site-endemic taxa in karstic landscapes are being threatened by exploitation and weak legal protection. In this study, we describe Odorranaconcelata Wang, Zeng, & Lin, sp. nov. , a limestone karst-restricted odorous frog from northern Guangdong, China. This new species shows distinctive genetic divergence and morphological differences from its congeners. Phylogenetic results suggest that the new species represents an independent lineage that is grouped with O.lipuensis and O.liboensis based on the mitochondrial 16S and 12S ribosomal RNA genes. We recommend the new species be listed as Vulnerable (VU) in the IUCN categorization as it is only known from the type locality with limited microhabitats and is threatened by habitat degradation., (Shi-Shi Lin, Yuan-Hang Li, Hong-Lin Su, Hui Yi, Zhong Pan, Yan-Jun Sun, Zhao-Chi Zeng, Jian Wang.)

Purpose: To examine the trajectory of decisional conflict and anxiety experienced by adolescents after the cancer diagnosis, and explore their perceptions on participation in shared decision-making (SDM)., Design: This longitudinal study used incorporated data from questionnaires and interviews., Methods: Participants recruited from an academic hospital in southern Taiwan ranged in age from 13 to 20 years with a cancer diagnosis within 1 month and received cancer treatment. Each participant completed questionnaires on decisional conflict and anxiety at diagnosis, 1, 3, and 6 months later. Individual interviews were to gain an in-depth understanding of SDM., Findings: Total scores on decisional conflict changed significantly over time (F = 2.98, p = 0.039); the scores at 1 month were higher than 3 months (t = 2.18, p = 0.04) and 6 months (t = 2.97, p = 0.008). Participants perceived significantly different levels of values clarify (F = 9.49, p < 0.01) and support (F = 8.46, p < 0.01) over time. Only 27.3% of participants were anxiety-free. No significant differences were found in anxiety over time. The perception of SDM was a situational involvement., Conclusions: Decisional conflict changed over time. Participants experienced greater decisional conflict at 4-8 weeks after diagnosis and their anxiety did not decrease over time. The different levels of participation in SDM during their treatment trajectory were found., Clinical Relevance: Participants experienced the highest decisional conflict during diagnosis, and highlighted how their roles in healthcare discussions varied from direct participation to indirect involvement. Further research is needed to develop an SDM model which accommodates different levels of needs and implements timely support., (© 2022 Sigma Theta Tau International.)

Cordyceps militaris (CM) is a popular medicinal fungus; however, few studies have focused on its impact on the male reproductive system. We evaluated the effects of CM fermentation products on the reproductive development of juvenile male (JM) mice. Mice were divided into four experimental groups, each fed 5% CM products (weight per weight (w/w) in normal diet): extracellular polysaccharides (EPS), fermentation broth (FB), mycelia (MY), and whole fermentation products (FB plus MY, FBMY) for 28 days, while mice in the control group (CT) were fed a normal diet. Basic body parameters, testicular structure, sperm parameters, and sex hormones concentrations were analyzed. Compared to the CT group, mice in the EPS, MY, and FBMY groups showed a significantly increased mean seminiferous tubule area (p < 0.05), mice in the FB and MY groups had significantly higher sperm concentrations (p < 0.05), and mice in the EPS, FB, and FBMY groups showed significantly increased ratios of motile sperm (p < 0.05). Meanwhile, EPS significantly promoted the ability of JM mice to synthesize testosterone (p < 0.05). Furthermore, all CM products significantly increased the food intake of JM mice (p < 0.05) but did not significantly change their water intake and body weight gain (p > 0.05). In conclusion, CM products, especially EPS, exhibit strong androgen-like activities that can promote male reproductive development., (© 2022. The Author(s).)

Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by bladder pain accompanied by irritative urinary symptoms, and typical cystoscopic and histological features. In this pilot study, we assessed the impact of lesion-targeted bladder injection therapy using a biocellular regenerative medicine on patients with refractory IC/BPS. The medicine, which was an autologous emulsified fat (Nanofat) and platelet-rich plasma (PRP) combination, was prepared intraoperatively. Six patients (aged 40-54 years), who completed a standard protocol of four consecutive treatments at 3-month intervals, were followed up at 6 months postoperatively. All patients (100%) reported marked (+3; +3 ~ -3) improvement of their overall bladder conditions. Mean bladder pain (from 8.2 to 1.7; range: 0 ~ 10), IC-related symptoms (from 18.5 to 5.7; range: 0 ~ 20), and bother (from 14.8 to 3.8; range: 0 ~ 16) improved significantly (p < 0.01). The normalization of bladder mucosal morphology with treatments was remarkable under cystoscopic examination, and no significant adverse events were found. The cultured mesenchymal stem cells from Nanofat samples of the six patients were verified in vitro. Our preliminary results suggest novel intravesical therapy with autologous Nanofat plus PRP grafting is safe and effective for refractory IC/BPS. Surgical efficacy might be attributed to an in vivo tissue engineering process., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Objective: To evaluate the short-term efficacy and perioperative safety of catheter-based intervention in patients with pulmonary vein stenosis caused by fibrosing mediastinitis (FM). Methods: It was a case series study. Consecutive patients with pulmonary vein stenosis caused by FM, who underwent percutaneous pulmonary vein angioplasty in Gansu Provincial Hospital from January 2018 to June 2020, were retrospective enrolled. The baseline characteristics, comorbidities, exercise capacity and hemodynamic data before and after treatment were compared, and the procedural related complications were evaluated. Results: A total of 30 patients ((64.3±7.1) years, 15 males) were included. Sixty-three pulmonary vein stenosis were treated by 32 percutaneous pulmonary vein angioplasty procedures. Forty-four stents were implanted in 41 pulmonary veins after balloon angioplasty, and the diameter of implanted stents was (8.3±1.2)mm. Balloon angioplasty was performed on 22 pulmonary vein stenosis, the mean balloon diameter was (4.2±2.1)mm. The pulmonary vein diameter increased from (2.6±1.3) to (6.6±2.6) mm ( P <0.001) and the pressure gradient across the pulmonary vein stenotic segment reduced from 19 (12, 29) to 2 (0, 4) mmHg (1 mmHg=0.133 kPa) ( P <0.001) immediately post procedure. The pulmonary vein flow grade was significantly improved compared with baseline ( P <0.001). The most common operation related complications were lung injury (44.0% (11/25)) and hemoptysis (18.8% (6/32)), which did not need special treatment. During the 2.0 (1.3, 3.2) months follow-up, the WHO functional class was significantly improved ( P <0.05), the 6-minute walking distance increased from (254.8±114.5) m to (342.8±72.4)m ( P <0.05), the mean pulmonary arterial pressure decreased from (40.9±8.3) mmHg to (35.4±7.7) mmHg ( P <0.01), 17 out of 19 patients with refractory pleural effusion experienced total remission during the follow-up period ( P <0.001). CT pulmonary venography was repeated in 17 patients. The incidence of in-stent restenosis of pulmonary vein was 24.0% (6/25). Conclusions: Percutaneous pulmonary vein angioplasty is effective for the treatment of pulmonary vein stenosis caused by fibrosing mediastinitis. However, it ' s not so safe, procedural related complication should be paid attention to and the rate of in-stent restenosis is relative high during the short-term follow-up.

Background: Adolescents have autonomous views and participatory rights. There is increasing support for involving adolescents with cancer in the healthcare decision-making process., Aims: The purpose of this study was to synthesize current knowledge to identify major components and outcomes of interventions to enhance shared decision-making (SDM) by adolescents with cancer during and after treatment., Methods: Six electronic databases (PubMed, CINHAL, MEDLINE, Cochrane, EBSCO, and Web of Science) were searched from their inceptions to February 2020. Eligibility criteria were intervention studies, studies of interventions to support adolescents with cancer involved in SDM, and studies of patients diagnosed with cancer between 10 and 18 years of age. Data extraction and quality appraisal were conducted by using a standardized data extraction form. Quality appraisal was based on the Cochrane Risk of Bias Tool., Results: Of 331 citations, five studies with a total of 648 participants aged between 13 and 21 years met inclusion criteria. Interventions included structured sessions held one to three times per week. SDM engagement strategies incorporated weekly assignments, live action videos, brochures, Five Wishes © advance directives, and follow-up counseling. Treatment preference congruence in adolescent and parent dyads was higher in intervention groups. Meta-analysis was performed on two studies and demonstrated statistically significant improvements in decision quality at 6 months (z = 3.37, p = .001; 95% CI = .174-.657) and 12 months (z = 3.17, p = .002; 95% CI = .150-.633) after SDM interventions in adolescent cancer survivors. No adverse events among patients were found, although anxiety scores increased in families in an intervention group., Linking Evidence to Action: This review identified essential components of SDM interventions. Our findings may guide the future design of interventions to support high-quality decision-making by adolescents with cancer. Coaching can educate adolescent cancer survivors on quality decision-making methods and can improve the quality of consequent decisions. More research is needed to determine outcomes of SDM interventions., (© 2021 Sigma Theta Tau International.)

Human parechovirus type 3 (PeV-A3) infection has been recognized as an emerging etiologic factor causing severe nerve disease or sepsis in infants and young children. But the neuropathogenic mechanisms of PeV-A3 remain unknown. To understand the pathogenesis of PeV-A3 infection in the neuronal system, PeV-A3-mediated cytopathic effects were analyzed in human glioblastoma cells and neuroblastoma cells. PeV-A3 induced interferons and inflammatory cytokine expression in these neuronal cells. The pronounced cytopathic effects accompanied with activation of death signaling pathways of apoptosis, autophagy, and pyroptosis were detected. A new experimental disease model of parechovirus encephalitis was established. In the disease model, intracranial inoculation with PeV-A3 in C57BL/6 neonatal mice showed body weight loss, hindlimb paralysis, and approximately 20% mortality. PeV-A3 infection in the hippocampus and cortex regions of the neonatal mouse brain was revealed. Mechanistic assay supported the in vitro results, indicating detection of PeV-A3 replication, inflammatory cytokine expression, and death signaling transduction in mouse brain tissues. These in vitro and in vivo studies revealed that the activation of death signaling and inflammation responses is involved in PeV-A3-mediated neurological disorders. The present results might account for some of the PeV-A3-associated clinical manifestations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jan, Su, Chang and Tsai.)

Background: Actual long-term survival rates for advanced epithelial ovarian cancer (EOC) are rarely reported., Objective: This study aimed to assess the role of histological subtypes in predicting the prognosis among long-term survivors (≥5 years) of advanced EOC., Methods: We performed a retrospective analysis of data among patients with stage III-IV EOC diagnosed from 2000 to 2014 using the Surveillance, Epidemiology, and End Results cancer data of the United States. We used the chi-square test, Kaplan-Meier analysis, and multivariate Cox proportional hazards model for the analyses., Results: We included 8050 patients in this study, including 6929 (86.1%), 743 (9.2%), 237 (2.9%), and 141 (1.8%) patients with serous, endometrioid, clear cell, and mucinous tumors, respectively. With a median follow-up of 91 months, the most common cause of death was primary ovarian cancer (80.3%), followed by other cancers (8.1%), other causes of death (7.3%), cardiac-related death (3.2%), and nonmalignant pulmonary disease (3.2%). Patients with the serous subtype were more likely to die from primary ovarian cancer, and patients with the mucinous subtype were more likely to die from other cancers and cardiac-related disease. Multivariate Cox analysis showed that patients with endometrioid (hazard ratio [HR] 0.534, P<.001), mucinous (HR 0.454, P<.001), and clear cell (HR 0.563, P<.001) subtypes showed better ovarian cancer-specific survival than those with the serous subtype. Similar results were found regarding overall survival. However, ovarian cancer-specific survival and overall survival were comparable among those with endometrioid, clear cell, and mucinous tumors., Conclusions: Ovarian cancer remains the primary cause of death in long-term ovarian cancer survivors. Moreover, the probability of death was significantly different among those with different histological subtypes. It is important for clinicians to individualize the surveillance program for long-term ovarian cancer survivors., (©Shi-Ping Yang, Hui-Luan Su, Xiu-Bei Chen, Li Hua, Jian-Xian Chen, Min Hu, Jian Lei, San-Gang Wu, Juan Zhou. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 17.11.2021.)

Amyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes motor neuron (MN) degeneration and results in patient death within a few years. To recapitulate the cytopathies of ALS patients' MNs, SOD1 G85R mutant and corrected SOD1 G85G isogenic-induced pluripotent stem cell (iPSC) lines were established. Two SOD1 mutant ALS ( SOD1 G85R and SOD1 D90A ), two SOD1 mutant corrected ( SOD1 G85G and SOD1 D90D ), and one sporadic ALS iPSC lines were directed toward MNs. After receiving ~90% purity for MNs, we first demonstrated that SOD1 G85R mutant ALS MNs recapitulated ALS-specific nerve fiber aggregates, similar to SOD1 D90A ALS MNs in a previous study. Moreover, we found that both SOD1 mutant MNs showed ALS-specific neurite degenerations and neurotransmitter-induced calcium hyperresponsiveness. In a small compound test using these MNs, we demonstrated that gastrodin, a major ingredient of Gastrodia elata , showed therapeutic effects that decreased nerve fiber cytopathies and reverse neurotransmitter-induced hyperresponsiveness. The therapeutic effects of gastrodin applied not only to SOD1 ALS MNs but also to sporadic ALS MNs and SOD1 G93A ALS mice. Moreover, we found that coactivation of the GSK3β and IGF-1 pathways was a mechanism involved in the therapeutic effects of gastrodin. Thus, the coordination of compounds that activate these two mechanisms could reduce nerve fiber cytopathies in SOD1 ALS MNs. Interestingly, the therapeutic role of GSK3β activation on SOD1 ALS MNs in the present study was in contrast to the role previously reported in research using cell line- or transgenic animal-based models. In conclusion, we identified in vitro ALS-specific nerve fiber and neurofunctional markers in MNs, which will be useful for drug screening, and we used an iPSC-based model to reveal novel therapeutic mechanisms (including GSK3β and IGF-1 activation) that may serve as potential targets for ALS therapy.

Different types of cells, such as endothelial cells, tumor-associated fibroblasts, pericytes, and immune cells, release extracellular vesicles (EVs) in the tumor microenvironment. The components of EVs include proteins, DNA, RNA, and microRNA. One of the most important functions of EVs is the transfer of aforementioned bioactive molecules, which in cancer cells may affect tumor growth, progression, angiogenesis, and metastatic spread. Furthermore, EVs affect the presentation of antigens to immune cells via the transfer of nucleic acids, peptides, and proteins to recipient cells. Recent studies have also explored the potential application of EVs in cancer treatment. This review summarizes the mechanisms by which EVs regulate melanoma development, progression, and their potentials to be applied in therapy. We initially describe vesicle components; discuss their effects on proliferation, anti-melanoma immunity, and drug resistance; and finally focus on the effects of EV-derived microRNAs on melanoma pathobiology. This work aims to facilitate our understanding of the influence of EVs on melanoma biology and initiate ideas for the development of novel therapeutic strategies.

Although clinically approved hepatitis B virus (HBV) polymerase inhibitors (lamivudine-3TC, entecavir, etc.) serve as effective therapeutics, the virus can easily generate resistance to them. Therefore, the treatment of HBV infection remains a public health problem. Numerous studies have shown that natural products have prospective anti-HBV activity. The purpose of this study was to isolate and extract des(rhamnosyl) verbascoside from Lindernia ruellioides (Colsm.) Pennell and explore its anti-HBV and hepatoprotective effects. Anti-HBV activity was evaluated in HepG2.2.15 cells, a human hepatocellular carcinoma cell line with HBV-stable infection, and its protective effect was evaluated in HL-7702 cells, a normal human liver cell line. HepG2.2.15 cells maintained normal growth morphology within the selected concentration range of des(rhamnosyl) verbascoside. It also inhibited the expression of HBV antigens and HBV DNA in a dose- and time-dependent manner in vitro. Further, western blot experiments showed that it could downregulate HBV X protein (HBx) expression in a dose-dependent manner. In the H 2 O 2 -induced hepatocyte injury model, the cell-survival rate of the HL-7702 cells with the highest drug dose reached 85.25%, which was significantly improved compared with that of the model group. Most of the cells returned to normal morphology, showing polygonal or fusiform structures. Thus, it may be stated that des(rhamnosyl) verbascoside exhibits anti-HBV activity and hepatoprotective effects in vitro and may exert an anti-HBV effect via antigen inhibition, HBV DNA secretion, and HBx protein expression., (© 2021 John Wiley & Sons Ltd.)

Background: Peripheral nerve injuries result in muscle denervation and apoptosis of the involved muscle, which subsequently reduces mitochondrial content and causes muscle atrophy. The local injection of mitochondria has been suggested as a useful tool for restoring the function of injured nerves or the brain., Objective: To determine outcomes following the administration of isolated mitochondria into denervated muscle after nerve injury that have not been investigated., Methods: Muscle denervation was conducted in a sciatic nerve crushed by a vessel clamp and the denervated gastrocnemius muscle was subjected to 195 μg hamster green fluorescent protein (GFP)-mitochondria intramuscular infusion for 10 min., Results: The mitochondria were homogeneously distributed throughout the denervated muscle after intramuscular infusion. The increases in caspase 3, 8-oxo-dG, Bad, Bax, and ratio of Bax/Bcl-2 levels in the denervated muscle were attenuated by mitochondrial infusion, and the downregulation of Bcl-2 expression was prevented by mitochondrial infusion. In addition, the decrease in the expression of desmin and the acetylcholine receptor was counteracted by mitochondrial infusion; this effect paralleled the amount of distributed mitochondria. The restoration of the morphology of injured muscles and nerves was augmented by the local infusion of mitochondria. Mitochondrial infusion also led to improvements in sciatic functional indexes, compound muscle action potential amplitudes, and conduction latencies as well as the parameters of CatWalk (Noldus) gait analysis., Conclusion: The local infusion of mitochondria can successfully prevent denervated muscle atrophy and augment nerve regeneration by reducing oxidative stress in denervated muscle., (© Congress of Neurological Surgeons 2021.)

A paradoxical impact of high rates of production and consumption of antibiotics is their widespread release in the environment. Consequently, low concentrations of antibiotics and their byproducts have been routinely identified from various environmental settings especially from aquatic environments. However, the impact of such low concentrations of antibiotics on the exposed host especially in early life remains poorly understood. We exposed zebrafish to two different environmental concentrations of oxytetracycline and sulfamethoxazole, from larval stage to adulthood (∼120 days) and characterized their impact on the taxonomic diversity, antibiotic resistance genes, and metabolic pathways of the gut microbiome using metagenomic shotgun sequencing and analysis. Long term exposure of environmental concentrations of oxytetracycline and sulfamethoxazole significantly impacted the taxonomic composition and metabolic pathways of zebrafish gut microbiome. The antibiotic exposed samples exhibited significant enrichment of multiple flavobacterial species, including Flavobacterium sp. F52, Flavobacterium johnsoniae and Flavobacterium sp. Fl, which are well known pathogenic bacteria. The relative abundance of antibiotic resistance genes, especially several tetratcycline and sulfonamide resistance genes were significantly higher in the exposed samples and showed a linear correlation with the antibiotic concentrations. Furthermore, several metabolic pathways, including folate biosynthesis, oxidative phosphorylation, and biotin metabolism pathways, showed significant enrichment in the antibiotic exposed samples. Collectively, our results suggest that early life exposure of the environmental concentrations of antibiotics can increase the abundance of unfavorable bacteria, antibiotic resistance genes and associated pathways in the gut microbiome of zebrafish., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

This paper aimed to explore the mechanism of the split components of Phytolaccae Radix by means of network pharmaco-logy. Based on the theoretical hypothesis of the nature and taste of traditional Chinese medicine, the chemical components of the separated components of Phytolaccae Radix were selected by using Traditional Chinese Medicine Systems Pharmacology Database(TCMSP) and Traditional Chinese Medicines IntegratedDatabase(TCMID) databases in combination with related literatures. Relevant target analysis was carried out based on PubChem and SwissTargetPrediction databases. Targets corresponding to disease were excavated based on GeneCards for each split component, corresponding potential targets were obtained through mapping the target set of target compounds to disease targets. GO biological process analysis and KEGG pathway enrichment analysis were performed on the mapped targets with the help of DAVID database. Based on Cytoscape software and the corresponding efficacy, the network diagram of &quot;medicinal material-split components-compound-target-pathway&quot; was constructed to explore the mechanism of different efficacy of the separated components of Cytoscape. And the target purgation and diuretic mapping was used as the target of the traditional efficacy of smoothening secretion for the first time. The study explored esculentoside component, fatty oil component and phenolic acid component, a total of 30 target compounds and 301 corresponding targets, involving 44 potential targets for &quot;anti-inflammatory&quot;, 50 potential targets for &quot;immunoregulation&quot;, 52 potential targets for &quot;smoothening secretion&quot;, 28 potential targets for &quot;antibacterial activity&quot;, 28 potential targets for &quot;antiviral effect&quot;, and 29 potential targets for &quot;antitumor effect&quot;. Topological analysis revealed 14 key gene targets such as MAPK8, MAPK14, EGFR and PTGS2. A total of 684 GO entries and 235 KEGG pathways were obtained through bioinformatics enrichment analysis, mainly involving TNF signaling pathway, NF-kappaB signaling pathway and MAPK signaling pathway. This study revealed the multi-component, multi-target, and multi-channel action mechanism of the split components of Phytolaccae Radix, which provided certain basis for the next step to clarify the split components of Phytolaccae Radix through the method of system biology, and injected new content and significance into the study of properties and flavors theory.

Human pluripotent stem cells (hPSCs) are sources of several somatic cell types for human developmental studies, in vitro disease modeling, and cell transplantation therapy. Improving strategies of derivation of high-purity specific neural and glial lineages from hPSCs is critical for application to the study and therapy of the nervous system. Here, we will focus on the principles behind establishment of neuron and glia differentiation methods according to developmental studies. We will also highlight the limitations and challenges associated with the differentiation of several "difficult" neural lineages and delay in neuronal maturation and functional integration. To overcome these challenges, we will introduce strategies and novel technologies aimed at improving the differentiation of various neural lineages to expand the application potential of hPSCs to the study of the nervous system.

A synthetic approach to quinindoline derivatives by the Cu-catalyzed dual cyclization has been developed. This catalytic reaction is a practical method for the systematic synthesis of quinindoline core structure, which contains a limited-step synthetic strategy and can tolerant a wide variety of substituents. In addition, the mechanistic study reveals that the reaction initiates from a Lewis acid accelerated addition of aniline to nitrile and provides the indole substructure, and then the subsequent Cu-catalyzed C-N coupling reaction furnishes the quinoline subunit and affords the quinindoline structure.

Natural products are favored because of their non-toxicity, low irritants, and market reacceptance. We collected examples, according to ancient wisdom, of natural products to be applied in transdermal delivery. A transdermal delivery system, including different types of agents, such as ointments, patches, and gels, has long been used for skin concerns. In recent years, many novel transdermal applications, such as nanoemulsions, liposomes, lipid nanoparticles, and microneedles, have been reported. Nanosized drug delivery systems are widely applied in natural product deliveries. Nanosized materials notably enhance bioavailability and solubility, and are reported to improve the transdermal permeation of many substances compared with conventional topical formulations. Natural products have been made into nanosized biomaterials in order to enhance the penetration effect. Before introducing the novel transdermal applications of natural products, we present traditional methods within this article. The descriptions of novel transdermal applications are classified into three parts: liposomes, emulsions, and lipid nanoparticles. Each section describes cases that are related to promising natural product transdermal use. Finally, we summarize the outcomes of various studies on novel transdermal agents applied to skin treatments.

Background: The Taiwan Human Disease iPSC Service Consortium was established to accelerate Taiwan's growing stem cell research initiatives and provide a platform for researchers interested in utilizing induced pluripotent stem cell (iPSC) technology. The consortium has generated and characterized 83 iPSC lines: 11 normal and 72 disease iPSC lines covering 21 different diseases, several of which are of high incidence in Taiwan. Whether there are any reprogramming-induced recurrent copy number variant (CNV) hotspots in iPSCs is still largely unknown., Methods: We performed genome-wide copy number variant screening of 83 Han Taiwanese iPSC lines and compared them with 1093 control subjects using an Affymetrix genome-wide human SNP array., Results: In the iPSCs, we identified ten specific CNV loci and seven "polymorphic" CNV regions that are associated with the reprogramming process. Additionally, we established several differentiation protocols for our iPSC lines. We demonstrated that our iPSC-derived cardiomyocytes respond to pharmacological agents and were successfully engrafted into the mouse myocardium demonstrating their potential application in cell therapy., Conclusions: The CNV hotspots induced by cell reprogramming have successfully been identified in the current study. This finding may be used as a reference index for evaluating iPSC quality for future clinical applications. Our aim was to establish a national iPSC resource center generating iPSCs, made available to researchers, to benefit the stem cell community in Taiwan and throughout the world.

Human cytomegalovirus (hCMV) is a ubiquitous herpesvirus, which results in the establishment of a latent infection that persists throughout the life of the host and can be reactivated when the immunity is low. Currently, there is no vaccine for hCMV infection, and the licensed antiviral drugs mainly target the viral enzymes and have obvious adverse reactions. Thus, it is important to search for compounds with anti-hCMV properties. The present study aimed to investigate the suppressive effects of piceatannol on hCMV Towne strain infection and the putative underlying mechanisms using human diploid fibroblast WI-38 cells. Piceatannol supplementation prevented the lytic changes induced by hCMV infection in WI-38 cells. Furthermore, piceatannol suppressed the expression of hCMV immediate-early (IE) and early (E) proteins as well as the replication of hCMV DNA in a dose-dependent manner. Moreover, hCMV-induced cellular senescence was suppressed by piceatannol, as shown by a decline in the senescence-associated β-galactosidase (SA-β-Gal) activity and decreased production of intracellular reactive oxygen species (ROS). p16 INK4a , a major senescence-associated molecule, was dramatically elevated by current hCMV infection that was attenuated by pre-incubation with piceatannol in a dose-dependent manner. These results demonstrated that piceatannol suppressed the hCMV infection via inhibition of the activation of p16 INK4a and cellular senescence induced by hCMV. Together, these findings indicate piceatannol as a novel and potent anti-hCMV agent with the potential to be developed as an effective treatment for chronic hCMV infection.

Objective: Haemophilia A and B are disorders caused by the lack of clotting factors VIII and IX, respectively. Repeated bleeding into the same joint leads to haemophilic arthropathy (HA). Interleukin (IL)-1β is responsible for the pro-inflammatory response and IL-37 is induced by IL-1β stimuli to have an anti-inflammatory response and prevent uncontrolled inflammation and tissue damage. Our objective was to investigate plasma levels of IL-1β and IL-37 in patients with severe haemophilia with different severities of HA., Methods: Peripheral blood samples were collected from 14 patients with severe haemophilia A and 6 with severe haemophilia B, and 18 healthy individuals. Plasma levels of IL-1β and IL-37 were detected by immunoassay, and severity of HA was evaluated using the Pettersson scoring system. Plasma levels of IL-1β and IL-37 were analysed in patients with severe haemophilia grouped by Pettersson score and in healthy individuals., Results: Plasma levels of IL-1β and IL-37 were significantly higher in patients with severe haemophilia compared with healthy individuals and significantly lower in those with moderate to severe HA than in those with no or mild HA., Conclusions: Plasma levels of IL-1β and IL-37 may be useful to track HA progression in patients with severe haemophilia.

OBJECTIVE Thrombopoietin (THPO) is well-known as a megakaryocyte growth and development factor (MGDF) involved in megakaryocyte proliferation and maturation. To explore the biological effects of THPO in gastric adenocarcinoma, we conducted this study. Methods: By accessing the TCGA database, the expression level of THPO was determined in tumor tissues. The association between THPO expression and clinical features, or prognostic significance was described by Cox regression analysis and Kaplan-Meier. The SiRNA method was used to decline the THPO expression; then cell viability, invasion, and migration were detected to verify the effects of the knockdown of THPO. qPCR and western blotting were implemented to examine the expression level of THPO. Results: The expression of THPO was increased in tumor tissue and cells, its high-regulation was associated with a poor prognosis in patients with gastric adenocarcinoma. Cell viability, invasion, and migration were suppressed in AGS with the down-regulation of THPO. Furthermore, on the basis of si-THPO transfection, E-cadherin was promoted while N-cadherin and Vimentin were attenuated. CONCLUSION Our results revealed that THPO may be a potent marker of gastric adenocarcinoma, providing a novel potential screening method for gastric adenocarcinoma.

Neurodegenerative diseases represent a significant unmet medical need in our aging society. There are no effective treatments for most of these diseases, and we know comparatively little regarding pathogenic mechanisms. Among the challenges faced by those involved in developing therapeutic drugs for neurodegenerative diseases, the syndromes are often complex, and small animal models do not fully recapitulate the unique features of the human nervous system. Human induced pluripotent stem cells (iPSCs) are a novel technology that ideally would permit us to generate neuronal cells from individual patients, thereby eliminating the problem of species-specificity inherent when using animal models. Specific phenotypes of iPSC-derived cells may permit researchers to identify sub-types and to distinguish among unique clusters and groups. Recently, iPSCs were used for drug screening and testing for neurologic disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), spinocerebellar atrophy (SCA), and Zika virus infection. However, there remain many challenges still ahead, including how one might effectively recapitulate sporadic disease phenotypes and the selection of ideal phenotypes and for large-scale drug screening. Fortunately, quite a few novel strategies have been developed that might be combined with an iPSC-based model to solve these challenges, including organoid technology, single-cell RNA sequencing, genome editing, and deep learning artificial intelligence. Here, we will review current applications and potential future directions for iPSC-based neurodegenerative disease models for critical drug screening.