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Bo-Chieh Chang,1 Meng-Hsuan Kuo,1 Chi-Hui Lee,1 Ya-Lan Chu,1 Kuang-Peng Chen,2 Chun-Liong Tung,2 Ya-Hui Yang,3 Chuan-Sheng Hung,4 Jui-Hsiu Tsai,2,5 Hung-Yi Chuang6 1Department of Pharmacy, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 2Department of Psychiatry, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan; 3Department of Long-Term Care and Health Management, Cheng Shiu University, Kaohsiung, Taiwan; 4Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan; 5School of Medicine, Tzu Chi University, Hualien, Taiwan; 6Department of Environmental and Occupational Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence: Jui-Hsiu Tsai, Department of Psychiatry, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 2, Min-Sheng Road, Dalin Town, Chiayi, 622, Taiwan, Email faanvangogh@gmail.comIntroduction: Poor adherence to antipsychotics in patients with schizophrenia is a leading cause of relapse and functional deterioration. Long-acting injectable paliperidone may reduce relapse risks, health-care utilisation, and health-care costs in these patients.Methods: In this 24-month mirror-image study, we compared health-care utilization and costs before and after the initiation of paliperidone palmitate 3-monthly (PP3M) treatment in patients with schizophrenia spectrum disorders. Before the initiation of PP3M, the patients received paliperidone 1-monthly (PP1M) treatment. The primary study outcomes were changes in health-care utilisation and costs over the study period.Results: This study included 34 patients with schizophrenia spectrum disorders. During the 12-months period after the initiation of PP3M treatment, the mean duration of hospitalisation decreased from 57.7 to 28.5 days (p = 0.03). Moreover, significant reductions were noted in emergency room visits (PP1M vs PP3M: 0.3 vs 0.0, respectively; p = 0.05) and health-care costs (PP1M vs PP3M: 107,328.8 vs 57,848.6, respectively; p = 0.03).Conclusion: PP3M may significantly reduce hospitalisation duration, emergency room visits, and health-care costs in patients with schizophrenia.Keywords: schizophrenia, long-acting injectable antipsychotics, paliperidone palmitate, health-care cost, health-care utilisation

Objective: The objective of this study was to undertake a proof of concept that demonstrated the use of primary care data and natural language processing and term extraction to assess emergency room use. The study extracted biopsychosocial concepts from primary care free text and related them to inappropriate emergency room use through the use of odds ratios.Methods: De-identified free text notes were extracted from a primary care clinic in Guelph, Ontario and analyzed with a software toolkit that incorporated General Architecture for Text Engineering (GATE) and MetaMap components for natural language processing and term extraction.Results: Over 10 million concepts were extracted from 13,836 patient records. Codes found in at least 1% percent of the sample were regressed against inappropriate emergency room use. 77 codes fell within the realm of biopsychosocial, were very statistically significant (p < 0.001) and had an OR > 2.0. Thematically, these codes involved mental health and pain related concepts.Conclusions: Analyzed thematically, mental health issues and pain are important themes; we have concluded that pain and mental health problems are primary drivers for inappropriate emergency room use. Age and sex were not significant. This proof of concept demonstrates the feasibly of combining natural language processing and primary care data to analyze a system use question. As a first work it supports further research and could be applied to investigate other, more complex problems. [ABSTRACT FROM AUTHOR]

Abnormal accumulation of tau protein in the brain is one pathological hallmark of Alzheimer's disease (AD). Many tau protein post-translational modifications (PTMs) are associated with the development of AD, such as phosphorylation, acetylation, and methylation. Therefore, a complete picture of the PTM landscape of tau is critical for understanding the molecular mechanisms of AD progression. Here, we offered a pilot study of combining two complementary analytical techniques, capillary zone electrophoresis (CZE)-tandem mass spectrometry (MS/MS) and reversed-phase liquid chromatography (RPLC)-MS/MS, for bottom-up proteomics of recombinant human tau-0N3R. We identified 50 phosphorylation sites of tau-0N3R in total, which is about 25% higher than that from RPLC-MS/MS alone. CZE-MS/MS provided more PTM sites (i.e., phosphorylation) and modified peptides of tau-0N3R than RPLC-MS/MS, and its predicted electrophoretic mobility helped improve the confidence of the identified modified peptides. We developed a highly efficient capillary isoelectric focusing (cIEF)-MS technique to offer a bird's-eye view of tau-0N3R proteoforms, with 11 putative tau-0N3R proteoforms carrying up to nine phosphorylation sites and lower pI values from more phosphorylated proteoforms detected. Interestingly, under native-like cIEF-MS conditions, we observed three putative tau-0N3R dimers carrying phosphate groups. The findings demonstrate that CE-MS is a valuable analytical technique for the characterization of tau PTMs, proteoforms, and even oligomerization.

The emergence and global spread of methicillin-resistant Staphylococcus aureus (MRSA) pose a serious threat to public health, underscoring the urgent need for novel antibacterial interventions. Here, we screened 18 newly synthesized N,N'-diarylurea derivatives to identify compounds with activity against MRSA. Our investigations led to the discovery of a small molecule, SCB-24, which exhibited promising antimicrobial activity against MRSA USA300. Notably, SCB-24 demonstrated high activity even in the presence of 10% fetal bovine serum and showed excellent selectivity for bacterial over mammalian cells. SCB-24 also showed potent activity against various MRSA strains, including those resistant to second- and third-line antibiotics. Importantly, the efficacy of SCB-24 was inferior to that of vancomycin in MRSA-infected Galleria mellonella larvae. Overall, our findings suggest that SCB-24 has great potential as a new therapeutic for multidrug-resistant S. aureus infections., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Abnormal accumulation of tau proteins is one pathological hallmark of Alzheimer□s disease (AD). Many tau protein post-translational modifications (PTMs) are associated with the development of AD, such as phosphorylation, acetylation, and methylation. Therefore, a complete picture of PTM landscape of tau is critical for understanding the molecular mechanisms of AD progression. Here, we offered a pilot study of combining two complementary analytical techniques, capillary zone electrophoresis (CZE)-tandem mass spectrometry (MS/MS) and reversed-phase liquid chromatography (RPLC)-MS/MS, for bottom-up proteomics of recombinant human tau-0N3R. We identified 53 phosphorylation sites of tau-0N3R in total, which is about 30% higher than that from RPLC-MS/MS alone. CZE-MS/MS provided more PTM sites (i.e., phosphorylation) and modified peptides of tau-0N3R than RPLC-MS/MS, and its predicted electrophoretic mobility helped improve the confidence of the identified modified peptides. We developed a highly efficient capillary isoelectric focusing (cIEF)-MS technique to offer a bird's-eye view of tau-0N3R proteoforms, with 11 putative tau-0N3R proteoforms carrying up to nine phosphorylation sites and lower pI values from more phosphorylated proteoforms detected. Interestingly, under a native-like cIEF-MS condition, we observed three putative tau-0N3R dimers carrying phosphate groups. The findings demonstrate that CE-MS is a valuable analytical technique for the characterization of tau PTMs, proteoforms, and even oligomerization.

Abnormal phosphorylation of the microtubule-binding protein tau in the brain is a key pathological marker for Alzheimer's disease and additional neurodegenerative tauopathies. However, how hyperphosphorylated tau causes cellular dysfunction or death that underlies neurodegeneration remains an unsolved question critical for the understanding of disease mechanism and the design of efficacious drugs. Using a recombinant hyperphosphorylated tau protein (p-tau) synthesized by the PIMAX approach, we examined how cells responded to the cytotoxic tau and explored means to enhance cellular resistance to tau attack. Upon p-tau uptake, the intracellular calcium levels rose promptly. Gene expression analyses revealed that p-tau potently triggered endoplasmic reticulum (ER) stress, unfolded protein response (UPR), ER stress-associated apoptosis, and pro-inflammation in cells. Proteomics studies showed that p-tau diminished heme oxygenase-1 (HO-1), an ER stress-associated anti-inflammation and anti-oxidative stress regulator, while stimulated the accumulation of MIOS and other proteins. p-Tau-induced ER stress-associated apoptosis and pro-inflammation are ameliorated by apomorphine, a brain-permeable prescription drug widely used to treat Parkinson's disease symptoms, and by overexpression of HO-1. Our results reveal probable cellular functions targeted by hyperphosphorylated tau. Some of these dysfunctions and stress responses have been linked to neurodegeneration in Alzheimer's disease. The observations that the ill effects of p-tau can be mitigated by a small compound and by overexpressing HO-1 that is otherwise diminished in the treated cells inform new directions of Alzheimer's disease drug discovery., (© 2023. The Author(s).)

Background: Rheumatoid arthritis (RA) patients seropositive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are at risk of hepatitis B virus (HBV) reactivation when treated with biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The study aims to investigate the risk in this population., Methods: From January 2004 through December 2020, 1068 RA patients undergoing b/tsDMARDs therapy and 416 patients with HBsAg-/HBcAb+ were enrolled. Factors associated with HBV reactivation were analysed., Results: During 2845 person-years of follow-up, 27 of 416 (6.5%,9.5 per 1000 person-years) patients developed HBV reactivation, with a cumulative rate of HBV reactivation of 3.5% at 5 years, 6.1% at 10 years and 24.2% at 17 years. The median interval from beginning b/tsDMARDs to HBV reactivation was 85 months (range: 9-186 months). The risk of HBV reactivation varied by type of b/tsDMARD, with rituximab having the highest risk (incidence rate: 48.3 per 1000 person-years), followed by abatacept (incidence rate: 24.0 per 1000 person-years). In multivariate analysis, rituximab (adjusted hazard ratio [aHR]: 15.77, 95% confidence interval [CI]: 4.12-60.32, p = .001), abatacept (aHR: 9.30, 1.83-47.19, p = .007), adalimumab (aHR: 3.86, 1.05-14.26, p = .04) and negative baseline HBV surface antibody (anti-HBs, <10 mIU/mL) (aHR: 3.89, 1.70-8.92, p < .001) were independent risk factors for HBV reactivation., Conclusion: HBsAg-/HBcAb+ RA patients are susceptible to HBV reactivation during b/tsDMARD therapy. Those with negative baseline anti-HBs and those on certain b/tsDMARDs, such as rituximab, abatacept and adalimumab, have high reactivation risks. Risk stratification and management should be based on the patient's baseline anti-HBs titre and type of therapy., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Alzheimer's disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia in both its free and extracellular vesicular-associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the number of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in biogenesis of EVs. Single-cell RNA-Seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.

Background and Aim: Transcatheter liver-directed intra-arterial therapies are mainstream treatment options for intermediate-stage hepatocellular carcinoma (HCC). However, the effect of low skeletal muscle mass (LSMM) on overall survival (OS) in these patients remains uncertain. We aimed to ascertain the prevalence and prognostic effect of LSMM in this population., Method: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a comprehensive search was performed in the PubMed and Embase databases until Oct 2023. Random-effects meta-analysis was performed to determine the pooled prevalence of LSMM and calculate the hazard ratio (HR) for OS with a 95% confidence interval (CI) in patients with intermediate-stage HCC undergoing various transarterial therapies, comparing those with and without LSMM., Results: Twelve studies involving 2450 patients were included. The pooled prevalence of LSMM was 46% (95% CI, 38-55%), and the results were consistent across different treatments, regions, and age subgroups. The meta-analysis indicated that LSMM was significantly associated with decreased OS (HR, 1.78; 95% CI, 1.36-2.33; I 2 , 75%). Subgroup analyses reassured the main findings across various therapies, including transarterial chemoembolization (TACE) (HR, 1.68; 95% CI, 1.23-2.30; I 2 , 81%), transarterial embolization (TAE) (HR, 2.45; 95% CI, 1.42-4.22; I 2 , 0%), and transarterial radioembolization (TARE) (HR, 1.94; 95% CI, 1.01-3.73; I 2 , 0%)., Conclusions: In intermediate-stage HCC, LSMM is common and associated with reduced OS. To achieve an optimal prognosis, clinicians should incorporate routine LSMM measurement into practice, while caring for patients with intermediate-stage HCC, irrespective of TACE, TAE, and TARE.

Background: Tocilizumab has demonstrated optimal efficacy and safety in patients with rheumatoid arthritis (RA) from clinical trials. However, the risk of hepatitis B virus reactivation (HBVr) in these patients remains uncertain because patients with underlying HBV have been excluded in phase III studies., Methods: Systematical reviews were conducted on PubMed, Embase, and the Cochrane Central Register of Controlled Trials up to 21 February 2023. Random-effects meta-analysis was performed to calculate the pooled incidence of HBV reactivation., Results: We included 0 clinical trials and 11 observational studies with a total of 25 HBsAg + and 322 HBsAg - /anti-HBc + RA patients. Among the HBsAg + patients without antiviral prophylaxis, the pooled rate was 69.4% (95% CI, 32.9-91.3), with a median time of 4 months (range, 1-8 months) from tocilizumab initiated. Half of these patients with HBVr experienced hepatitis flare-up but no deaths. HBVr was eliminated with prophylaxis in this population. Among HBsAg - /anti-HBc + patients, the pooled incidence of reactivation was 3.3% (95% CI, 1.6-6.7), with a median time of 10 months (range, 2-43 months) from tocilizumab initiated. HBVr was not associated with hepatitis flare-up and death. HBsAg - /anti-HBc + patients without anti-HBs antibodies had a significantly higher risk of HBVr (Odds ratio, 12.20; 95% CI, 1.16-128.06)., Conclusions: This systematic review indicated that the risk of HBVr in RA patients with anti-HBs - , HBsAg + , or HBsAg - /anti-HBc + cannot be ignored but may be avoided. Clinicians should consider implementing appropriate antiviral prophylaxis and monitoring policies for RA patients to avoid unnecessary hepatic side effects from tocilizumab treatment.

Background: Climate change poses uncertainties in the effectiveness of classical biological control (CBC), and there is a lack of information on the establishment of natural enemy populations under present and future climatic conditions. The objective is to explore current traces of two alien predators (Neoseiulus californicus and Neoseiulus fallacis; introduced for the CBC program in the 1980s) and their future expansion under climate change in Taiwan., Results: The results indicated that N. californicus was present in alpine orchards (e.g., Lishan and Meifeng) but N. fallacis was not found. Under current climate condition, most areas in Taiwan were deemed highly suitable for N. californicus, but not for N. fallacis, which may explain the outcomes of the CBC program. With intensifying climate change, the ranges of both species are projected to contract to varying extents in Taiwan but expand in some countries., Conclusion: The findings from this study can provide insights for evaluating and developing future CBC programs worldwide, and can help predict the implications of climate change on biological control efforts. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder underlying dementia in the geriatric population. AD manifests by two pathological hallmarks: extracellular amyloid-β (Aβ) peptide-containing senile plaques and intraneuronal neurofibrillary tangles comprised of aggregated hyperphosphorylated tau protein (p-tau). However, more than half of AD cases also display the presence of aggregated α-synuclein (α-syn)-containing Lewy bodies. Conversely, Lewy bodies disorders have been reported to have concomitant Aβ plaques and neurofibrillary tangles. Our drug discovery program focuses on the synthesis of multitarget-directed ligands to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to slow the progression of AD and related dementias. To this end, we synthesized 11 compounds with a triazine-linker and evaluated their effectiveness in reducing α-syn, tau isoform 2N4R, and p-tau isoform 1N4R aggregation. We utilized biophysical methods such as thioflavin T (ThT) fluorescence assays, transmission electron microscopy (TEM), photoinduced cross-linking of unmodified proteins (PICUP), and M17D intracellular inclusion cell-based assays to evaluate the antiaggregation properties and cellular protection of our best compounds. We also performed disaggregation assays with isolated Aβ-plaques from human AD brains. Our results demonstrated that compound 10 was effective in reducing both oligomerization and fibril formation of α-syn and tau isoform 2N4R in a dose-dependent manner via ThT and PICUP assays. Compound 10 was also effective at reducing the formation of recombinant α-syn, tau 2N4R, and p-tau 1N4R fibrils by TEM. Compound 10 reduced the development of α-syn inclusions in M17D neuroblastoma cells and stopped the seeding of tau P301S using biosensor cells. Disaggregation experiments showed smaller Aβ-plaques and less paired helical filaments with compound 10 . Compound 10 may provide molecular scaffolds for further optimization and preclinical studies for neurodegenerative proteinopathies.

Background: Urbanization has led to the proliferation of high-rise buildings, which have substantially influenced the distribution of dengue vectors, such as Aedes aegypti (L.). However, knowledge gaps exist regarding the individual and combined effects of architectural and spatiotemporal factors on dengue vector. This study investigated the interrelationship between Ae. aegypti presence, building architectural features, and spatiotemporal factors in urban environments., Results: The mosquito Ae. aegypti presence varied by location and seasons, being higher in outdoor environments than in indoor environments. Lingya (Kaohsiung City, Taiwan) had the highest mosquito numbers, particularly in basement and first floor areas. Ae. aegypti was found on multiple floors within buildings, and their presence was greater in summer and autumn. The XGBoost model revealed that height within a building, temperature, humidity, resident density, and rainfall were key factors influencing mosquito presence, whereas openness had a relatively minor impact., Conclusion: To effectively address the problems caused by urbanization, the three-dimensional distribution of Ae. aegypti, including their spatial distribution across heights and areas within the urban environment, must be considered. By incorporating these multiple factors, this approach provides valuable insights for those responsible for urban planning and disease management strategies. Understanding the interplay between architectural features, environmental conditions, and the presence of Ae. aegypti is essential for developing targeted interventions and mitigating the adverse impacts of urbanization on public health. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

The P301L mutation in tau protein is a prevalent pathogenic mutation associated with neurodegenerative frontotemporal dementia, FTD. The mechanism by which P301L triggers or facilitates neurodegeneration at the molecular level remains unclear. In this work, we examined the effect of the P301L mutation on the biochemical and biological characteristics of pathologically relevant hyperphosphorylated tau. Hyperphosphorylated P301L tau forms cytotoxic aggregates more efficiently than hyperphosphorylated wildtype tau or unphosphorylated P301L tau in vitro. Mechanistic studies establish that hyperphosphorylated P301L tau exacerbates endoplasmic reticulum (ER) stress-associated gene upregulation in a neuroblastoma cell line when compared to wildtype hyperphosphorylated tau treatment. Furthermore, the microtubule cytoskeleton is severely disrupted following hyperphosphorylated P301L tau treatment. A hyperphosphorylated tau aggregation inhibitor, apomorphine, also inhibits the harmful effects caused by P301L hyperphosphorylated tau. In short, the P301L single mutation within the core repeat domain of tau renders the underlying hyperphosphorylated tau more potent in eliciting ER stress and cytoskeleton damage. However, the P301L mutation alone, without hyperphosphorylation, is not sufficient to cause these phenotypes. Understanding the conditions and mechanisms whereby selective mutations aggravate the pathogenic activities of tau can provide pivotal clues on novel strategies for drug development for frontotemporal dementia and other related neurodegenerative tauopathies, including Alzheimer's disease.

Background: During flight, G force compels blood to stay in leg muscles and reduces blood flow to the heart. Cardiovascular responses activated by the autonomic nerve system and strengthened by anti-G straining maneuvers can alleviate the challenges faced during G loading. To our knowledge, no definite cardiac information measured using a mobile health device exists for analyzing G tolerance. However, our previous study developed the cardiac force index (CFI) for analyzing the G tolerance of military aircrew., Objective: This study used the CFI to verify participants' cardiac performance when walking and obtained a formula for predicting an individual's G tolerance during centrifuge training., Methods: Participants from an air force aircrew undertook high-G training from January 2020 to December 2022. Their heart rate (HR) in beats per minute and activity level per second were recorded using the wearable BioHarness 3.0 device. The CFI was computed using the following formula: weight × activity / HR during resting or walking. Relaxed G tolerance (RGT) and straining G tolerance (SGT) were assessed at a slowly increasing rate of G loading (0.1 G/s) during training. Other demographic factors were included in the multivariate regression to generate a model for predicting G tolerance from the CFI., Results: A total of 213 eligible trainees from a military aircrew were recruited. The average age was 25.61 (SD 3.66) years, and 13.1% (28/213) of the participants were women. The mean resting CFI and walking CFI (WCFI) were 0.016 (SD 0.001) and 0.141 (SD 0.037) kg × G/beats per minute, respectively. The models for predicting RGT and SGT were as follows: RGT = 0.066 × age + 0.043 × (WCFI × 100) - 0.037 × height + 0.015 × systolic blood pressure - 0.010 × HR + 7.724 and SGT = 0.103 × (WCFI × 100) - 0.069 × height + 0.018 × systolic blood pressure + 15.899. Thus, the WCFI is a positive factor for predicting the RGT and SGT before centrifuge training., Conclusions: The WCFI is a vital component of the formula for estimating G tolerance prior to training. The WCFI can be used to monitor physiological conditions against G stress., (©Ming-Hao Kuo, You-Jin Lin, Wun-Wei Huang, Kwo-Tsao Chiang, Min-Yu Tu, Chi-Ming Chu, Chung-Yu Lai. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 26.07.2023.)

Intracellular deposition of α-synuclein and tau are hallmarks of synucleinopathies and tauopathies, respectively. Recently, several dye-based imaging probes with selectivity for tau aggregates have been developed, but suitable imaging biomarkers for synucleinopathies are still unavailable. Detection of both of these aggregates early in the disease process may allow for prophylactic therapies before functional impairments have manifested, highlighting the importance of developing specific imaging probes for these lesions. In contrast to the β sheet dyes, single-domain antibodies, found in camelids and a few other species, are highly specific, and their small size allows better brain entry and distribution than whole antibodies. Here, we have developed such imaging ligands via phage display libraries derived from llamas immunized with α-synuclein and tau preparations, respectively. These probes allow noninvasive and specific in vivo imaging of α-synuclein versus tau pathology in mice, with the brain signal correlating strongly with lesion burden. These small antibody derivatives have great potential for in vivo diagnosis of these diseases.

Hybrid organic-inorganic metal halide perovskites (HOIP) have become a promising visible light sensing material due to their excellent optoelectronic characteristics. Despite the superiority, overcoming the stability issue for commercialization remains a challenge. Herein, an extremely stable photodetector was demonstrated and fabricated with Cs 0.06 FA 0.94 Pb(I 0.68 Br 0.32 ) 3 perovskite by an all-vacuum process. The photodetector achieves a current density up to 1.793 × 10 -2 A cm -2 under standard one sun solar illumination while maintaining a current density as low as 8.627 × 10 -10 A cm -2 at zero bias voltage. The linear dynamic range (LDR) and transient voltage response were found to be comparable to the silicon-based photodetector (Newport 818-SL). Most importantly, the device maintains 95% of the initial performance after 960 h of incessant exposure under one sun solar illumination. The achievements of these outstanding results contributed to the all-vacuum deposition process delivering a film with high stability and good uniformity, which in turn delays the degradation process. The degradation mechanism is further investigated by impedance spectroscopy to reveal the charge dynamics in the photodetector under different exposure times.

Low skeletal muscle mass (LSMM) is associated with poor outcomes in hepatocellular carcinoma (HCC) patients. With the emergence of new systemic therapeutics, understanding the effect of LSMM on HCC treatment outcomes is critically important. This systematic review and meta-analysis investigates the prevalence and effect of LSMM among HCC patients undergoing systemic therapy as reported in studies identified in searches of the PubMed and Embase databases published through 5 April 2023. The included studies ( n = 20; 2377 HCC patients undergoing systemic therapy) reported the prevalence of LSMM assessed by computer tomography (CT) and compared the survival outcomes [overall survival (OS) or progression-free survival (PFS)] between HCC patients with and without LSMM. The pooled prevalence of LSMM was 43.4% (95% CI, 37.0-50.0%). A random-effects meta-analysis showed that HCC patients receiving systemic therapy with comorbid LSMM had a lower OS (HR, 1.70; 95% CI, 1.46-1.97) and PFS (HR, 1.32; 95% CI, 1.16-1.51) than did those without. Subgroup analysis according to systemic therapy type (sorafenib, lenvatinib, or immunotherapy) yielded similar results. In conclusion, LSMM is prevalent among HCC patients undergoing systemic therapy and is associated with poorer survival. Early intervention or prevention strategies to improve muscle mass may be necessary for this patient population.

Microplastic pollution is an urgent threat to the biota of aquatic ecosystems and is generally recognized as a global issue. Identifying the sources of microplastics is acknowledged as the most effective approach for mitigating microplastic pollution. However, the factors that regulate the spatiotemporal dynamics of microplastics in urban river networks, such as microplastic sources and other variables, have not been studied together at the watershed scale, let alone regarding their impact on internal microplastics. Here, we define "internal microplastics" as microplastics in biota, either in the digestive system or internal organs of organisms. We estimated the effects of anthropogenic activities (land cover and wastewater treatment plants) and seasonality on the concentration of internal microplastics in midge larvae (Diptera: Chironomidae) in an urban river system at a watershed scale in Taiwan. Agricultural activities, but not industrial activities, had a significant negative nonlinear effect on microplastic concentration. However, seasonality was the most crucial factor, as the microplastic concentration was significantly lower during the wet season. Although the presence of a wastewater treatment plant significantly increased the microplastic concentration at downstream sampling sites, its effect appeared to be minor. We conclude that seasonality overrides the effects of anthropogenic activities on the variation in the concentration of internal microplastics in midge larvae in an urban river system., 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 B.V. All rights reserved.)

In contrast to A β plaques, the spatiotemporal distribution of neurofibrillary tangles of hyperphosphorylated tau (p-tau) predicts cognitive impairment in Alzheimer's disease (AD), underscoring the key pathological role of p-tau and the utmost need to develop AD therapeutics centering upon the control of p-tau aggregation and cytotoxicity. Our drug discovery program is focused on compounds that prevent the aggregation and cytotoxicity of p-tau moieties of the tau isoform 1N4R due to its prevalence (1 N) and long-distance trans-synaptic propagation (4R). We prepared and tested twenty-four newly synthesized small molecules representing the urea ( 1, 2, 3 ), sulfonylurea ( 4 ), and sulfonamide ( 5-24 ) series and evaluated their anti-aggregation effects with biophysical methods (thioflavin T and S fluorescence assays, transmission electron microscopy) and intracellular inclusion cell-based assays. Pre-evaluation was performed on alpha-synuclein ( α -syn) to identify molecules to be challenged with p-tau. The sulfonamide derivatives 18 and 20 exhibited an anti-fribrillization activity on α -syn and p-tau. Sulfonamide compounds 18 and 20 reduced inclusion formation in M17D neuroblastoma cells that express inclusion-prone α Synuclein3K::YFP. This project advances new concepts in targeting prone-to-aggregate proteins such as α -syn and p-tau, and provides a molecular scaffold for further optimization and pre-clinical studies focused on AD drug development., Competing Interests: Declaration of Competing Interest The authors declare no competing interest.

High-grade neuroendocrine tumors (NETs) of the lung consist of small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high-grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR-TKI selection enriched VGF expression in TKI-resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature., (© 2022 UICC.)

Background: Eleven tau immunoglobulin G (IgG) antibodies have entered clinical trials to treat tauopathies, including Alzheimer's disease, but it is unclear which IgG subclass/subtype has the ideal efficacy and safety profile. Only two subtypes, with or without effector function, have been examined in the clinic and not for the same tau antibody. The few preclinical studies on this topic have only compared two subtypes of one antibody each and have yielded conflicting results., Methods: We selected two single domain antibodies (sdAbs) derived from a llama immunized with tau proteins and utilized them to generate an array of Fc-(sdAb) 2 subclasses containing identical tau binding domains but differing Fc region. Unmodified sdAbs and their IgG subclasses were tested for efficacy in primary cultures and in vivo microdialysis using JNPL3 tauopathy mice., Findings: Unmodified sdAbs were non-toxic, blocked tau toxicity and promoted tau clearance. However, the efficacy/safety profile of their Fc-(sdAb) 2 subclasses varied greatly within and between sdAbs. For one of them, all its subtypes were non-toxic, only those with effector function cleared tau, and were more effective in vivo than unmodified sdAb. For the other sdAb, all its subtypes were toxic in tauopathy cultures but not in wild-type cells, suggesting that bivalent binding of its tau epitope stabilizes a toxic conformation of tau, with major implications for tau pathogenesis. Likewise, its subclasses were less effective than the unmodified sdAb in clearing tau in vivo., Interpretation: These findings indicate that tau antibodies with effector function are safe and better at clearing pathological tau than effectorless antibodies, Furthermore, tau antibodies can provide a valuable insight into tau pathogenesis, and some may aggravate it., Funding: Funding for these studies was provided by the National Institute of Health (R01 AG032611, R01 NS077239, RF1 NS120488, R21 AG 069475, R21 AG 058282, T32AG052909), and the NYU Alzheimer's Disease Center Pilot Grant Program (via P30 AG008051)., Competing Interests: Declaration of interests EMS is an inventor on patents on tau immunotherapies and related diagnostics, which are assigned to New York University, and some of those are licensed to H. Lundbeck A/S. Notably, this licensing does not include tau sdAbs such as the 2B8 and 1D9 antibodies used in these experiments. All other authors have nothing to declare., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Abbreviations: ATG14: autophagy related 14; CDH2: cadherin 2; ChIP-qPCR: chromatin immunoprecipitation quantitative polymerase chain reaction; CQ: chloroquine; ECAR: extracellular acidification rate; EMT: epithelial-mesenchymal transition; EPCAM: epithelial cell adhesion molecule; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP1LC3C/LC3C: microtubule associated protein 1 light chain 3 gamma; NDUFV2: NADH:ubiquinone oxidoreductase core subunit V2; OCR: oxygen consumption rate; ROS: reactive oxygen species; RT-qPCR: reverse-transcriptase quantitative polymerase chain reaction; SC: scrambled control; sh RNA : short hairpin RNA; SNAI2: snail family transcriptional repressor 2; SOX2: SRY-box transcription factor 2; SQSTM1/p62: sequestosome 1; TGFB/TGF-β: transforming growth factor beta; TOMM20: translocase of outer mitochondrial membrane 20; ZEB1: zinc finger E-box binding homeobox 1.

This paper reports on the assembly of a compact, low-cost, pulsed-power facility used for plasma studies. The construction uses two modules placed on opposite sides of the test chamber to minimize the system impedance and improve access to test samples. The stored energy is 1  kJ with a peak current of 135  kA and a 1592  ns quarter-period time. Up until now, an imploding conical-wire array has been studied by using time-integrated (visible) imaging, and time-resolved laser imaging, providing a measure of the plasma jet speed in the range of 170  km/s. Our future plans will continue to investigate high-energy-density plasmas that are relevant to the space environment, fusion, and spectroscopy.

Most research on the ecological responses to extreme floods examines impacts at short time scales, whereas long-term datasets combining hydrological and biological information remain rare. Using such data, we applied time-series analysis to investigate simultaneous effects of a biotic factor (density dependence), an abiotic factor (extreme floods), and spatial synchrony in the population dynamics of three riverine insects. Spatial synchronization of population dynamics by extreme floods varied among species. These different responses to extreme floods could be explained by species-specific biological traits. Moreover, density dependence influenced the population dynamics under the context of extreme floods. Accordingly, quasi-extinction risks were highest for species that were simultaneously influenced by biotic and abiotic factors. An understanding of ecological responses to increasing hydrological extremes may be enhanced by recognizing long-term, climatic non-stationarity., 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 B.V. All rights reserved.)

Microplastic pollution is no longer neglected worldwide, as recent studies have unveiled its potential harm to ecosystems and, even worse, to human health. Numerous studies have documented the ubiquity of microplastics, reflecting the necessity of formulating corresponding policies to mitigate the accumulation of microplastics in natural environments. Although anthropogenic activities are generally acknowledged as the primary source of microplastics, a robust approach to identify sources of microplastics is needed to provide scientific suggestions for practical policymaking. This review elucidates recent microplastic studies on various approaches for quantifying or reflecting the degree to which anthropogenic activities contribute to microplastic pollution. Population density (i.e., often used to quantify anthropogenic activities) was not always significantly correlated with microplastic abundance. Furthermore, this review argues that considering potential sources near sample sites as characteristics that may serve to predict the spatial distribution of microplastics in aquatic environments is equivocal. In this vein, a watershed-scale measure that uses land-cover datasets to calculate different percentages of land use in the watershed margins delineated by using Geographic Information System (GIS) software is discussed and suggested. Progress in strategies for quantifying anthropogenic activities is important for guiding future microplastic research and developing effective management policies to prevent microplastic contamination in aquatic ecosystems.

Background/purpose: To investigate the impact of pharmaceutical care programs for the management of contraindicated drug-drug interactions (DDIs) in direct-acting antivirals (DAAs) therapy., Methods: A prospective observational study was performed at Dalin Tzu Chi Hospital between January 2018 and December 2019. Pharmacists screened DDIs for all hepatitis C patients before DAA therapy. The study outcome included the frequency of contraindicated DDIs, acceptance rate, and cost avoidance of the pharmaceutical care program., Results: A total of 1053 patients were enrolled in the study, with a mean age of 67.1 ± 11.9 years. Most patients received therapy with sofosbuvir/ledipasvir (37.1%; n = 391), elbasvir/grazoprevir (23.8%; n = 251), or glecaprevir/pibrentasvir (21.1%; n = 222). A total of 796 (75.6%) patients received at least one co-medication, with the average number of co-medications being 5.2 per patient (SD: 4.4/patient). In total, 1356 DDIs were identified, with the average DDIs per patient of 1.3 (SD: 1.7). For patients with contraindicated DDIs (2%, n = 102), statins and amiodarone were the most common co-medications. Physicians often accepted pharmacists' recommendations (acceptance rate of 72.5%) or withheld co-medication to avoid severe adverse drug events (ADEs). The estimated cost avoidance of preventable ADEs was USD 14,033 for contraindicated DDIs with pharmaceutical care programs., Conclusion: The implementation of pharmaceutical care programs in DAA therapy provides a favorable outcome and substantial cost avoidance., (Copyright © 2021 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background and Aim: To investigate the risk of hepatitis B virus reactivation in patients undergoing long-term tocilizumab therapy for rheumatoid arthritis., Method: From January 2011 through August 2019, a total of 97 patients were enrolled in this retrospective study. Clinical data, comedications, and the occurrence of HBV reactivation were recorded., Results: Seven patients were HBsAg+ (7.2%), 64 were HBsAg-/HBcAb+ (65.9%), and 26 were HBsAg-/HBcAb- (26.8%). The median disease follow-up time was 9 years. TCZ was administered for a median of 29 months. Four patients (4.1%) experienced HBV reactivation after tocilizumab therapy. Of the 7 HBsAg+ patients, 4 received antiviral prophylaxis and had no HBV reactivation; the remaining 3 patients did not receive antiviral prophylaxis, and all 3 (100%) experienced HBV reactivation and hepatitis flare-up. Hyperbilirubinemia occurred in 2 of these 3 patients, with mild prothrombin time prolongation in one. After salvage entecavir treatment, all patients had a favorable outcome. Of the 64 HBsAg-/HBcAb+ patients, only one became positive for serum HBV DNA (2.5 × 10 7  IU/mL) after 18 months of tocilizumab treatment (1.6%; 1/64). This patient was immediately treated with entecavir, which prevented hepatitis flare-up., Conclusions: Tocilizumab is widely used in treating rheumatoid arthritis and has the potential to reduce the mortality rate among severe COVID-19 patients. However, HBV reactivation needs to be considered. HBsAg+ patients have a high risk of HBV reactivation, which could be prevented by antiviral prophylaxis. Although the risk of reactivation is low in HBsAg-/HBcAb+ patients, strict monitoring is necessary., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N 6 -methyladenosine (m 6 A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m 6 A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m 6 A and the m 6 A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m 6 A that contributes to the integrated stress response of oTau., Competing Interests: Declaration of interests B.W. is a co-founder and chief scientific officer of Aquinnah Pharmaceuticals Inc., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, is recognized as a potential target for cancer immunotherapy as well as for the induction of transplantation tolerance. However, how the crosstalk between stem cell programming and cytokine signaling regulates PD-L1 expression during stem cell differentiation and cancer cell plasticity remains unclear. Herein, we reported that PD-L1 expression was regulated by SOX2 during embryonic stem cell (ESC) differentiation and lung cancer cell plasticity. PD-L1 was induced during ESC differentiation to fibroblasts and was downregulated during SOX2-mediated reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). Furthermore, SOX2 activation affected cancer cell plasticity and inhibited PD-L1 expression in lung cancer cells. We discovered that the H3K27ac signal at the PD-L1 locus was enhanced during ESC differentiation to fibroblasts as well as during cancer plasticity of SOX2-positive lung cancer cells to SOX2-negative counterparts. Romidepsin, an epigenetic modifier, induced PD-L1 expression in lung cancer cells, whereas TGF-β stimulation downregulated SOX2 but upregulated PD-L1 expression in lung cancer cells. Furthermore, in addition to PD-L1, the expressions of EGFR and its ligand HBEGF were downregulated by activation of endogenous SOX2 expression during lung cancer cell plasticity and iPSC reprogramming, and the activation of EGFR signaling by HBEGF upregulated PD-L1 expression in lung cancer cells. Together, our results reveal the crosstalk between SOX2 programming and cytokine stimulation influences PD-L1 expression, and these findings may provide insights into PD-L1-mediated therapeutics., (© 2021 AlphaMed Press.)

Adults with schizophrenia usually have impairments in theory of mind (ToM), which subsequently cause them problems in social interaction. Therefore, it is important for healthcare providers to assess their ToM using adequate measures. This systematic review evaluated current ToM measures (or ToM tasks) for adults with schizophrenia and summarized their specific characteristics, including the concept and construct, administration, and psychometric properties. From a review of 117 articles, 13 types of ToM tasks were identified, and the findings from these articles were qualitatively synthesized. The results showed that ToM tasks are diverse in their presentation modalities, answer modes, strategies of controlling cognitive confounders, and scoring. Most tasks employ cognitive and affective dimensions and target a specific, single ToM concept. The present systematic review found that psychometric evidence supporting the ToM tasks, such as internal consistency, test-retest reliability, unidimensionality, and convergent, criterion, and ecological validities, is insufficient. Based on the results, we propose several principles for selecting appropriate ToM tasks in practice, e.g., selecting a task with multiple ToM concepts, or an exclusive ToM construct containing the cognitive and affective dimensions. Moreover, future studies are needed to provide more psychometric evidence on each type of ToM task applied in people with schizophrenia.

Background: The successful completion of medical practices often relies on information collection and analysis. Government agencies and medical institutions have encouraged people to use medical information technology (MIT) to manage their conditions and promote personal health. In 2014, Taiwan established the first electronic personal health record (PHR) platform, My Health Bank (MHB), which allows people to access and manage their PHRs at any time. In the face of the COVID-19 pandemic in 2020, Taiwan has used MIT to effectively prevent the spread of COVID-19 and undertaken various prevention measures before the onset of the outbreak. Using MHB to purchase masks in an efficient and orderly way and thoroughly implementing personal protection efforts is highly important to contain disease spread., Objective: This study aims to understand people's intention to use the electronic PHR platform MHB and to investigate the factors affecting their intention to use this platform., Methods: From March 31 to April 9, 2014, in a promotion via email and Facebook, participants were asked to fill out a structured questionnaire after watching an introductory video about MHB on YouTube. The questionnaire included seven dimensions: perceived usefulness, perceived ease of use, health literacy, privacy and security, computer self-efficacy, attitude toward use, and behavioral intention to use. Each question was measured on a 5-point Likert scale ranging from "strongly disagree" (1 point) to "strongly agree" (5 points). Descriptive statistics and structural equation analysis were performed using SPSS 21 and AMOS 21 software., Results: A total of 350 valid questionnaire responses were collected (female: 219/350, 62.6%; age: 21-30 years: 238/350, 68.0%; university-level education: 228/350, 65.1%; occupation as student: 195/350, 56.6%; average monthly income 2 310 =2.63), goodness-of-fit index (0.85), adjusted goodness-of-fit index (0.81), comparative fit index (0.91), and root mean square error of approximation (0.07), were calculated. The results indicated a good fit. Further analysis indicated that the most important factor affecting respondents' behavioral intention to use MHB was their attitude toward use (0.78), followed by perceived ease of use (0.65), perceived usefulness (0.41), health literacy (0.10), and privacy and security (0.07)., Conclusions: From the perspective of the populace, this study explored the factors affecting the use of MHB and constructed an interpretation model with a strong goodness of fit. The results of our analysis are consistent with the technology acceptance model. Through the diverse value-added services of MHB, Taiwan's experience in pandemic prevention with smart technology can facilitate future responses to unknown, emerging infectious diseases., (©Wen-Hsun Tsai, Yi-Syuan Wu, Chia-Shiang Cheng, Ming-Hao Kuo, Yu-Tien Chang, Fu-Kang Hu, Chien-An Sun, Chi-Wen Chang, Ta-Chien Chan, Chao-Wen Chen, Chia-Cheng Lee, Chi-Ming Chu. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 21.04.2021.)

Genetic co-expression network (GCN) analysis augments the understanding of breast cancer (BC). We aimed to propose GCN-based modeling for BC relapse-free survival (RFS) prediction and to discover novel biomarkers. We used GCN and Cox proportional hazard regression to create various prediction models using mRNA microarray of 920 tumors and conduct external validation using independent data of 1056 tumors. GCNs of 34 identified candidate genes were plotted in various sizes. Compared to the reference model, the genetic predictors selected from bigger GCNs composed better prediction models. The prediction accuracy and AUC of 3 ~ 15-year RFS are 71.0-81.4% and 74.6-78% respectively (rfm, ACC 63.2-65.5%, AUC 61.9-74.9%). The hazard ratios of risk scores of developing relapse ranged from 1.89 ~ 3.32 (p < 10 -8 ) over all models under the control of the node status. External validation showed the consistent finding. We found top 12 co-expressed genes are relative new or novel biomarkers that have not been explored in BC prognosis or other cancers until this decade. GCN-based modeling creates better prediction models and facilitates novel genes exploration on BC prognosis.

The presence of microplastics (MPs) in the environment has generated global concerns. However, the explicit assessment of the effect of multiple anthropogenic activities on the existence of MPs in the freshwater system is scarcely reported. This study quantified anthropogenic activities and analyzed their relationship with MPs on a freshwater organism: the midge larvae (Diptera: Chironomidae). The study took place in an urban river and consisted of comparing the abundance and types of MPs. Our results highlight that, while industrial area was the most important variable contributing to the total MP concentration in midge larvae, residential area also influenced the concentration of microfibers in midge larvae. The impact of a residential area on the relative abundance of microfibers in each sample site was diluted by the proximity to an industrial area. In conclusion, we suggest that industrial areas are a potential source of MP pollution in river sediment, and midge larvae can be a good indicator of the MP concentrations in urban river systems. Quantifying anthropogenic activities can help discern their effects on MP concentration in a river system and promote management strategies.

Alzheimer's disease (AD) is a neurodegenerative disorder without a cure or prevention to date. Hyperphosphorylated tau forms the neurofibrillary tangles (NFTs) that correlate well with the progression of cognitive impairments. Animal studies demonstrated the pathogenic role of hyperphosphorylated tau. Understanding how abnormal phosphorylation renders a normal tau prone to form toxic fibrils is key to delineating molecular pathology and to developing efficacious drugs for AD. Production of a tau bearing the disease-relevant hyperphosphorylation and molecular characters is a pivotal step. Here, we report the preparation and characterization of a recombinant hyperphosphorylated tau (p-tau) with strong relevance to disease. P-tau generated by the PIMAX approach resulted in phosphorylation at multiple epitopes linked to the progression of AD neuropathology. In stark contrast to unmodified tau that required an aggregation inducer, and which had minimal effects on cell functions, p-tau formed inducer-free fibrils that triggered a spike of mitochondrial superoxide, induced apoptosis, and caused cell death at sub-micromolar concentrations. P-tau-induced apoptosis was suppressed by inhibitors for reactive oxygen species. Hyperphosphorylation apparently caused rapid formation of a disease-related conformation. In both aggregation and cytotoxicity, p-tau exhibited seeding activities that converted the unmodified tau into a cytotoxic species with an increased propensity for fibrillization. These characters of p-tau are consistent with the emerging view that hyperphosphorylation causes tau to become an aggregation-prone and cytotoxic species that underlies diffusible pathology in AD and other tauopathies. Our results further suggest that p-tau affords a feasible tool for Alzheimer's disease mechanistic and drug discovery studies.

Regulation of the stemness factor, SOX2, by cytokine stimuli controls self-renewal and differentiation in cells. Activating mutations in EGFR are proven therapeutic targets for tyrosine kinase inhibitors (TKI) in lung adenocarcinoma, but acquired resistance to TKIs inevitably occurs. The mechanism by which stemness and differentiation signaling emerge in lung cancers to affect TKI tolerance and lung cancer dissemination has yet to be elucidated. Here, we report that cross-talk between SOX2 and TGFβ signaling affects lung cancer cell plasticity and TKI tolerance. TKI treatment favored selection of lung cancer cells displaying mesenchymal morphology with deficient SOX2 expression, whereas SOX2 expression promoted TKI sensitivity and inhibited the mesenchymal phenotype. Preselection of EGFR-mutant lung cancer cells with the mesenchymal phenotype diminished SOX2 expression and TKI sensitivity, whereas SOX2 silencing induced vimentin, but suppressed BCL2L11, expression and promoted TKI tolerance. TGFβ stimulation downregulated SOX2 and induced epithelial-to-mesenchymal transdifferentiation accompanied by increased TKI tolerance, which can interfere with ectopic SOX2 expression. SOX2-positive lung cancer cells exhibited a lower dissemination capacity than their SOX2-negative counterparts. Tumors expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in patients with EGFR mutations. These findings provide insights into how cancer cell plasticity regulated by SOX2 and TGFβ signaling affects EGFR-TKI tolerance and lung cancer dissemination. SIGNIFICANCE: These findings suggest the potential of SOX2 as a prognostic marker in EGFR-mutant lung cancer, as SOX2-mediated cell plasticity regulated by TGFβ stimulation and epigenetic control affects EGFR-TKI tolerance and cancer dissemination., (©2020 American Association for Cancer Research.)

The neurodegenerative Alzheimer's disease (AD) affects more than 30 million people worldwide. There is thus far no cure or prevention for AD. Aggregation of hyperphosphorylated tau in the brain correlates with the cognitive decline of patients of AD and other neurodegenerative tauopathies. Intracerebral injection of tau aggregates isolated from tauopathy brains causes similar pathology in the recipient mice, demonstrating the pathogenic role of abnormally phosphorylated tau. Compounds controlling the aggregation of hyperphosphorylated tau therefore are probable modulators for the disease. Here we report the use of recombinant hyperphosphorylated tau (p-tau) to identify potential tauopathy therapeutics and risk factors. Hyperphosphorylation renders tau prone to aggregate and to impair cell viability. Taking advantage of these two characters of p-tau, we performed a screen of a 1280-compound library, and tested a selective group of prescription drugs in p-tau aggregation and cytotoxicity assays. R-(-)-apomorphine and raloxifene were found to be p-tau aggregation inhibitors that protected p-tau-treated cells. In contrast, a subset of benzodiazepines exacerbated p-tau cytotoxicity apparently via enhancing p-tau aggregation. R-(-)apomorphine and raloxifene have been shown to improve cognition in animals or in humans, whereas benzodiazepines were linked to increased risks of dementia. Our results demonstrate the feasibility and potential of using hyperphosphorylated tau-based assays for AD drug discovery and risk factor identification.

Background: Long-distance running can be a form of stress to the heart. Technological improvements combined with the public's gradual turn toward mobile health (mHealth), self-health, and exercise effectiveness have resulted in the widespread use of wearable exercise products. The monitoring of dynamic cardiac function changes during running and running performance should be further studied., Objective: We investigated the relationship between dynamic cardiac function changes and finish time for 3000-meter runs. Using a wearable device based on a novel cardiac force index (CFI), we explored potential correlations among 3000-meter runners with stronger and weaker cardiac functions during running., Methods: This study used the American product BioHarness 3.0 (Zephyr Technology Corporation), which can measure basic physiological parameters including heart rate, respiratory rate, temperature, maximum oxygen consumption, and activity. We investigated the correlations among new physiological parameters, including CFI = weight * activity / heart rate, cardiac force ratio (CFR) = CFI of running / CFI of walking, and finish times for 3000-meter runs., Results: The results showed that waist circumference, smoking, and CFI were the significant factors for qualifying in the 3000-meter run. The prediction model was as follows: ln (3000 meters running performance pass probability / fail results probability) = -2.702 - 0.096 × [waist circumference] - 1.827 × [smoke] + 0.020 × [ACi7]. If smoking and the ACi7 were controlled, contestants with a larger waist circumference tended to fail the qualification based on the formula above. If waist circumference and ACi7 were controlled, smokers tended to fail more often than nonsmokers. Finally, we investigated a new calculation method for monitoring cardiac status during exercise that uses the CFI of walking for the runner as a reference to obtain the ratio between the cardiac force of exercise and that of walking (CFR) to provide a standard for determining if the heart is capable of exercise. A relationship is documented between the CFR and the performance of 3000-meter runs in a healthy 22-year-old person. During the running period, data are obtained while participant slowly runs 3000 meters, and the relationship between the CFR and time is plotted. The runner's CFR varies with changes in activity. Since the runner's acceleration increases, the CFR quickly increases to an explosive peak, indicating the runner's explosive power. At this period, the CFI revealed a 3-fold increase (CFR=3) in a strong heart. After a time lapse, the CFR is approximately 2.5 during an endurance period until finishing the 3000-meter run. Similar correlation is found in a runner with a weak heart, with the CFR at the beginning period being 4 and approximately 2.5 thereafter., Conclusions: In conclusion, the study results suggested that measuring the real-time CFR changes could be used in a prediction model for 3000-meter running performance., (©Po-Jen Hsiao, Chih-Chien Chiu, Ke-Hsin Lin, Fu-Kang Hu, Pei-Jan Tsai, Chun-Ting Wu, Yuan-Kai Pang, Yu Lin, Ming-Hao Kuo, Kang-Hua Chen, Yi-Syuan Wu, Hao-Yi Wu, Ya-Ting Chang, Yu-Tien Chang, Chia-Shiang Cheng, Chih-Pin Chuu, Fu-Huang Lin, Chi-Wen Chang, Yuan-Kuei Li, Jenq-Shyong Chan, Chi-Ming Chu. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 21.07.2020.)

Signaling elicited by the stem cell factors SOX2, OCT4, KLF4, and MYC not only mediates reprogramming of differentiated cells to pluripotency but has also been correlated with tumor malignancy. In this study, we found SOX2 expression signifies poor recurrence-free survival and correlates with advanced pathological grade in bladder cancer. SOX2 silencing attenuated bladder cancer cell growth, while its expression promoted cancer cell survival and proliferation. Under low-serum stress, SOX2 expression promoted AKT phosphorylation and bladder cancer cells' spheroid-forming capability. Furthermore, pharmacological inhibition of AKT phosphorylation, using MK2206, inhibited the SOX2-mediated spheroid formation of bladder cancer cells. Gene expression profiling showed that SOX2 expression, in turn, induced IGF2 expression, while SOX2 silencing inhibited IGF2 expression. Moreover, knocking down IGF2 and IGF1R diminished bladder cancer cell growth. Lastly, pharmacological inhibition of IGF1R, using linsitinib, also inhibited the SOX2-mediated spheroid formation of bladder cancer cells under low-serum stress. Our findings indicate the SOX2-IGF2 signaling affects the aggressiveness of bladder cancer cell growth. This signaling could be a promising biomarker and therapeutic target for bladder cancer intervention.

As the first line of treatment for hepatitis C virus (HCV) infection, direct-acting antivirals (DAAs) have greater efficacy and fewer adverse effects than other treatments; however, drug-drug interactions (DDIs) must be avoided when used in combination with other medications, such as statins. HCV patients are mostly in the need for polypharmacy, particularly the comedication of DAAs and cardiovascular drugs such as statins. This poses a risk of pharmacokinetic interactions between the two classes of drugs that may lead to severe myopathy or even rhabdomyolysis. Therefore, evaluating the severity of the DDIs and managing them is important. A multidisciplinary team-based model of care for HCV patients receiving DAAs can review the pharmacology profiles of other drugs for relevant DDIs with the DAAs, before prescription. Such a model can also follow the patients through the therapeutic cycle to make sure that their medical regimen is safe and effective. This article reviews the comedication rate and DDI-prevalence in HCV patients receiving statins along with the DAAs, details the mechanisms involved, gives recommendations for management, and shares our experience with a multidisciplinary team-based care program for the treatment of HCV patients., Competing Interests: There is no conflict of interest., (Copyright: © 2020 Tzu Chi Medical Journal.)

To investigate the incidence and risk factors of hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg) - / HBV core antibody (HBcAb) + patients who underwent rituximab (RTX) therapy for rheumatoid arthritis (RA). From January 2000 through December 2017, a total of 134 RA patients with various HBV serostatuses who received RTX at Dalin Tzu Chi Hospital were screened. Finally, 50 HBsAg - /HBcAb + patients were enrolled in this retrospective study. Baseline characteristics, comedications, and the occurrence of HBV reactivation were recorded. Four HBsAg - /HBcAb + RA patients (8%; 4/50) experienced HBV reactivation after treatment with RTX. Hepatitis flare-up occurred in 2 of these 4 patients, with a fatal outcome in one. HBV reactivation occurred approximately 1-4 years after the first dose of RTX and 0.5-1.5 years after the last one. In HBsAg - /HBcAb + patients, HBV reactivation was significantly more common in those who were HBV surface antibody (HBsAb) - at baseline than in those who were HBsAb + (30% vs 4%; p = 0.02). A history of adalimumab use was associated with HBV reactivation (100% vs 39%; p = 0.02). A moderate risk of HBV reactivation was observed in HBsAg - /HBcAb + RA patients receiving RTX therapy. The reactivation may induce acute hepatitis and even death. To reduce the risk of HBV reactivation, regular monitoring of liver function is insufficient; monitoring of viral load and HBsAg or prophylaxis with antiviral therapy should be considered.

Ischemic stroke is a leading cause of human death in present times. Two phases of pathological impact occur during an ischemic stroke, namely, ischemia and reperfusion. Both periods include individual characteristic effects on cell injury and apoptosis. Moreover, these conditions can cause severe cell defects and harm the blood-brain barrier (BBB). Also, the BBB components are the major targets in ischemia-reperfusion injury. The BBB owes its enhanced protective roles to capillary endothelial cells, which maintain BBB permeability. One of the nerve growth factor (NGF) receptors initiating cell signaling, once activated, is the p75 neurotrophin receptor (p75NTR). This receptor is involved in both the survival and apoptosis of neurons. Although many studies have attempted to explain the role of p75NTR in neurons, the mechanisms in endothelial cells remain unclear. Endothelial cells are the first cells to encounter p75NTR stimuli. In this study, we found the upregulated p75NTR expression and reductive expression of tight junction proteins after in vivo and in vitro ischemia-reperfusion injury. Moreover, astaxanthin (AXT), an antioxidant drug, was utilized and was found to reduce p75NTR expression and the number of apoptotic cells. This study verified that p75NTR plays a prominent role in endothelial cell death and provides a novel downstream target for AXT., Competing Interests: The authors declare no conflict of interest.

Breast cancer brain metastasis commonly occurs in one-fourth of breast cancer patients and is associated with poor prognosis. Abnormal glucose metabolism is found to promote cancer metastasis. Moreover, the tumor microenvironment is crucial and plays an active role in the metabolic adaptations and survival of cancer cells. Glucose transporters are overexpressed in cancer cells to increase glucose uptake. The glucose transporter 3 (GLUT3) is a high-affinity glucose transporter that is highly expressed in mammalian neurons. GLUT3 is also overexpressed in several malignant brain tumors. However, the role of GLUT3 in breast cancer brain metastasis remains unknown. The results of the present study demonstrated that GLUT3 is highly overexpressed in brain metastatic breast cancers and mediates glucose metabolic reprogramming. Furthermore, knockdown of cAMP-response element binding protein (CREB) could directly regulate GLUT3 expression in brain metastatic breast cancer cells. Notably, we verified and provided a novel role of GLUT3 in mediating glucose metabolism and assisting breast cancer cells to survive in the brain to promote brain metastasis., Competing Interests: The authors declare no conflict of interest.

Hypoxia, the reduction of oxygen levels in cells or tissues, elicits a set of genes to adjust physiological and pathological demands during normal development and cancer progression. OCT4, a homeobox transcription factor, is essential for self-renewal of embryonic stem cells, but little is known about the role of OCT4 in non-germ-cell tumorigenesis. Here, we report that hypoxia stimulates a short isoform of OCT4, called OCT4B, via a HIF2α-dependent pathway to induce the epithelial-mesenchymal transition (EMT) and facilitate cancer dissemination. OCT4B overexpression decreased epithelial barrier properties, which led to an increase in cell migration and invasion in lung cancer cells. OCT4B knockdown attenuated HIF2α-induced EMT and inhibited cancer dissemination in cell-line and animal models. We observed that OCT4B bound the SLUG promoter and enhanced its expression, and SLUG silencing inhibited OCT4B-mediated EMT, accompanied with decreased cell migration and invasion. Correlation analysis revealed that OCT4B expression was significantly associated with the SLUG level in lung tumors. These results provide novel insights into OCT4B-mediated oncogenesis in cancer dissemination.