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Thrombolytic (clot-busting) therapies with plasminogen activators (PAs) are first-line treatments against acute thrombosis and ischemic stroke. However, limitations such as narrow therapeutic windows, low success rates, and bleeding complications hinder their clinical use. Drug-loaded polyphenol-based nanoparticles (NPs) could address these shortfalls by delivering a more targeted and safer thrombolysis, coupled with advantages such as improved biocompatibility and higher stability in vivo. Herein, a template-mediated polyphenol-based supramolecular assembly strategy is used to prepare nanocarriers of thrombolytic drugs. A thrombin-dependent drug release mechanism is integrated using tannic acid (TA) to cross-link urokinase-type PA (uPA) and a thrombin-cleavable peptide on a sacrificial mesoporous silica template via noncovalent interactions. Following drug loading and template removal, the resulting NPs retain active uPA and demonstrate enhanced plasminogen activation in the presence of thrombin (1.14-fold

Objective: Patients with stroke often have accompanying sleep disorders. However, sleep quality plays a crucial role in motor function recovery and brain reorganization. Improving sleep disorders is therefore of great clinical importance. Studies have shown that exercise and increased physical activity have positive effects on sleep disorders and sleep quality. However, studies supporting the use of rehabilitation exercise to achieve a similar effect on sleep quality in patients with stroke are still limited. Therefore, in this study, actigraphy was used to analyze the relationship between the amount and intensity of rehabilitation exercise and sleep. This study contributes to understanding regarding the effects of rehabilitation exercise on sleep quality in patients with stroke. Methods:An observational study was conducted to investigate the correlation between the amount and intensity of rehabilitation exercise in patients with stroke and their sleep quality. Results: We observed a positive correlation between moderate- and high-intensity exercise duration and sleep efficiency, but only the correlation between high-intensity exercise duration and sleep efficiency was significant (p≦0.001). We found a negative correlation between high-, moderate-, and low-intensity exercise duration and real sleep time. However, only low-intensity exercise duration was significantly correlated with real sleep time (p≦0.001). We also observed a significant negative correlation between high- (p≦0.001), moderate- (p≦0.001), and low-intensity (p = 0.008) exercise duration and total sleep time. Almost no significant correlation was noted between adjustment factors (gender, age, stroke type, and motor disability severity) and sleep efficiency; we only noted a significant negative correlation between left-sided strokes and sleep efficiency (p = 0.001). Conclusions: High-intensity rehabilitation exercise had a significant positive effect on sleep efficiency in the observed patients with stroke. Rehabilitation exercise, regardless of its intensity, could reduce required sleep time in the patients with stroke. Furthermore, we recommend instructing patients to engage in not only rehabilitation exercise, but specifically, moderate- or high-intensity rehabilitation exercise, because only such exercise could effectively improve patients’ sleep quality.

ObjectiveTo study the association of α2,6-sialic acid (SIA) content in serum IgG anti-dsDNA with human systemic lupus erythematosus disease activity index (SLEDAI) and the effect of sialylated and desialylated (deSIA) IgG anti-dsDNA on lupus B cells.MethodsBlood from lupus patients was collected to determine the ratio of SIA in isolated IgG anti-dsDNA over serum IgG anti-dsDNA (SIA/IgG anti-dsDNA) ratios, which were plotted against SLEDAI using a receiver-operating-characteristics curve. Lupus B cells were cultured in vitro with chimeric sialylated IgG anti-dsDNA and its deSIA form. Culture supernatants were assayed for anti-inflammatory IL-10 and SIA/IgG anti-dsDNA ratios, which were compared among different pre-treatment groups using t-tests.ResultsThe area-under-the-curve (AUC) for anti-dsDNA levels against SLEDAI was 0.791 positively (95% confidence interval [C.I.]: 0.699–0.884) and SIA/IgG anti-dsDNA ratios against SLEDAI yielded an AUC of 0.705 inversely (95% C.I: 0.601–0.809): not significantly different. SIA/IgG anti-dsDNA ratios discriminated significantly between patients without and patients with proteinuria ( p = .046). SIA/IgG anti-dsDNA ratios correlated significantly and positively with serum C3c and C4 levels. Pre-treatment with IgG anti-dsDNA and its immune complexes (dsDNA/IgG anti-dsDNA IC) induced higher IL-10 from lupus B cells than medium pre-treatment (most p < .01 from day 2 to day 5 culture). DeSIA IgG anti-dsDNA IC induced lower IL-10 ( p < .05) and lower SIA/IgG anti-dsDNA ratios ( p < .001) from lupus B cells than medium and dsDNA pre-treatment.Conclusionα2,6-SIA/IgG anti-dsDNA ratios inversely forecasted SLEDAI scores. Possible mechanisms may be due to the different effects of sialylated and deSIA IgG anti-dsDNA on lupus B cells in terms of IL-10 secretion and SIA/IgG anti-dsDNA ratios.

Thorough quality assessment of novel interactions identified by proteome-wide cross-linking mass spectrometry (XL-MS) studies is critical. Almost all current XL-MS studies have validated cross-links against known 3D structures of representative protein complexes. Here we provide theoretical and experimental evidence demonstrating this approach can drastically underestimate error rates for proteome-wide XL-MS datasets, and propose a comprehensive set of four data-quality metrics to address this issue., Editorial summary: The current standard approach for estimating error in proteome-scale crosslinking-mass spectrometry datasets has severe limitations. A proposed set of data-quality metrics provides a more accurate assessment of error rate.

The pyrophosphate ion (P2O74-, PPi) plays a critical role in various biological processes and acts as an essential indicator for physiological mechanism investigations and disease control monitoring. However, most of the currently available approaches for PPi species detection for practical usage still lack appropriate indicator generation, straightforward detection requirements, and operation convenience. In this study, a highly sensitive and selective PPi detection approach via the use of nanozymatic carbon dots (CDs) is introduced. This strategy eliminates the common need for metal ions in the detection process, where a direct indicator-PPi interaction is adopted to provide straightforward signal reports, and importantly, through a green indicator preparation. The preparation of this nanozymatic CDs' indicator utilizes an aqueous solution refluxing, employing galactose and histidine as the precursor materials. The mild conditions of the solution refluxing produce fluorescent CDs exhibiting peroxidase-mimic properties, which can catalyze the o-phenylenediamine oxidation under the presence of H2O2. The introduction of PPi species, interestingly, inhibits this process very efficiently, the extent of which can be colorimetrically monitored by the generated yellow product 2,3-diaminophenazine. Spectroscopic results point to CD surface functional groups' selective binding toward PPi species, which severely interferes with the electron transfer process in the enzymatic catalysis. Relying on this CD peroxidase-mimetic property inhibition, sensitive and selective recognition of PPi reaches a detection limit of 4.29 nM, enabling practical usage in complex matrixes. Owing to the superior compatibility and high stability of nanozymatic CDs, they can also be inkjet-printed on paper-based devices to create a portable and convenient platform for PPi detection. Both the solution and the paper-device-based selective recognitions confirm this unique and robust metal-free inhibitive PPi detection, which is supported by a convenient green preparation of nanozymatic CDs.

We report the development of a theranostic collagen targeted cell penetrating drug delivery system toward treatment of cardiovascular disease. Caused by the action of matrix metalloproteinases (MMP...

The main purpose of this study was to investigate the effects of neurofeedback training (NFT) of theta activity on working memory (WM) and episodic memory (EM) in healthy participants via a systematic review and meta-analysis. A total of 337 articles obtained from electronic databases were assessed; however, only 11 articles met the criteria for meta-analysis after manually screening and eliminating unnecessary studies. A meta-analysis calculating the Hedges’ g effect size metric with 95% confidence intervals using random effects models was employed. Heterogeneity was estimated using I2 statistics. Theta NFT is effective in improving memory outcomes, including WM with a Hedges’ g of 0.56 [0.10; 1.02] (I2 = 62.9% and p = 0.02), and EM with a Hedges’ g of 0.62 [0.13; 1.10] (I2 = 42.04% and p = 0.01). Overall, the results suggest that theta NFT seems to be useful as nonpharmacological/adjunct training to improve WM and EM in healthy participants.

The provision by nurses of effective swallowing assessments and eating safety guidance improves eating safety in the elderly. The authors of this study found that elderly clients experienced a high proportion of aspiration pneumonia after choking episodes and that the rate of implementation of eating safety guidance among these clients by nursing staff was only 64.6%. The problems identified included a lack of education and training related to eating safety for the elderly, inconsistent health education methods, oral health education only, lack of unified health education content, and lack of proper health education guidance aids.To raise the rate of implementing eating safety guidance among the elderly from 64.6% to 90.0%.The project included promoting an eating safety guidance workflow for the elderly using cross-team collaboration, using human body models and food models, promoting oral healthcare and oral exercises, using multilingual instructional leaflets and videos on eating safety and hygiene education, promoting a treasure hunting activity to the elderly related to eating safely using a food texture selection chart, and implementing a workshop on simulated eating safety scenarios.After project implementation, the eating safety guidance implementation rate increased from 64.6% to 92.1%, demonstrating that the intervention measures achieved remarkable results.Formulating care procedures and cooperating across teams to draft concrete and feasible improvement measures effectively increased the rate of eating safety guidance implementation for elderly clients by nursing staff.提升高齡長者進食安全指導執行率.有效的吞嚥評估及進食安全指導，可提升高齡長者進食安全，經現況分析發現高齡長者發生嗆咳後，導致吸入性肺炎比例高，護理人員對高齡長者進食安全指導執行率僅64.6%，歸納原因為未接受過高齡長者進食安全相關教育訓練、教導內容不一致，僅採口頭衛教指導、沒有統一的衛教內容及沒有適當衛教指導輔助工具。.護理人員對高齡長者進食安全指導執行率，由64.6%提升至90.0%。.經由跨團隊合作推展高齡長者進食安全指導作業流程、運用人體模型及食物模型、推行口腔保健及健口操、使用多元語言進食安全衛教指導單張及影片、推展樂齡長者進食安全尋寶趣~食物質地選擇圖卡、實施進食安全情境模擬工作坊。.經由專案實施改善後，護理人員對於高齡長者進食安全指導執行率，由64.6%提升至92.1%，表示介入措施的成效顯著。.藉由制訂照護流程及與跨團隊合作擬定具體可行之改善措施，以有效提升護理人員對高齡長者進食安全指導執行率。.

Each human genome carries tens of thousands of coding variants. The extent to which this variation is functional and the mechanisms by which they exert their influence remains largely unexplored. To address this gap, we leverage the ExAC database of 60,706 human exomes to investigate experimentally the impact of 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions, generating interaction profiles for 4797 SNV-interaction pairs, of which 421 SNVs segregate at > 1% allele frequency in human populations. We find that interaction-disruptive SNVs are prevalent at both rare and common allele frequencies. Furthermore, these results suggest that 10.5% of missense variants carried per individual are disruptive, a higher proportion than previously reported; this indicates that each individual’s genetic makeup may be significantly more complex than expected. Finally, we demonstrate that candidate disease-associated mutations can be identified through shared interaction perturbations between variants of interest and known disease mutations., Low frequency coding single-nucleotide variants (SNVs) are predicted to disproportionately affect protein function. Here, the authors evaluate 2,009 missense SNVs across 2,185 protein-protein interactions using yeast two-hybrid and protein complementation assays and find that disruptive SNVs often occur in disease-associated genes.

Drug carriers typically require both stealth and targeting properties to minimize nonspecific interactions with healthy cells and increase specific interaction with diseased cells. Herein, the assembly of targeted poly(ethylene glycol) (PEG) particles functionalized with cyclic peptides containing Arg-Gly-Asp (RGD) (ligand) using a mesoporous silica templating method is reported. The influence of PEG molecular weight, ligand-to-PEG molecule ratio, and particle size on cancer cell targeting to balance stealth and targeting of the engineered PEG particles is investigated. RGD-functionalized PEG particles (PEG-RGD particles) efficiently target U-87 MG cancer cells under static and flow conditions in vitro, whereas PEG and cyclic peptides containing Arg-Asp-Gly (RDG)-functionalized PEG (PEG-RDG) particles display negligible interaction with the same cells. Increasing the ligand-to-PEG molecule ratio improves cell targeting. In addition, the targeted PEG-RGD particles improve cell uptake via receptor-mediated endocytosis, which is desirable for intracellular drug delivery. The PEG-RGD particles show improved tumor targeting (14% ID g-1) when compared with the PEG (3% ID g-1) and PEG-RDG (7% ID g-1) particles in vivo, although the PEG-RGD particles show comparatively higher spleen and liver accumulation. The targeted PEG particles represent a platform for developing particles aimed at balancing nonspecific and specific interactions in biological systems.

The DNA mismatch repair (MMR) factor Mlh1–Pms1 contains long intrinsically disordered regions (IDRs) whose exact functions remain elusive. We performed cross-linking mass spectrometry to identify interactions within Mlh1–Pms1 and used this information to insert FRB and FKBP dimerization domains into their IDRs. Baker's yeast strains bearing these constructs were grown with rapamycin to induce dimerization. A strain containing FRB and FKBP domains in the Mlh1 IDR displayed a complete defect in MMR when grown with rapamycin. but removing rapamycin restored MMR functions. Strains in which FRB was inserted into the IDR of one MLH subunit and FKBP into the other subunit were also MMR defective. The MLH complex containing FRB and FKBP domains in the Mlh1 IDR displayed a rapamycin-dependent defect in Mlh1–Pms1 endonuclease activity. In contrast, linking the Mlh1 and Pms1 IDRs through FRB-FKBP dimerization inappropriately activated Mlh1–Pms1 endonuclease activity. We conclude that dynamic and coordinated rearrangements of the MLH IDRs both positively and negatively regulate how the MLH complex acts in MMR. The application of the FRB-FKBP dimerization system to interrogate in vivo functions of a critical repair complex will be useful for probing IDRs in diverse enzymes and to probe transient loss of MMR on demand.

Particle‐based pulmonary delivery has great potential for delivering inhalable therapeutics for local or systemic applications. The design of particles with enhanced aerodynamic properties can improve lung distribution and deposition, and hence the efficacy of encapsulated inhaled drugs. This study describes the nanoengineering and nebulization of metal–phenolic capsules as pulmonary carriers of small molecule drugs and macromolecular drugs in lung cell lines, a human lung model, and mice. Tuning the aerodynamic diameter by increasing the capsule shell thickness (from ≈100 to 200 nm in increments of ≈50 nm) through repeated film deposition on a sacrificial template allows precise control of capsule deposition in a human lung model, corresponding to a shift from the alveolar region to the bronchi as aerodynamic diameter increases. The capsules are biocompatible and biodegradable, as assessed following intratracheal administration in mice, showing >85% of the capsules in the lung after 20 h, but 90% of capsules remaining nonassociated with cells. The amenability to nebulization, capacity for loading, tunable aerodynamic properties, high biocompatibility, and biodegradability make these capsules attractive for controlled pulmonary delivery., The aerodynamic diameters of metal–phenolic capsules are nanoengineered by increasing their shell thickness, which facilitates tailored capsule deposition in a mechanical lung model. The engineered capsules are promising for pulmonary delivery owing to their robustness for nebulization, biocompatibility, biodegradability, and their capacity for cargo loading and surface functionalization.

Objective The prevalence of Helicobacter pylori resistance to amoxicillin was less than 5% in most countries. Proton pump inhibitor (PPI)-amoxicillin dual therapy dosing four times daily (q.i.d.) for 14 days could achieve an eradication rate of more than 85%. It is unclear whether dual therapy with shorter treatment duration or lower dosing frequency could also attain a satisfactory cure rate. We conducted a randomized controlled trial to assess the efficacy and safety of two modified esomeprazole-amoxicillin dual therapies, 10-day q.i.d. and 14-day three times daily (t.i.d.) dual therapy, and investigate the factors that might affect the eradication rates. Participants and methods A total of 253 patients were screened for eligibility and 208 patients were randomly assigned to 10-day dual therapy (esomeprazole 20 mg and amoxicillin 750 mg, all given four times daily) or 14-day dual therapy (esomeprazole 20 mg and amoxicillin 1000 mg, all given three times daily). Results In the intention-to-treat analysis, the eradication rates for 10-day and 14-day groups were 79.8% [95% confidence interval (CI): 70.2-87.4%] and 83.5% (95% CI: 74.3-90.5%) as first-line therapies; and 80% (95% CI: 44.4-97.5%) and 76.9% (95% CI: 46.2-95.0%) as rescue therapies. The adverse event rates were 5.9% and 5.0% for 10-day and 14-day groups, respectively. Smoking and compliance significantly affected the efficacy of PPI-amoxicillin dual therapies. Conclusion The eradication rate of 10-day q.i.d. dual therapy was unacceptable, while that of the 14-day t.i.d. dual therapy was borderline acceptable for first-line therapy. The two dual therapies were well tolerated with few adverse effects.

Development of new stroke therapies requires animal models that recapitulate the pathophysiological and functional consequences of ischemic brain damage over time-frames relevant to the therapeutic intervention. This is particularly relevant for the rapidly developing area of stem cell therapies, where functional replacement of circuitry will require maturation of transplanted human cells over months. An additional challenge is the establishment of models of ischemia with stable behavioral phenotypes in chronically immune-suppressed animals to allow for long-term survival of human cell grafts. Here we report that microinjection of endothelin-1 into the sensorimotor cortex of athymic rats results in ischemic damage with a sustained deficit in function of the contralateral forepaw that persists for up to 9 months. The histological post-mortem analysis revealed chronic and diffuse atrophy of the ischemic cortical hemisphere that continued to progress over 9 months. Secondary atrophy remote to the primary site of injury and its relationship with long-term cognitive and functional decline is now recognized in human populations. Thus, focal cortical infarction in athymic rats mirrors important pathophysiological and functional features relevant to human stroke, and will be valuable for assessing efficacy of stem cell based therapies.

Introduction: Neck has typical and sophisticated facial structures. A good understanding of the anatomical features of cervical fascia and fascial space around thyroid can improve the surgical oper...

After Fukushima Daiichi disaster, the safety analysis of severe accidents became one of the safety concerns in Taiwan. At the same time, Taiwan Power Company built up an event basis strategy called Ultimate Response Guideline (URG) to cope with the accident like Fukushima. The analysis of the effectiveness of URG also became the most popular issue in Taiwan. However, the beyond design basis accident was very complicate and combined with many different aspects. Although researchers in Taiwan did lots of analysis of URG using different codes with different aspects, the differences of codes in the severe accident analysis were not mention in any of those studies. Thus, a Fukushima-like accident of Chinshan Nuclear Power Plant (NPP) was done by four codes in this study: MELCOR2.1, TRACE, PCTRAN and MAAP5.03. All four codes shared the same boundary conditions in the accident simulations. The crosswalk of these codes was discussed in detail and showed the similarity and differences among these codes. Those similarity and differences can help the improvement of URG analysis and make that this kind of analysis has more reliability. Also, the application field of each code can be clearly distinguished and help the improvement of code use in future NPP safety analysis.

Background Diabetes mellitus is associated with inadequate delivery of oxygen to tissues. Cellular hypoxia is associated with mitochondrial dysfunction which increases oxidative stress and hyperglycaemia. Hyperbaric oxygenation therapy, which was shown to improve insulin sensitivity, is impractical for regular use. We evaluated the effects of water which is stably-enriched with oxygen (ELO water) to increase arterial blood oxygen levels, on mitochondrial function in the presence of normal- or high-glucose environments, and as glucose-lowering therapy in humans. Methods We compared arterial blood oxygen levels in Sprague-Dawley rats after 7 days of ad libitum ELO or tap water consumption. Mitochondrial stress testing, and flow cytometry analysis of mitochondrial mass and membrane potential, were performed on human HepG2 cells cultured in four Dulbecco’s Modified Eagle Medium media, made with ELO water or regular (control) water, at normal (5.5 mM) or high (25 mM) glucose concentrations. We also randomized 150 adults with type 2 diabetes (mean age 53 years, glycated haemoglobin HbA1c 8.9% [74 mmol/mol], average duration of diabetes 12 years) to drink 1.5 litres daily of bottled ELO water or drinking water. Results ELO water raised arterial oxygen tension pO2 significantly (335 ± 26 vs. 188 ± 18 mmHg, p = 0.006) compared with tap water. In cells cultured in control water, mitochondrial mass and membrane potential were both significantly lower at 25 mM glucose compared with 5.5 mM glucose; in contrast, mitochondrial mass and membrane potential did not differ significantly at normal or high glucose concentrations in cells cultured in ELO water. The high-glucose environment induced a greater mitochondrial proton leak in cells cultured in ELO water compared to cells cultured in control medium at similar glucose concentration. In type 2 diabetic adults, HbA1c decreased significantly (p = 0.002) by 0.3 ± 0.7% (4 ± 8 mmol/mol), with ELO water after 12 weeks of treatment but was unchanged with placebo. Conclusions ELO water raises arterial blood oxygen levels, appears to have a protective effect on hyperglycaemia-induced reduction in mitochondrial mass and mitochondrial dysfunction, and may be effective adjuvant therapy for type 2 diabetes.

Stem cell transplants offer significant hope for brain repair following ischemic damage. Pre-clinical work suggests that therapeutic mechanisms may be multi-faceted, incorporating bone-fide circuit reconstruction by transplanted neurons, but also protection/regeneration of host circuitry. Here, we engineered hydrogel scaffolds to form "bio-bridges" within the necrotic lesion cavity, providing physical and trophic support to transplanted human embryonic stem cell-derived cortical progenitors, as well as residual host neurons. Scaffolds were fabricated by the self-assembly of peptides for a laminin-derived epitope (IKVAV), thereby mimicking the brain's major extracellular protein. Following focal ischemia in rats, scaffold-supported cell transplants induced progressive motor improvements over 9 months, compared to cell- or scaffold-only implants. These grafts were larger, exhibited greater neuronal differentiation, and showed enhanced electrophysiological properties reflective of mature, integrated neurons. Varying graft timing post-injury enabled us to attribute repair to both neuroprotection and circuit replacement. These findings highlight strategies to improve the efficiency of stem cell grafts for brain repair.

The biophysical properties of cellular membranes intimately influence the delivery of cargoes into cells by cell-penetrating peptides (CPPs) and the bactericidal activity of antimicrobial peptides (AMPs). Here, we discuss how lipid oxidation creates important chemical and biophysical changes in membranes, and hypothesize about the observed synergy between oxidized membranes and membrane-active peptides.

After the Fukushima Daichii accidents, Taiwan Power Company developed a strategy to cope with such extended SBO (Station Blackout) cases at nuclear power plants, which called URG. The MAAP and PCTRAN were used to perform the study for Kuosheng BWR/6 nuclear power plant (NPP) ultimate response guideline (URG). The main actions of URG are the depressurization and low pressure water injection of the reactor and the venting of the containment. This study focuses to confirm the URG efficiency. The analysis results depict that following the URG, the fuel can be covered by the coolant, no exposure. It can also prevent the radiation release and the large evacuation. It indicated that Kuosheng NPP was at the safe situation. It shows that the two-step depressurizations can extend the time of the preparation of alternate water source. The minimum injection rate to prevent the fuel to expose is 192 gpm in MAAP.

Cell delivery or cell killing processes often involve the crossing or disruption of cellular membranes. We review how, by modifying the composition and properties of membranes, membrane oxidation can be exploited to enhance the delivery of macromolecular cargoes into live human cells. We also describe how membrane oxidation can be utilized to achieve efficient killing of bacteria by antimicrobial peptides. Finally, we present recent evidence highlighting how membrane oxidation is intimately engaged in natural biological processes such as antigen delivery in dendritic cells and in the killing of bacteria by antimicrobial peptides. Overall, the insights that have been recently gained in this area should facilitate the development of more effective delivery technologies and antimicrobial therapeutic approaches.

Carbon dots are admirable fluorescent nanomaterials due to their low cost, high photostability, excellent biocompatibility, and environmental friendliness. Most conventional carbon dot fabrication approaches produce single-colored fluorescent material in the preparation process; different methods are therefore required to synthesize distinct carbon dots for specific optical applications. In this study, carbon dots carrying different emission colors are prepared through a one-step refluxing process. The emission of these materials can be well-tuned by sodium hydroxide content in the precursor solution. The carbon dots produced are used as sensing probes based on the spectrofluorometric inner filter effect for target molecule detection. Three sensing categories that combine carbon dots and inner filter effect are demonstrated, including direct, metal nanoparticle-assisted, and enzymatic reaction-supported detection. Caffeine, melamine, and fenitrothion are selected as targets to demonstrate the strategies, respectively. These multifunctional carbon dot-based sensors achieve comparable sensitivity toward analytes with a much more convenient preparation route.

After Fukushima Daiichi disaster, the safety analysis of severe accidents became one of the safety concerns in Taiwan. The Emergency Operating Procedure (EOP) cannot cope with a multiple system failure situation under a severe accident since it is a “Symptom-basis” procedure. To deal with that, Taiwan Power Company built up a new strategy for Fukushima-like accident called Ultimate Response Guideline (URG). It is a simple strategy with three main conditions: loss of regular motor driven injection system, loss of all AC power and tsunami/earthquake warning. If two of three happen, the operating procedure will change from EOP to URG and start the main works by following the strategy. There are three main works in URG: controlled-depressurization, line up low pressure injection water and prepare containment venting. In this study, MELCOR2.1 was used to calculate the cases of URG and checked the goal of the strategy that prevents the accident or not. There were three steps in this research. First, a model of Chinshan nuclear power plant (NPP) was built. Second, one was the case with URG and the other was not by using the above MELCOR model. The results were compared to MAAP5.0, TRACE and PCTRAN. Finally, some sensitivity studies of depressurization and water injection rate were done.

Cell-penetrating peptides (CPPs) are well established as delivery agents for otherwise cell-impermeable cargos. CPPs can also theoretically be used to modulate intracellular processes. However, their susceptibility to proteolytic degradation often limits their utility in these applications. Previous studies have explored the consequences for cellular uptake of converting the residues in CPPs from l- to d-stereochemistry, but conflicting results have been reported and specific steps en route to intracellular activity have not been explored. Here we use dimeric fluorescence TAT as a model CPP to explore the broader consequences of l- to d-stereochemical conversion. We show that inversion of chirality provides protease resistance without altering the overall mode of cellular entry, a process involving endocytic uptake followed by endosomal escape and cytosolic access. However, whereas inversion of chirality reduces endocytic uptake, the d-peptide, once in the endosome, is significantly more prone to escape than its l-counterpart. Moreover, the d-peptide is retained in the cytosol of cells for several days, whereas the l-peptide is degraded within hours. Notably, while the l-peptide is relatively innocuous to cells, the d-peptide exerts a prolonged anti-proliferative activity. Together, our results establish connections between chirality, protease resistance, cellular penetration, and intracellular activity that may be useful for the development of future delivery agents with improved properties.

Protein-protein interactions play a vital role in nearly all cellular functions. Hence, understanding their interaction patterns and three-dimensional structural conformations can provide crucial insights about various biological processes and underlying molecular mechanisms for many disease phenotypes. Cross-linking mass spectrometry (XL-MS) has the unique capability to detect protein-protein interactions at a large scale along with spatial constraints between interaction partners. The inception of MS-cleavable cross-linkers enabled the MS2-MS3 XL-MS acquisition strategy that provides cross-link information from both MS2 and MS3 level. However, the current cross-link search algorithm available for MS2-MS3 strategy follows a "MS2-centric" approach and suffers from a high rate of mis-identified cross-links. We demonstrate the problem using two new quality assessment metrics ["fraction of mis-identifications" (FMI) and "fraction of interprotein cross-links from known interactions" (FKI)]. We then address this problem, by designing a novel "MS3-centric" approach for cross-link identification and implementing it as a search engine named MaXLinker. MaXLinker outperforms the currently popular search engine with a lower mis-identification rate, and higher sensitivity and specificity. Moreover, we performed human proteome-wide cross-linking mass spectrometry using K562 cells. Employing MaXLinker, we identified a comprehensive set of 9319 unique cross-links at 1% false discovery rate, comprising 8051 intraprotein and 1268 interprotein cross-links. Finally, we experimentally validated the quality of a large number of novel interactions identified in our study, providing a conclusive evidence for MaXLinker's robust performance.

Deep Neural Networks (DNN) have shown significant advantagesin many domains such as pattern recognition, prediction, and controloptimization. The edge computing demand in the Internet-of-Things era has motivated many kinds of computing platforms toaccelerate the DNN operations. The most common platforms areCPU, GPU, ASIC, and FPGA. However, these platforms suffer fromlow performance (i.e., CPU and GPU), large power consumption(i.e., CPU, GPU, ASIC, and FPGA), or low computational flexibilityat runtime (i.e., FPGA and ASIC). In this paper, we suggest theNoC-based DNN platform as a new accelerator design paradigm.The NoC-based designs can reduce the off-chip memory accessesthrough a flexible interconnect that facilitates data exchange betweenprocessing elements on the chip. We first comprehensivelyinvestigate conventional platforms and methodologies used in DNNcomputing. Then we study and analyze different design parametersto implement the NoC-based DNN accelerator. The presentedaccelerator is based on mesh topology, neuron clustering, randommapping, and XY-routing. The experimental results on LeNet, MobileNet,and VGG-16 models show the benefits of the NoC-basedDNN accelerator in reducing off-chip memory accesses and improvingruntime computational flexibility. QC 20200604

Thrombosis is characterized by the formation of in vivo blood clots that are localized within arterial or venous blood vessels. These thrombi form beyond the need for physiologically healthy hemostatic responses and can lead to significant medical issues for affected individuals. Unfortunately, the existing standard-of-care therapies for treating thrombosis are systemic in their therapeutic design; therefore, they interfere with the patient's physiological hemostasis. Examples of the severe clinical side effects commonly associated with currently available therapies include, but are not limited to, bleeding complications. Therefore, there is a profound demand for novel therapeutic interventions that can circumvent these debilitating complications, while offering improved therapeutic efficacy. Recent advancements in nanotechnology present an opportunity to develop novel and improved drug delivery systems to meet this clinical demand. Preclinical investigations have begun to uncover the potential of nanotechnology, particularly in the treatment of thrombosis and also in nonhemostatic cardiovascular diseases. This article reviews recent preclinical studies aimed at developing a diverse array of different nanotechnologies for treating thrombosis as well as heart diseases. This review will also outline the limitations with current nanotechnologies and what challenges need to be overcome to translate these novel therapies to the clinic.

This study assessed the effectiveness, adverse events, patient adherence, and costs of modified dual therapy compared with bismuth-containing quadruple therapy for treating Helicobacter pylori infection in Chinese patients. We also sought to determine whether modified dual therapy could be used as an alternative first-line treatment for H. pylori infection.A total of 232 H. pylori-infected, treatment-naive patients were enrolled in this open-label, randomized controlled clinical trial. Patients were randomly allocated into 2 groups: the 14-day modified dual therapy group and the bismuth-containing quadruple therapy group. Eradication rates, drug-related adverse events, patient compliance, and drug costs were compared between the 2 groups.The modified dual therapy group achieved eradication rates of 87.9%, 91.1%, and 91.1% as determined by the intention-to-treat, per-protocol, and modified intention-to-treat analyses, respectively. The eradication rates were similar compared with the bismuth-containing quadruple therapy group: 89.7%, 91.2%, and 90.4%. In addition, modified dual therapy ameliorated variations in the CYP2C19, IL-1B-511, and H. pylori VacA genotypes. There were no significant differences in the compliance rates between the 2 groups. The modified dual therapy group exhibited significantly less overall side effects compared with the bismuth-containing quadruple therapy group (P0.001). Furthermore, the cost of medications in the modified dual therapy was lower compared with that in the bismuth-containing quadruple therapy.Modified dual therapy at high dose and administration frequency is equally effective and safer and less costly compared with bismuth-containing quadruple therapy.

Endosomal entrapment is a severely limiting bottleneck in the delivery of biologics into cells. The compound dfTAT was recently found to circumvent this problem by mediating endosomal leakage efficiently and without toxicity. Herein, we report on the mechanism of endosomal escape of this cell-penetrating peptide. By modulating the trafficking of the peptide within the endocytic pathway, we identify late endosomes as the organelles rendered leaky by dfTAT. We establish that dfTAT binds bis(monoacylglycero)phosphate (BMP), a lipid found in late endosomes, and that the peptide causes the fusion and leakage of bilayers containing BMP. Together, these data identify late endosomes as desirable gateways for cell penetration and BMP as a cellular factor that can be exploited for the development of future delivery agents.

With the brain's limited capacity for repair there is a need for new and innovative therapies to promote regeneration. Stem/progenitor cell transplantation has received increasing attention, and whilst clinical trials demonstrating functional integration exist, inherent variability between patients has hindered development of this therapy. Variable outcomes have largely been attributed to poor survival and insufficient reinnervation of target tissues due in part to the suboptimal host environment. Here we examined whether improving the physical properties of the host milieu, by way of bioengineered scaffolds, may enhance engraftment. We developed a composite scaffold, incorporating electrospun poly(l-lactic acid) short nanofibers embedded within a thermo-responsive xyloglucan hydrogel, which could be easily injected into the injured brain. Furthermore, to improve the trophic properties of the host brain, glial derived neurotrophic factor (GDNF), a protein known to promote cell survival and axonal growth, was blended into and/or covalently attached onto the composite scaffolds to provide controlled delivery. In vitro we confirmed the ability of the scaffolds to support ventral midbrain (VM) dopamine progenitors, and provide sustained delivery of GDNF - capable of eliciting effects on cell survival and dopaminergic axon growth. In Parkinsonian mice, we show that these composite scaffolds, whilst having no deleterious impact on the host immune response, enhanced the survival of VM grafts and reinnervation of the striatum, an effect that was augmented through the scaffold delivery of GDNF. Taken together, these functionalized composite scaffolds provide a means to significantly improve the milieu of the injured brain, enabling enhanced survival and integration of grafted neurons.

Viral vector gene delivery is a promising technique for the therapeutic administration of proteins to damaged tissue for the improvement of regeneration outcomes in various disease settings including brain and spinal cord injury, as well as autoimmune diseases. Though promising results have been demonstrated, limitations of viral vectors, including spread of the virus to distant sites, neutralization by the host immune system, and low transduction efficiencies have stimulated the investigation of biomaterials as gene delivery vehicles for improved protein expression at an injury site. Here, we show how Nfluorenylmethyloxycarbonyl (Fmoc) self-assembling peptide (SAP) hydrogels, designed for tissue-specific central nervous system (CNS) applications via incorporation of the laminin peptide sequence isoleucine–lysine–valine–alanine–valine (IKVAV), are effective as biocompatible, localized viral vector gene delivery vehicles in vivo. Through the addition of a C-terminal lysine (K) residue, we show that increased electrostatic interactions, provided by the additional amine side chain, allow effective immobilization of lentiviral vector particles, thereby limiting their activity exclusively to the site of injection and enabling focal gene delivery in vivo in a tissue-specific manner. When the C-terminal lysine was absent, no difference was observed between the number of transfected cells, the volume of tissue transfected, or the transfection efficiency with and without the Fmoc-SAP. Importantly, immobilization of the virus only affected transfection cell number and volume, with no impact observed on transfection efficiency. This hydrogel allows the sustained and targeted delivery of growth factors post injury. We have established Fmoc-SAPs as a versatile platform for enhanced biomaterial design for a range of tissue engineering applications.

The astonishing development in the field of artificial neural networks (ANN) has brought significant advancement in many application domains, such as pattern recognition, image classification, and computer vision. ANN imitates neuron behaviors and makes a decision or prediction by learning patterns and features from the given data set. To reach higher accuracies, neural networks are getting deeper, and consequently, the computation and storage demands on hardware platforms are steadily increasing. In addition, the massive data communication among neurons makes the interconnection more complex and challenging. To overcome these challenges, ASIC-based DNN accelerators are being designed which usually incorporate customized processing elements, fixed interconnection, and large off-chip memory storage. As a result, DNN computation involves large memory accesses due to frequent load/off-loading data, which significantly increases the energy consumption and latency. Also, the rigid architecture and interconnection among processing elements limit the efficiency of the platform to specific applications. In recent years, Network-on-Chip-based (NoC-based) DNN becomes an emerging design paradigm because the NoC interconnection can help to reduce the off-chip memory accesses while offers better scalability and flexibility. To evaluate the NoC-based DNN in the early design stage, we introduce a cycle-accurate NoC-based DNN simulator, called DNNoC-sim. To support various operations such as convolution and pooling in the modern DNN models, we first propose a DNN flattening technique to convert diverse DNN operation into MAC-like operations. In addition, we propose a DNN slicing method to evaluate the large-scale DNN models on a resource-constraint NoC platform. The evaluation results show a significant reduction in the off-chip memory accesses compared to the state-of-the-art DNN model. We also analyze the performance and discuss the trade-off between different design parameters.

Background: Helicobacter pylori resistance to amoxicillin remains rare in many regions. Proton pump inhibitor-amoxicillin-containing high dose dual therapy (HDDT) has been proposed to treat H. pylori infection. We aimed to assess the effectiveness and safety of PPI-amoxicillin HDDT for treatment of H. pylori infection in comparison with other regimens. Methods: Databases, including PubMed, Embase, and the Cochrane Register of Controlled Trials, were searched to find relevant publications. Randomized controlled trials comparing HDDT with control regimens for H. pylori eradication in adult patients were included. The primary outcome was eradication rate by intention-to-treat analysis. Adverse events were analyzed as second outcome. Results: A total of 15 trials with 3818 patients qualified for inclusion. The eradication rate of HDDT was neither significantly inferior nor superior to the recommended regimens such as triple therapy, bismuth quadruple therapy, and non-bismuth quadruple therapy [relative risk (RR): 1.00, 95% confidence interval (CI): 0.96–1.05, p = 0.870]. This finding was robust through subgroup analyses and sensitivity analyses. Trial sequential analysis showed that HDDT was equivalent to control regimens, and further similar trials were unlikely to alter the conclusions of this analysis. The frequency of adverse events was significantly lower in HDDT group (RR: 0.48, 95% CI: 0.37–0.64, p Conclusion: HDDT was equivalent to recommended first-line or rescue regimens with fewer adverse effects. The evidence from this meta-analysis supports the use of HDDT as first-line or rescue treatment for H. pylori infection. Trial registration: PROSPERO CRD42019133002

Interfacial self-assembly is a powerful organizational force for fabricating functional nanomaterials, including nanocarriers, for imaging and drug delivery. Herein, the interfacial self-assembly of pH-responsive metal-phenolic networks (MPNs) on the liquid-liquid interface of oil-in-water emulsions is reported. Oleic acid emulsions of 100-250 nm in diameter are generated by ultrasonication, to which poly(ethylene glycol) (PEG)-based polyphenolic ligands are assembled with simultaneous crosslinking by metal ions, thus forming an interfacial MPN. PEG provides a protective barrier on the emulsion phase and renders the emulsion low fouling. The MPN-coated emulsions have a similar size and dispersity, but an enhanced stability when compared with the uncoated emulsions, and exhibit a low cell association in vitro, a blood circulation half-life of ≈50 min in vivo, and are nontoxic to healthy mice. Furthermore, a model anticancer drug, doxorubicin, can be encapsulated within the emulsion phase at a high loading capacity (≈5 fg of doxorubicin per emulsion particle). The MPN coating imparts pH-responsiveness to the drug-loaded emulsions, leading to drug release at cell internalization pH and a potent cell cytotoxicity. The results highlight a straightforward strategy for the interfacial nanofabrication of pH-responsive emulsion-MPN systems with potential use in biomedical applications.

Various densely charged polycationic species, whether of biological or synthetic origin, can penetrate human cells, albeit with variable efficiencies. The molecular underpinnings involved in such transport remain unclear. Herein, we assemble one, two, or three copies of the HIV peptide TAT on a synthetic scaffold to generate branched cell-permeable prototypes with increasing charge density. We establish that increasing TAT copies dramatically increases the cell penetration efficiency of the peptides while simultaneously enabling the efficient cytosolic delivery of macromolecular cargos. Cellular entry involves the leaky fusion of late endosomal membranes enriched with the anionic lipid BMP. Derivatives with multiple TAT branches induce the leakage of BMP-containing lipid bilayers, liposomal flocculation, fusion, and an increase in lamellarity. In contrast, while the monomeric counterpart 1TAT binds to the same extent and causes liposomal flocculation, 1TAT does not cause leakage, induce fusion or a significant increase in lamellarity. Overall, these results indicate that an increase in charge density of these branched structures leads to the emergence of lipid specific membrane-disrupting and cell-penetrating activities.

Due to limited self-healing capacity in cartilages, there is a rising demand for an innovative therapy that promotes chondrocyte proliferation while maintaining its biofunctionality for transplantation. Chondrocyte transplantation has received notable attention; however, the tendencies of cell de-differentiation and de-activation of biofunctionality have been major hurdles in its development, delaying this therapy from reaching the clinic. We believe it is due to the non-stimulative environment in the injured cartilage, which is unable to provide sustainable physical and biological supports to the newly grafted chondrocytes. Therefore, we evaluated whether providing an appropriate matrix to the transplanted chondrocytes could manipulate cell fate and recovery outcomes. Here, we proposed the development of electrosprayed nanoparticles composed of cartilage specific proteins, namely collagen type II and hyaluronic acid, for implantation with pre-seeded chondrocytes into articular cartilage defects. The fabricated nanoparticles were pre-cultured with chondrocytes before implantation into injured articular cartilage. The study revealed a significant potential for nanoparticles to support pre-seeded chondrocytes in cartilage repair, serving as a protein delivery system while improving the survival and biofunctionality of transplanted chondrocytes for prolonged period of time.

Neurotrophic growth factors are effective in slowing progressive degeneration and/or promoting neural repair through the support of residual host and/or transplanted neurons. However, limitations including short half-life and enzyme susceptibility of growth factors highlight the need for alternative strategies to prolong localised delivery at a site of injury. Here, we establish the utility of minimalist N-fluorenylmethyloxycarbonyl (Fmoc) self-assembling peptides (SAPs) as growth factor delivery vehicle, targeted at supporting neural transplants in an animal model of Parkinson's disease. The neural tissue specific SAP, Fmoc-DIKVAV, demonstrated sustained release of glial cell line derived neurotrophic factor (GDNF), up to 172 hours after gel loading. This represents a significant advance in drug delivery, since its lifetime in phosphate buffered saline (PBS) was less than 1 hour. In vivo transplantation of neural progenitor cells, together with our growth factor-loaded material, into the injured brain improved graft survival compared to cell transplants alone. We show for the first time the use of minimalist Fmoc-SAP in an in vivo disease model for sustaining the delivery of neurotrophic growth factors, facilitating their spatial and temporal delivery in vivo, whilst also providing an enhanced niche environment for transplanted cells.