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Paneth cells at the bottom of small intestinal crypts secrete antimicrobial peptides, enzymes, and growth factors and contribute to pathogen clearance and maintenance of the stem cell niche. Loss of Paneth cells and their dysfunction occur commonly in various pathologies, but the mechanism underlying the control of Paneth cell function remains largely unknown. Here, we identified microRNA-195 (miR-195) as a repressor of Paneth cell development and activity by altering SOX9 translation via interaction with RNA-binding protein HuR. Tissue-specific transgenic expression of miR-195 (miR195-Tg) in the intestinal epithelium decreased the levels of mucosal SOX9 and reduced the numbers of lysozyme-positive (Paneth) cells in mice. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restored Paneth cell development ex vivo. miR-195 did not bind to Sox9 mRNA but it directly interacted with HuR and prevented HuR binding to Sox9 mRNA, thus inhibiting SOX9 translation. Intestinal mucosa from mice that harbored both Sox9 transgene and ablation of the HuR locus exhibited lower levels of SOX9 protein and Paneth cell numbers than those observed in miR-195-Tg mice. Inhibition of miR-195 activity by its specific antagomir improved Paneth cell function in HuR-deficient intestinal organoids. These results indicate that interaction of miR-195 with HuR regulates Paneth cell function by altering SOX9 translation in the small intestinal epithelium. NEW & NOTEWORTHY: Our results indicate that intestinal epithelial tissue-specific transgenic miR-195 expression decreases the levels of SOX9 expression, along with reduced numbers of Paneth cells. Ectopically expressed SOX9 in the intestinal organoids derived from miR-195-Tg mice restores Paneth cell development ex vivo. miR-195 inhibits SOX9 translation by preventing binding of HuR to Sox9 mRNA. These findings suggest that interaction between miR-195 and HuR controls Paneth cell function via SOX9 in the intestinal epithelium. [ABSTRACT FROM AUTHOR]

The RquA protein is required for rhodoquinone biosynthesis; however, its exact function is not yet known. Here, the authors demonstrate that RquA is homologous to SAM-dependent methyltransferases but functions as an aminotransferase using Mn2+ as cofactor to convert ubiquinone to rhodoquinone.

Intestinal epithelial integrity is commonly disrupted in patients with critical disorders, but the exact underlying mechanisms are unclear. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control different cell functions and are involved in pathologies. Here, we investigated the role of T-UCRs in intestinal epithelial homeostasis and identified T-UCR uc.230 as a major regulator of epithelial renewal, apoptosis, and barrier function. Compared with controls, intestinal mucosal tissues from patients with ulcerative colitis and from mice with colitis or fasted for 48 hours had increased levels of uc.230. Silencing uc.230 inhibited the growth of intestinal epithelial cells (IECs) and organoids and caused epithelial barrier dysfunction. Silencing uc.230 also increased IEC vulnerability to apoptosis, whereas increasing uc.230 levels protected IECs against cell death. In mice with colitis, reduced uc.230 levels enhanced mucosal inflammatory injury and delayed recovery. Mechanistic studies revealed that uc.230 increased CUG-binding protein 1 (CUGBP1) by acting as a natural decoy RNA for miR-503, which interacts with Cugbp1 mRNA and represses its translation. These findings indicate that uc.230 sustains intestinal mucosal homeostasis by promoting epithelial renewal and barrier function and that it protects IECs against apoptosis by serving as a natural sponge for miR-503, thereby preserving CUGBP1 expression.

Vault RNAs (vtRNAs) are small noncoding RNAs and highly expressed in many eukaryotes. Here, we identified vtRNA2‐1 as a novel regulator of the intestinal barrier via interaction with RNA‐binding protein HuR. Intestinal mucosal tissues from patients with inflammatory bowel diseases and from mice with colitis or sepsis express increased levels of vtRNAs relative to controls. Ectopically expressed vtRNA2‐1 decreases the levels of intercellular junction (IJ) proteins claudin 1, occludin, and E‐cadherin and causes intestinal epithelial barrier dysfunction in vitro, whereas vtRNA2‐1 silencing promotes barrier function. Increased vtRNA2‐1 also decreases IJs in intestinal organoid, inhibits epithelial renewal, and causes Paneth cell defects ex vivo. Elevating the levels of tissue vtRNA2‐1 in the intestinal mucosa increases the vulnerability of the gut barrier to septic stress in mice. vtRNA2‐1 interacts with HuR and prevents HuR binding to claudin 1 and occludin mRNAs, thus decreasing their translation. These results indicate that vtRNA2‐1 impairs intestinal barrier function by repressing HuR‐facilitated translation of claudin 1 and occludin. Synopsis: Vault RNAs (vtRNAs) are small noncoding RNAs, and their levels increase in intestinal mucosa from patients with IBD. vtRNA2‐1 disrupts intestinal epithelial barrier function by decreasing intercellular junctions via interaction with HuR. vtRNA2‐1 inhibits expression of claudin 1, occludin, and E‐cadherin posttranscriptionally.vtRNA2‐1 impairs intestinal epithelial renewal and causes Paneth cell defects ex vivo.Elevating tissue vtRNA2‐1 levels increases vulnerability of gut barrier to septic stress in mice.vtRNA2‐1 interacts with HuR and prevents HuR binding to mRNAs. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various malignancies, but are associated with serious adverse events like pancreatitis. Current guidelines are limited to the first step in treating acute ICI-related pancreatitis with steroids but lack treatment advices for steroid dependent pancreatitis. We describe a case series of 3 patients who developed ICI-related pancreatitis with chronic features such as exocrine insufficiency and pancreatic atrophy at imaging. Our first case developed after treatment with pembrolizumab. The pancreatitis responded well after discontinuation of immunotherapy but imaging showed pancreatic atrophy and exocrine pancreatic insufficiency persisted. Cases 2 and 3 developed after treatment with nivolumab. In both, pancreatitis responded well to steroids. However during steroid tapering, pancreatitis recurred and the latter developed exocrine pancreatic insufficiency and pancreatic atrophy at imaging. Our cases demonstrate resemblances with autoimmune pancreatitis based on clinical and imaging findings. In line, both diseases are T-cell mediated and for autoimmune pancreatitis azathioprine is considered as maintenance therapy. Guidelines of other T-cell mediated diseases like ICI-related hepatitis suggest tacrolimus. After adding tacrolimus in case 2 and azathioprine in case 3, steroids could be completely tapered and no new episodes of pancreatitis have occurred. These findings support the idea that the treatment modalities for other T-cell mediated diseases are worthwhile options for steroid dependent ICI-related pancreatitis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

This study aimed to identify parental needs for pediatric palliative care and obtain their opinions on developing pediatric palliative care in South Korea. This qualitative research design used inductive and deductive methods. The data were collected through semistructured interviews. A total of 6 parents actively caring for a child with life-threatening conditions and 7 bereaved parents participated in this study. A total of 707 significant statements, 43 subthemes, and 16 themes according to 6 structured matrices (advance care planning and symptom control, psychological and spiritual care, supporting everyday lives, end-of-life care and bereavement support, delivery model of pediatric palliative care, and unmet needs within current services) on the care and bereavement experiences of parents of children with life-threatening conditions were derived. Palliative care for children is a multidisciplinary approach to evaluate, prevent, and manage multifaceted symptoms and to support children with life-threatening conditions and their families. Our findings suggest that parents of children with life-threatening conditions in South Korea present multidimensional needs across the diagnostic groups and the illness trajectories and inform policy makers and health care professionals to design a pediatric palliative care delivery model. Further studies examining the unmet needs are required to enhance the quality of pediatric palliative care., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 by The Hospice and Palliative Nurses Association. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Efficient immune responses require Ca 2+ fluxes across ORAI1 channels during engagement of T cell receptors (TCR) at the immune synapse (IS) between T cells and antigen presenting cells. Here, we show that ZDHHC20-mediated S-acylation of the ORAI1 channel at residue Cys143 promotes TCR recruitment and signaling at the IS. Cys143 mutations reduced ORAI1 currents and store-operated Ca 2+ entry in HEK-293 cells and nearly abrogated long-lasting Ca 2+ elevations, NFATC1 translocation, and IL-2 secretion evoked by TCR engagement in Jurkat T cells. The acylation-deficient channel remained in cholesterol-poor domains upon enforced ZDHHC20 expression and was recruited less efficiently to the IS along with actin and TCR. Our results establish S-acylation as a critical regulator of ORAI1 channel trafficking and function at the IS and reveal that ORAI1 S-acylation enhances TCR recruitment to the synapse., Competing Interests: AC, LA, KJ, WW, CH, MF, MD, Fv, ND No competing interests declared, (© 2021, Carreras-Sureda et al.)

The diarylheptanoid, 5-hydroxy-7-(4"-hydroxy-3"-metho-xyphenyl)-1-phenyl-3-heptanone (HPH), is isolated from rhizomes of Alpinia officinarum. There is no reported biological function for this compound other than the inhibition of pancreatic lipase. Cell viability, the expression of endoplasmic reticulum (ER) stress genes, the activation of ER stress sensors, and the induction of apoptosis and autophagy were confirmed following HPH treatment of PC12 cells. No cytotoxicity was observed when the cells were treated with 50 μg/ml HPH, but 40% cell death was observed using MTT assays with 100 μg/ml HPH. Although HPH did not change the expression of the ER chaperones PDI, binding BiP, and calnexin, it upregulated the expression of genes for the ER stress sensors ATF6, eIF2α, and PERK. HPH also induced apoptosis via the activation of ATF6 fragmentation, the phosphorylation of eIF2α, and XBP1 mRNA splicing. Eventually, the results of this study demonstrated that HPH induces apoptosis through upregulation of gene expression of ER stress sensors, which may provide a basis for the development of new drugs using HPH.

One of the most urgent contemporary tasks for taxonomists and evolutionary biologists is to estimate the number of species on earth. Recording alpha diversity is crucial for protecting biodiversity, especially in areas of elevated species richness, which coincide geographically with increased anthropogenic environmental pressures - the world's so-called biodiversity hotspots. Although the distribution of Puddle frogs of the genus Occidozyga in South and Southeast Asia includes five biodiversity hotspots, the available data on phylogeny, species diversity, and biogeography are surprisingly patchy. Samples analyzed in this study were collected throughout Southeast Asia, with a primary focus on Sundaland and the Philippines. A mitochondrial gene region comprising ~ 2000 bp of 12S and 16S rRNA with intervening tRNA Valine and three nuclear loci (BDNF, NTF3, POMC) were analyzed to obtain a robust, time-calibrated phylogenetic hypothesis. We found a surprisingly high level of genetic diversity within Occidozyga, based on uncorrected p-distance values corroborated by species delimitation analyses. This extensive genetic diversity revealed 29 evolutionary lineages, defined by the > 5% uncorrected p-distance criterion for the 16S rRNA gene, suggesting that species diversity in this clade of phenotypically homogeneous forms probably has been underestimated. The comparison with results of other anuran groups leads to the assumption that anuran species diversity could still be substantially underestimated in Southeast Asia in general. Many genetically divergent lineages of frogs are phenotypically similar, indicating a tendency towards extensive morphological conservatism. We present a biogeographic reconstruction of the colonization of Sundaland and nearby islands which, together with our temporal framework, suggests that lineage diversification centered on the landmasses of the northern Sunda Shelf. This remarkably genetically structured group of amphibians could represent an exceptional case for future studies of geographical structure and diversification in a widespread anuran clade spanning some of the most pronounced geographical barriers on the planet (e.g., Wallace's Line). Studies considering gene flow, morphology, ecological and bioacoustic data are needed to answer these questions and to test whether observed diversity of Puddle frog lineages warrants taxonomic recognition., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The receptor for advanced glycation end-products (RAGE or AGER) is a transmembrane, immunoglobulin-like receptor that, due to its multiple isoform structures, binds to a diverse range of endo- and exogenous ligands. RAGE activation caused by the ligand binding initiates a cascade of complex pathways associated with producing free radicals, such as reactive nitric oxide and oxygen species, cell proliferation, and immunoinflammatory processes. The involvement of RAGE in the pathogenesis of disorders such as diabetes, inflammation, tumor progression, and endothelial dysfunction is dictated by the accumulation of advanced glycation end-products (AGEs) at pathologic states leading to sustained RAGE upregulation. The involvement of RAGE and its ligands in numerous pathologies and diseases makes RAGE an interesting target for therapy focused on the modulation of both RAGE expression or activation and the production or exogenous administration of AGEs. Despite the known role that the RAGE/AGE axis plays in multiple disease states, there remains an urgent need to develop noninvasive, molecular imaging approaches that can accurately quantify RAGE levels in vivo that will aid in the validation of RAGE and its ligands as biomarkers and therapeutic targets. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Diagnostic Tools > Biosensing., (© 2023 The Authors. WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

In this triple-blind, randomized clinical trial, 60 menopausal women between the ages of 45 and 65 were randomized to receive 78% dark chocolate (12 g/day) or milk chocolate (12 g/day) for eight weeks. The primary outcome was depression scores. Secondary outcomes included sleep quality and anthropometric indices. ANCOVA with baseline adjustment showed that the mean depression score after the intervention in the group receiving dark chocolate was significantly reduced compared to the milk chocolate group (mean difference: -2.3; 95% confidence interval: -3.9 to -0.8; p = 0.003; Cohen's d = -0.54). However, no statistically significant difference in the overall sleep quality score and its subdomains was observed between the two groups after the intervention (p > 0.05). Furthermore, after the intervention, there was no statistically significant difference between the two groups in terms of anthropometric indices, including weight (p = 0.075), BMI (p = 0.137), waist circumference (p = 0.463), and hip circumference (p = 0.114). The study suggests that consuming 78% dark chocolate for eight weeks may contribute to improvements in depression scores, but it does not appear to improve sleep quality or anthropometric indices. Trial registration: IRCT20220926056046N1; December 2022. [ABSTRACT FROM AUTHOR]

Spread through air spaces (STAS) is a recognized aggressive pattern in lung cancer, serving as a crucial risk factor for postoperative recurrence. However, its phenotype and related spatial structure have remained elusive. To address these limitations, we conducted a comprehensive study based on spatial data, analyzing over 30,000 spots from 14 non-STAS samples and one STAS sample. We observed increased proliferation activities and angiogenesis in STAS, identifying S100P as a potential biomarker for STAS. Furthermore, our investigation into the heterogeneity of STAS tumor cells revealed a subset identified as S100P + TFF1 +, exhibiting a negative impact on patients' survival in public datasets. This subtype exhibited the highest activities in the TGFb and hypoxia, suggesting its potential pro-tumor role within the tumor microenvironment. To assess the role of S100P + TFF1 + tumor cells in therapy response, we included data from two clinical trial cohorts (BPI-7711 for EGFR-TKI therapy and ORIENT-3 for immunotherapy). The presence of S100P + TFF1 + tumor cells correlated with worse responses to both EGFR-TKI therapy and immunotherapy. Notably, TFF1 emerged as a serum marker for predicting EGFR-TKI response. Cell–cell communication analysis revealed that the TGFb signaling pathway was the most activated in S100P + TFF1 + tumor cells, with TGFB2-TGFBR2 identified as the main ligand-receptor pair. This was further validated by multiplex immunofluorescence performed on twenty NSCLC samples. In summary, our study identified S100P as the biomarker for STAS and highlighted the adverse role of S100P + TFF1 + tumor cells in survival outcomes. [ABSTRACT FROM AUTHOR]

Advances in AI techniques have fueled research on using EEG data for psychiatric disorder diagnosis. Despite EEG's cost-effectiveness and high temporal resolution, low Signal-to-Noise Ratio (SNR) hampers critical marker extraction and model improvement, while denoising techniques will lead to a loss of effective information in EEG. The aim of this study is to employ AI methods for the processing of raw EEG data. The primary objectives of the processing are twofold: first, to acquire more reliable markers for schizophrenia, and second, to construct a superior automatic classification for schizophrenia. To remove the noises and retain task-related (classification tasks) effective information mostly, we introduce an Effective Information Estimation Framework (EIEF) based on three key principles: the task-centered approach, leveraging 1D-CNNs' test metrics to gauge effective information proportion, and feedback. We address a theoretical foundation by integrating these principles into mathematical derivations to propose the mathematical model of EIEF. In experiments, we established a paradigm pool of 66 denoising paradigms, with EIEF successfully identifying the optimal paradigms (on two datasets) for restoring effective information. Utilizing the processed dataset, we trained a 3D-CNN for automatic schizophrenia diagnosis, achieving outstanding test accuracies of 99.94 % on dataset 1 and 98.02 % on dataset 2 in subject-dependent evaluations, and accuracies of 89.85 % on dataset 1 and 98.02 % on dataset 2 in subject-independent evaluations. Additionally, we extracted 38 features from each channel of both processed and raw datasets, revealing that 20.86 % (dataset 1) of feature distribution differences between the patients and the healthy exhibited significant changes after implementing the optimal paradigm. We enhance model performance and extract more reliable electrobiological markers. These findings have promising implications for advancing the field of the clinical diagnosis and pathological analysis of Schizophrenia. [ABSTRACT FROM AUTHOR]

Objective Hemiparesis occurs when a stroke causes paresis on the body, contralateral to the lesioned brain. In poststroke patients, upper limb impairments induce functional restrictions. Arm ability training is a unilateral treatment for mild arm paresis. We evaluated the effectiveness of arm ability training on functional mobility and dexterity in hemiparetic subjects Materials and Methods Forty-two hemiparetic subjects were selected by convenient sampling technique. The subjects were given 40 minutes of arm ability training and 20 minutes of conventional physiotherapy daily, five sessions a week extending for 4 weeks. Functional mobility was assessed through wolf motor function test (WMFT) and dexterity by box and block test (BBT). Results The pre- and post-test scores were evaluated by paired t -test using SPSS software after 4 weeks of training period subjects showed much improvement for the BBT (mean ± standard deviation [SD]: 20.31 ± 4.075 vs. 23.79 ± 4.291), functional ability of WMFT (mean ± SD: 45.38 ± 3.615 vs. 54.07 ± 3.790), time of WMFT (mean ± SD: 479.29 ± 117.79 vs. 434.4 ± 116.455), the strength of WMFT was (mean ± SD: 2.95 ± 0.731 vs. 3.9 ± 0.759), and grip strength of WMFT (mean ± SD: 2.9 ± 1.559 vs. 4.21 ± 1.539), all variables indicating statistical significance (p < 0.05). Conclusion Arm ability training proved effective in improving functional mobility and dexterity in hemiparetic subjects. [ABSTRACT FROM AUTHOR]

Accurate reservoir characterization is necessary to effectively monitor, manage, and increase production. A seismic inversion methodology using a genetic algorithm (GA) and particle swarm optimization (PSO) technique is proposed in this study to characterize the reservoir both qualitatively and quantitatively. It is usually difficult and expensive to map deeper reservoirs in exploratory operations when using conventional approaches for reservoir characterization hence inversion based on advanced technique (GA and PSO) is proposed in this study. The main goal is to use GA and PSO to significantly lower the fitness (error) function between real seismic data and modeled synthetic data, which will allow us to estimate subsurface properties and accurately characterize the reservoir. Both techniques estimate subsurface properties in a comparable manner. Consequently, a qualitative and quantitative comparison is conducted between these two algorithms. Using two synthetic data and one real data from the Blackfoot field in Canada, the study examined subsurface acoustic impedance and porosity in the inter-well zone. Porosity and acoustic impedance are layer features, but seismic data is an interface property, hence these characteristics provide more useful and applicable reservoir information. The inverted results aid in the understanding of seismic data by providing incredibly high-resolution images of the subsurface. Both the GA and the PSO algorithms deliver outstanding results for both simulated and real data. The inverted section accurately delineated a high porosity zone ( > 20 % ) that supported the high seismic amplitude anomaly by having a low acoustic impedance (6000–8500 m/s ∗ g/cc). This unusual zone is categorized as a reservoir (sand channel) and is located in the 1040–1065 ms time range. In this inversion process, after 400 iterations, the fitness error falls from 1 to 0.88 using GA optimization, compared to 1 to 0.25 using PSO. The convergence time for GA is 670,680 s, but the convergence time for PSO optimization is 356,400 s, showing that the former requires 88 % more time than the latter. [ABSTRACT FROM AUTHOR]

Kinema, a sticky-textured fermented soybean food with umami flavour, is originated in the historical Limbuwan region, now situated in the eastern districts of Nepal. It has since expanded to different areas in Darjeeling Hills and Sikkim in India and Bhutan. The Limboo community, one of the oldest indigenous groups in the Himalayas, has developed a method for fermenting soybeans to produce kinema. Bacillus is the main bacterial genus responsible for fermenting kinema, along with lactic acid bacteria, yeasts, and fungi. Kinema is full of nutrients like protein, fats, carbohydrates, amino acids, vitamins, and minerals and offers health benefits through its antioxidant, anti-inflammatory, antiobesity, and antidiabetic properties. A novel strain of Bacillus subtilis Tamang has been identified in kinema samples from Darjeeling Hills, India, exhibiting elevated levels of γ-PGA and various biomarker genes for health benefits and biological functionalities. Kinema contains secondary metabolites including several bioactive compounds, immunomodulators, vitamin B-complexes, and others that help promote good health. The transcriptome of the B. subtilis Tamang strain reveals genes associated with GABA production, Vitamin B12 synthesis, and fibrinolytic activity. Safety evaluations have demonstrated that the strain and the production of kinema do not pose any toxicity risks based on animal studies. Despite facing challenges in terms of its strong taste and slimy consistency for broader acceptance, the bioactive elements and safe starter cultures found in kinema hold promise for the development of functional food. [ABSTRACT FROM AUTHOR]

Introduction: Acute pancreatitis (AP) following drug-induced hypertriglyceridemia is a rare clinical phenomenon. Immune checkpoint inhibitors have revolutionized treatment for a variety of solid organ and hematological malignancies. Pembrolizumab is a programmed cell death receptor-1 (PD-1) inhibitor that has shown promising responses in many advanced cancers. However, a constellation of immune-related adverse events has also been described. There are reports of pembrolizumab-induced hypertriglyceridemia, but AP as a result of this side effect remains an exceedingly rare clinical sequela. Case report: We delineate a case of a patient with stage IVB non-small-cell lung cancer who developed progressive abdominal pain and nausea following administration of pembrolizumab for four months. Laboratory studies revealed increased serum lipase and triglyceride levels at 12,562 IU/L and 16,901 mg/dL, respectively. The diagnosis of AP was made based on the revised Atlanta classification criteria. After ruling out alternative causes, pembrolizumab-induced hypertriglyceridemia was considered the likely etiology of AP. Management and outcome: The patient was transferred to the medical intensive care unit for close monitoring. Treatment was initiated with intravenous fluids, pain medications, and an insulin infusion. However, her hypertriglyceridemia levels remained persistently elevated, necessitating therapeutic apheresis. She recovered well with no complications after triglyceride apheresis. Discussion: AP following pembrolizumab-associated hypertriglyceridemia remains a rare clinicopathologic entity. Given the widespread clinical use of immune checkpoint inhibitors, knowledge of such rare adverse events is crucial. Evaluation of serum triglyceride levels before and after initiating pembrolizumab therapy may be mandated, especially in patients with metabolic comorbidities. [ABSTRACT FROM AUTHOR]

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The article focuses on developing a model for monitoring and planning local territorial development in Latvian municipalities as a business process. Topics include the application of business process modeling (BPM), the evaluation of BPM maturity levels, and the relationship between BPM practices and local economic development.

Workflows orchestrate a collection of computing tasks to form a complex workflow logic. Different from the traditional monolithic workflow management systems, modern workflow systems often manifest high throughput, concurrency and scalability. As service-based systems, execution time monitoring is an important part of maintaining the performance for those systems. We developed a trace profiling approach that leverages quantitative verification (also known as probabilistic model checking) to analyse complex time metrics for workflow traces. The strength of probabilistic model checking lies in the ability of expressing various temporal properties for a stochastic system model and performing automated quantitative verification. We employ semi-Makrov chains (SMCs) as the formal model and consider the first passage times (FPT) measures in the SMCs. Our approach maintains simple mergeable data summaries of the workflow executions and computes the moment parameters for FPT efficiently. We describe an application of our approach to AWS Step Functions, a notable workflow web service. An empirical evaluation shows that our approach is efficient for computer high-order FPT moments for sizeable workflows in practice. It can compute up to the fourth moment for a large workflow model with 10,000 states within 70 s. [ABSTRACT FROM AUTHOR]

Surface engineering techniques can be used to develop high-performance gas sensing materials and advance the development of sensors. In this study, we improved the gas sensing performance of two-dimensional (2D) WO3 nanoplates by combining surface Zn modification and the in situ formation of ZnWO4/WO3 heterojunctions. Introducing Zn atoms by surface modification can reconstruct the atomic surface of 2D WO3 nanoplates, creating additional active sites. This allowed for the preparation of various types of ZnWO4/WO3 heterojunctions on the surface of the WO3 nanoplates, which improved the selectivity and sensitivity to the target gas triethylamine. The sensor exhibited good gas sensing performance for triethylamine even at low operating temperatures and strongly resisted humidity changes. The ZnWO4/WO3 material we prepared demonstrated a nearly threefold improvement in the triethylamine (TEA) response, with a gas sensing responsivity of 40.75 for 10 ppm of TEA at 250 °C. The sensor based on ZnWO4/WO3 has a limit of detection (LOD) for TEA of 200 ppb in practical measurements (its theoretical LOD is even as low as 31 ppb). The method of growing ZnWO4 on the surface of WO3 nanoplates using surface modification techniques to form surface heterojunctions differs from ordinary composites. The results suggest that the in situ construction of surface heterojunctions using surface engineering strategies, such as in situ modifying, is a practical approach to enhance the gas sensing properties and resistance to the humidity changes of metal oxide materials. [ABSTRACT FROM AUTHOR]

Introduction: Polymyxin B is widely used to treat infections caused by multidrug-resistant Gram-negative bacteria. However, the pharmacokinetic study data of PB in the elderly are scarce. Herein, a simple method to measure the concentration of PB in human plasma was developed and validated by high performance liquid chromatography--tandem mass spectrometry, and it was applied to a PK study in the elderly. Methods: PB was extracted from human plasma by a rapid protein-precipitation method using 0.1% formic acid in methanol and then separated on an ultimate AQ-C18 column using linear gradient elution with a 0.5-mL/min flow rate. Subsequently, PB was detected using a mass spectrometer operated in positive-ion and multiple-reaction-monitoring modes. Results: The lower limits of quantification of the method for Polymyxin B1 and Polymyxin B2 were 1.00 and 0.10 μg/mL, respectively. The linear ranges for PB1 and PB2 were 1.00-20.02 and 0.10-2.04 μg/mL, respectively. Patients receiving a 75-mg maintenance dose every 12h had AUCss, 24 h, and Css, av values of 117.70 ± 37.03 μg h/mL and 4.14 ± 1.74 μg/mL, respectively. For patients receiving a 100 mg maintenance dose, these values were 152.73 ± 70.09 μg h/mL and 5.43 ± 2.85 μg/mL, respectively. Conclusion: The validated HPLC--MS/MS method was successfully applied to a study on the pharmacokinetics of PB in elderly patients infected with multidrug-resistant Gram-negative bacteria. Both two dose strategies in this study would have a excessive PB exposure in the elderly patients then the therapeutic window recommended by guidelines. [ABSTRACT FROM AUTHOR]