Pharmacokinetic Modeling of Ceftiofur Sodium Using Nonlinear Mixed-Effects in Healthy Beagle Dogs

Ceftiofur (CEF) sodium is a third-generation broad-spectrum cephalosporin commonly used in an extra-label manner in dogs for the treatment of respiratory and urinary system infections. To contribute to the literature supporting CEF use in companion animals, we have developed a compartmental, nonlinear mixed-effects (NLME) model of CEF pharmacokinetics in dogs (PK). We then used the mathematical model to predict (via Monte Carlo simulation) the duration of time for which plasma concentrations of CEF and its pharmacologically active metabolites remained above minimum inhibitory concentrations (respiratory tract Escherichia coli spp). Twelve healthy beagle dogs were administered either 2.2 mg/kg ceftiofur-sodium (CEF-Na) intravenously (I.V) or 2.2 mg/kg CEF-Na subcutaneously (S.C). Plasma samples were collected over a period of 72 hours post-administration. To produce a measurement of total CEF, both CEF and CEF metabolites were derivatized into desfuroylceftiofur acetamide (DCA) before analysis by UPLC-MS/MS. No adverse effects were reported after I.V or S.C dosing. The NLME PK models were parameterized using the stochastic approximation expectation maximization algorithm as implemented in Monolix 2018R2. A two-compartment mammillary model with first-order elimination and first-order S.C absorption best described the available kinetic data. Final parameter estimates indicate that CEF has a low systemic clearance (0.25 L/h/kg) associated with a low global extraction ratio E = 0.02) and a moderate volume of distribution (2.97 L/kg) in dogs. The absolute bioavailability after S.C administration was high (93.7%). Gender was determined to be a significant covariate in explaining the variability of S.C absorption. Our simulations predicted that a dose of 2.2 mg/kg CEF-Na S.C would produce median plasma concentrations of CEF of at least 0.5 µg/mL (MIC50) for approximately 30 hours

AutoHint: Automatic Prompt Optimization with Hint Generation

This paper presents AutoHint, a novel framework for automatic prompt engineering and optimization for Large Language Models (LLM). While LLMs have demonstrated remarkable ability in achieving high-quality annotation in various tasks, the key to applying this ability to specific tasks lies in developing high-quality prompts. Thus we propose a framework to inherit the merits of both in-context learning and zero-shot learning by incorporating enriched instructions derived from input-output demonstrations to optimize original prompt. We refer to the enrichment as the hint and propose a framework to automatically generate the hint from labeled data. More concretely, starting from an initial prompt, our method first instructs a LLM to deduce new hints for selected samples from incorrect predictions, and then summarizes from per-sample hints and adds the results back to the initial prompt to form a new, enriched instruction. The proposed method is evaluated on the BIG-Bench Instruction Induction dataset for both zero-shot and few-short prompts, where experiments demonstrate our method is able to significantly boost accuracy for multiple tasks

Individual and Group Dynamics in Purchasing Activity

As a major part of the daily operation in an enterprise, purchasing frequency is of constant change. Recent approaches on the human dynamics can provide some new insights into the economic behaviors of companies in the supply chain. This paper captures the attributes of creation times of purchase orders to an individual vendor, as well as to all vendors, and further investigates whether they have some kind of dynamics by applying logarithmic binning to the construction of distribution plot. It's found that the former displays a power-law distribution with approximate exponent 2.0, while the latter is fitted by a mixture distribution with both power-law and exponential characteristics. Obviously, two distinctive characteristics are presented for the interval time distribution from the perspective of individual dynamics and group dynamics. Actually, this mixing feature can be attributed to the fitting deviations as they are negligible for individual dynamics, but those of different vendors are cumulated and then lead to an exponential factor for group dynamics. To better describe the mechanism generating the heterogeneity of purchase order assignment process from the objective company to all its vendors, a model driven by product life cycle is introduced, and then the analytical distribution and the simulation result are obtained, which are in good line with the empirical data

Autophagy protects against palmitate-induced apoptosis in hepatocytes

BACKGROUND: Non-alcoholic fatty liver disease, one of the most common liver diseases, has obtained increasing attention. Palmitate (PA)-induced liver injury is considered a risk factor for the development of non-alcoholic fatty liver disease. Autophagy, a cellular degradative pathway, is an important self-defense mechanism in response to various stresses. In this study, we investigated whether autophagy plays a protective role in the progression of PA-induced hepatocytes injury. RESULTS: Annexin V-FITC/PI staining by FCM analysis, TUNEL assay and the detection of PARP and cleaved caspase3 expression levels demonstrated that PA treatment prominently induced the apoptosis of hepatocytes. Meanwhile, treatment of PA strongly induced the formation of GFP-LC3 dots, the conversion from LC3I to LC3II, the decrease of p62 protein levels and the increase of autophagosomes. These results indicated that PA also induced autophagy activation. Autophagy inhibition through chloroquine pretreatment or Atg5shRNA infection led to the increase of cell apoptosis after PA treatment. Moreover, induction of autophagy by pretreatment with rapamycin resulted in distinct decrease of PA-induced apoptosis. Therefore, autophagy can prevent hepatocytes from PA-induced apoptosis. In the further study, we explored pathway of autophagy activation in PA-treated hepatocytes. We found that PA activated PKCα in hepatocytes, and had no influence on mammalian target of rapamycin and endoplasmic reticulum stress pathways. CONCLUSIONS: These results demonstrated that autophagy plays a protective role in PA-induced hepatocytes apoptosis. And PA might induce autophagy through activating PKCα pathway in hepatocytes

Birman-Wenzl-Murakami Algebra and the Topological Basis

In this paper, we use entangled states to construct 9x9-matrix representations of Temperley-Lieb algebra (TLA), then a family of 9x9-matrix representations of Birman-Wenzl-Murakami algebra (BWMA) have been presented. Based on which, three topological basis states have been found. And we apply topological basis states to recast nine-dimensional BWMA into its three-dimensional counterpart. Finally, we find the topological basis states are spin singlet states in special case.Comment: 11pages, 1 figur

Gallic acid ameliorates dextran sulfate sodium-induced ulcerative colitis in mice via inhibiting NLRP3 inflammasome

Background: Ulcerative colitis (UC) is a chronic recurrent inflammatory bowel disease (IBD). The conventional drugs for UC may induce severe side effects. Herbal medicine is considered as a complementary and alternative choice for UC.Purpose: This study aims to estimate the effect of natural polyphenol gallic acid (GA) on the NLRP3 inflammasome with dextran sulfate sodium (DSS)-induced colitis in mice.Study design: The body weights and symptoms of BALB/c mice were recorded. Histological evaluation, ELISA, q-PCR, immunohistochemistry, and western blotting were carried out to observe the morphology, cytokine contents, mRNA expressions, and protein expressions, respectively. Lipopolysaccharide (LPS)-induced RAW264.7 macrophage was used to probe GA’s effect on relative protein expression.Results: GA attenuated weight loss (p < 0.05), relieved symptoms, and ameliorated colonic morphological injury (p < 0.05) in mice with colitis induced by DSS. GA also lowered the contents of TNF-α, IL-1β, IL-18, IL-33, and IFN-γ in the serum and colon of mice, which were elevated by DSS, downregulated protein, and mRNA expressions of the NLRP3 pathway in the colon tissue. Furthermore, GA downregulated the expressions of NLRP3 (p < 0.05), iNOS (p < 0.01), COX2 (p < 0.01), and P-p65 (p < 0.05), and suppressed NO release (p < 0.001) in LPS-induced RAW264.7 cells.Conclusion: GA ameliorated DSS-induced UC in mice via inhibiting the NLRP3 inflammasome. These findings furnish evidence for the anti-inflammatory effect of herbal medicines containing GA on UC

A Review of the Engineering Role of Burrowing Animals: Implication of Chinese Pangolin as an Ecosystem Engineer

Ecosystem engineers are organisms that alter the distribution of resources in the environment by creating, modifying, maintaining and/or destroying the habitat. They can affect the structure and function of the whole ecosystem furthermore. Burrowing engineers are an important group in ecosystem engineers as they play a critical role in soil translocation and habitat creation in various types of environment.However, few researchers have systematically summarized and analyzed the studies of burrowing engineers. We reviewing the existing ecological studies of burrowing engineer about their interaction with habitat through five directions: (1) soil turnover; (2)changing soil physicochemical properties; (3) changing plant community structure; (4) providing limited resources for commensal animals;and/or (5) affecting animal communities. The Chinese pangolin (Manis pentadactyla) is a typical example of burrowing mammals, in part (5), we focus on the interspecific relationships among burrow commensal species of Chinese pangolin. The engineering effects vary with environmental gradient, literature indicates that burrowing engineer play a stronger role in habitat transformation in the tropical and subtropical areas.The most common experiment method is comparative measurements (include different spatial and temporal scale),manipulative experiment is relatively few. We found that most of the engineering effects had positive feedback to the local ecosystem, increased plant abundance and resilience, increased biodiversity and consequently improved ecosystem functioning. With the global background of dramatic climate change and biodiversity loss in recent decades, we recommend future studies should improving knowledge of long-term engineering effects on population scale and landscape scale, exploring ecological cascades through trophic and engineering pathways, to better understand the attribute of the burrowing behavior of engineers to restore ecosystems and habitat creation. The review is presented as an aid to systematically expound the engineering effect of burrowing animals in the ecosystem, and provided new ideas and advice for planning and implementing conservation management

An adolescent with primary cutaneous follicle center lymphoma: a case report and literature review

Primary cutaneous follicle center lymphoma (PCFCL) differs from follicular lymphoma in biological behavior and molecular profile and is treated as a distinct entity, according to the 5th edition of the World Health Organization classification of hematolymphoid tumors. It is an uncommon cutaneous B-cell lymphoma that is considerably rare in children and adolescents. To date, only 13 cases of individuals younger than 20 years of age have been reported in the literature. The lack of relevant clinical epidemiological data in this population has hampered the investigation of its clinical and diagnostic aspects. Here we report the case of a 17-year-old male with PCFCL, who may be the first PCFCL patient under 20 years of age reported in China. He was admitted to the hospital with a solitary nodule on his face. After complete surgical excision, the patient’s facial mass was histologically identified as PCFCL. The patient’s prognosis was favorable, with no recurrence at 17 months of follow-up after the surgical resection. We present a case of an adolescent PCFCL patient and systematically review the literature with a view to increase the awareness of the disease and inform the diagnosis and treatment of this age group