Establishment of an isotope dilution LC-MS/MS method revealing kinetics and distribution of co-occurring mycotoxins in rats

An isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a fast sample preparation using homemade clean-up cartridges was developed for simultaneous determination of co-occurring mycotoxins exemplified with aflatoxin B1 (AFB1) and T-2 toxin (T-2) in representative biomatrices of rat plasma, heart, liver, kidney, spleen, lung and brain in a total run time of 7 min. The established approach using stable internal standards of [C-13(17)]-AFB1 and [C-13(24)]-T-2 was extensively validated by determining the specificity, linearity (R-2 >= 0.9990), sensitivity (lower limit of quantitation at 0.05 ng mL(-1)), accuracy (70.9-107.7%), precision (RSD = 70.8%). Based on this methodological advance, the subsequent kinetics and tissue distribution after oral administration of 0.5 mg kg(-1) b.w. of both AFB1 and T-2 in rats were thoroughly studied. As revealed, both AFB1 and T-2 were rapidly eliminated with the half-life time (t(1/2)) in plasma of 8.44 +/- 4.02 h and 8.12 +/- 4.05 h, respectively. Moreover, AFB1 accumulated in all organs where the highest concentration was observed in liver (1.34 mu g kg(-1)), followed by kidney (0.76 mu g kg(-1)). Notably, only low levels of T-2 were observed in spleen (0.70 mu g kg(-1)) and in liver (0.15 mu g kg(-1)). The achieved data as supporting evidence would substantially promote the practical application of the proposed LC-MS/MS method for in vivo toxicokinetics and toxicity studies of co-occurring mycotoxins imitating natural incidence in rat system

Human Ecology, Process Philosophy and the Global Ecological Crisis

This paper argues that human ecology, based on process philosophy and challenging scientific materialism, is required to effectively confront the global ecological crisis now facing us

Addressing Parental Smoking in Pediatric Settings of Chinese Hospitals: A Qualitative Study of Parents

This study explored factors associated with SHS exposure from parental smoking in Chinese families and assessed nature of antismoking discussions parents had with their children's pediatricians and how pediatricians might best engage with parents in an effort to reduce children's exposure to SHS. Six focus group discussions (FGDs) were conducted among 33 Chinese parents attending six major hospitals in Guangxi province, China. Most participants (32/33) had family members who smoke, and only 21% had strict restriction on smoking at home. Some parents did not know about health consequences of smoking and effects of SHS exposure on children. Situations that made it especially hard to avoid the child's SHS exposure were having an elderly smoker at home and having a visitor who smoked. Only few parents were asked by pediatricians about child's exposure to SHS at home, but only when child's illness was related to smoking. Parents believed that suggestions coming from pediatricians about smoke-free home and parental quitting would be acceptable to parents and other household members. The findings provide insight into SHS exposure reduction effort among Chinese parents and underscore the demand for pediatrician's engagement in addressing parental tobacco use

Secondhand smoke exposure assessment and counseling in the Chinese pediatric setting: a qualitative study

Background: Assisting smoking parents to quit smoking and eliminating the secondhand smoke (SHS) exposure of their children is a global health priority. Engaging healthcare workers in developing countries to address this priority has been a challenge. This study intends to explore issues around current practice related to SHS exposure assessment and counseling and identify barriers to SHS exposure reduction counseling in the Chinese pediatric setting. Methods: We conducted qualitative interviews (11 focus groups discussions (FGDs) with pediatricians, 6 FGDs with pediatric nurses and 11 in-depth interviews (IDIs) with hospital administrators) among 101 health-care professionals (HCP) from 5 hospitals in four major cities of Guangxi Province, China. All FGDs/ IDIs were audio recorded and analysed thematically. Results: The findings suggest that few Chinese pediatricians routinely address the SHS exposure of children in their usual practice. All HCPs felt the need for clinical interventions to promote SHS exposure reduction for children. Primary barriers to SHS exposure reduction counseling in the Chinese pediatric setting included: lack of skills and training in tobacco use reduction and cessation counseling; time constraints and heavy workloads, uncertainty about the usefulness of smoking cessation interventions and lack of hospital-wide systems requiring pediatricians to record tobacco use or SHS exposure information. Ideas for overcoming these barriers were building capacity of pediatricians, collaboration with international organization to initiate training, engaging top level leaders in the effort and ensuring financial resources to support the program. Conclusions: This study among hospital administrators and service providers in China demonstrated a high level of interest in delivering SHS exposure reduction interventions in the pediatric setting. The findings can inform the creation and delivery of clinical interventions in China to promote SHS exposure reduction to children in the pediatric setting. Electronic supplementary material The online version of this article (doi:10.1186/1471-2431-14-266) contains supplementary material, which is available to authorized users

Pharmacologic suppression of JAK1/2 by JAK1/2 inhibitor AZD1480 potently inhibits IL-6-induced experimental prostate cancer metastases formation.

Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6-activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6-driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6-induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer in vivo in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis in vitro and in vivo via Jak-Stat3 signaling pathway, and that IL-6-driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer

Resilient Consensus Through Dynamic Event-Triggered Mechanism

In this brief, the resilient consensus problem for multi-agent systems (MASs) is addressed based on the dynamic event-triggered (DE) mechanism, when the network is subject to malicious attacks. A dynamic variable is introduced in the DE mechanism to adjust the threshold dynamically. Via the proposed dynamic event-triggered mean-subsequence-reduced (DE-MSR) algorithm, all cooperative agents are guaranteed to reach an agreement on the same consensus value, so that the MAS achieves resilient consensus despite the influence of some noncooperative agents in the network. Compared to existing event-based resilient algorithms, the proposed DE-MSR algorithm is superior in reducing communication overheads while maintaining a resilient consensus. Finally, a comparative case study is conducted to validate the theoretical findings.</p

A Survey of Resilient Coordination for Cyber-Physical Systems Against Malicious Attacks

Cyber-physical systems (CPSs) facilitate the integration of physical entities and cyber infrastructures through the utilization of pervasive computational resources and communication units, leading to improved efficiency, automation, and practical viability in both academia and industry. Due to its openness and distributed characteristics, a critical issue prevalent in CPSs is to guarantee resilience in presence of malicious attacks. This paper conducts a comprehensive survey of recent advances on resilient coordination for CPSs. Different from existing survey papers, we focus on the node injection attack and propose a novel taxonomy according to the multi-layered framework of CPS. Furthermore, miscellaneous resilient coordination problems are discussed in this survey. Specifically, some preliminaries and the fundamental problem settings are given at the beginning. Subsequently, based on a multi-layered framework of CPSs, promising results of resilient consensus are classified and reviewed from three perspectives: physical structure, communication mechanism, and network topology. Next, two typical application scenarios, i.e., multi-robot systems and smart grids are exemplified to extend resilient consensus to other coordination tasks. Particularly, we examine resilient containment and resilient distributed optimization problems, both of which demonstrate the applicability of resilient coordination approaches. Finally, potential avenues are highlighted for future research.Comment: 35 pages, 7 figures, 5 table

Resilient distributed optimization for cyber–physical systems under adversarial environments:An event-based method

This work presents a resilient distributed optimization algorithm based on the event-triggering mechanism for cyber–physical systems (CPSs) to optimize an average of convex cost functions corresponding to multiple agents under adversarial environments. Two attack scenarios, including the f-total (each agent is affected by at most f malicious agents in the whole network) and the f-local (each agent is affected by at most f malicious agents in its in-neighbor set) attacks are considered. Subsequently, the convergence conditions under these two attack scenarios are provided, respectively, both of which guarantee that the state values of benign agents converge to a bounded error range. The optimality conditions are also presented by theoretical analysis, which guarantee that the state values of benign agents converge to a safety interval constructed by local optimal values under certain graph conditions, despite the misbehavior of malicious agents. In addition, four numerical examples are presented to show the effectiveness and superiority of the event-triggering resilient distributed optimization (RDO-E) algorithm. Compared to existing resilient algorithms, the proposed method achieves resilient distributed optimization with higher accuracy and less demanding communication overheads. Finally, by applying the proposed method to the multi-microgrid system, a resilient economic dispatch problem (REDP) is successfully solved, which validates the practical viability of the RDO-E algorithm.</p

Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia.

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl-mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5μmol/L) and Stat5b (IC50 = 3.5 μmol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies