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Abstract The advancement of lightweight protective armors holds critical importance for enhancing the maneuverability and combat capabilities of helicopters. Leveraging insights from bionics, it provides a new idea for high-performance armor design. In this study, a new type of composite armor was designed by referring to the structural characteristics of hard phase-protection, soft phase-buffering of unitization armadillo shell. Through the numerical study, the anti-ballistic performance of armor with varying thickness ratios of the dense ceramic layer to the interpenetrating layer is obtained, and the influence of different structures of armor on the anti-ballistic performance is analyzed. The results show that compared with the traditional laminated composite armor, the Al2O3/Al biomimetic composite armor not only improves the separation phenomenon caused by wave impedance mismatch, but also greatly improves the speed drop in resisting high-speed and penetrating bullets. When the thickness ratio is 2:1, the armor has higher ballistic protection performance.

Citrus trees face an array of threats that can impact fruit development and overall tree health. Pests, including aphids, mites, and other insects, can damage fruit and transmit diseases. Extreme weather events, such as hailstorms or heavy rains, can cause physical harm, leading to blemishes and reduced market value. In addition, citrus growers have consistently faced persistent challenges in the form of bacterial diseases, including citrus canker and citrus greening. These diseases not only have a negative impact on the quality of fruits, but also create a potential risk to the long-term viability of citrus industry.

Nutrient sensing and metabolic homeostasis play an important role in the proper growth and development of an organism, and also in the energy intensive process of reproduction. Signals in response to nutritional and metabolic status is received and integrated by the brain to ensure homeostasis. In Drosophila, the fat body is one of the key organs involved in energy and nutrient sensing, storage and utilization. It also relays the nutritional status of the animal to the brain, activating specific circuits which modulate the synthesis and release of insulin-like peptides to regulate metabolism. Here, we review the molecular and cellular mechanisms involved in nutrient sensing with an emphasis on the neural pathways that modulate this process and discuss some of the open questions that need to be addressed. [ABSTRACT FROM AUTHOR]

The paper presents experimental results of the work conducted to improve the adhesion between alumina ceramics and urea-urethane elastomer in the interpenetrating phase composites (IPCs), in which these two phases are interpenetrating three-dimensionally and topologically throughout the microstructure. Measurements of the contact angle, surface roughness, and shear tests were used to evaluate the effectivity and select the quantity of a silane coupling agent and the ceramic fabrication method. The tests were conducted using samples of dense alumina ceramic obtained by three- or four-step methods. In the four-step process, hot isostatic pressing (HIP) was applied additionally. As a result of the coupling agent coat and HIP application, the ceramic substrate wettability by the elastomer was improved. The water contact angle was reduced from 80 to 60%. In the next step, porous ceramic preforms were fabricated using HIP sintering and a solution of silane coupling agent treated their surface. The composites were produced using vacuum-pressure infiltration of porous alumina ceramics by urea-urethane elastomer in liquid form. The influence of the coupling agent application on the microstructure and mechanical properties of the composites was estimated. The microstructure of the composites was identified using SEM microscopy and X-ray tomography. As a result of using the coupling agent, residual porosity decreased from 7 to 2%, and compressive strength, as well as stress at a plateau, increased by more than 20%, from 25 to 33 MPa and from 15 to 24 MPa, respectively, for the composites fabricated by infiltration ceramic preforms with 40% of porosity. [ABSTRACT FROM AUTHOR]

Nutrient sensing and metabolic homeostasis play an important role in the proper growth and development of an organism, and also in the energy intensive process of reproduction. Signals in response to nutritional and metabolic status is received and integrated by the brain to ensure homeostasis. In Drosophila, the fat body is one of the key organs involved in energy and nutrient sensing, storage and utilization. It also relays the nutritional status of the animal to the brain, activating specific circuits which modulate the synthesis and release of insulin-like peptides to regulate metabolism. Here, we review the molecular and cellular mechanisms involved in nutrient sensing with an emphasis on the neural pathways that modulate this process and discuss some of the open questions that need to be addressed.

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A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH2O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents.

In previous and ongoing research performed by our team at SWFREC (see articles in Citrus Industry 100 and 103 issues), we have demonstrated that IPCs are an effective tool for excluding psyllids from newly planted citrus trees, keeping them HLB-free for more than 2 years after planting and with several additional benefits for plant health. A question arose on the possibility of having the beneficial effects of IPC coverage while not covering all the trees in a solid planting but covering the ‘strategic’ trees only (i.e., trees on hot spots or at the edge of grove). In other words, we were interested in finding out whether covering only a subsection of trees in a solid replant would also be effective in maintaining a generally healthy and productive citrus grove. This would dramatically reduce the costs associated with purchase and installation of the IPCs. Therefore, we started testing the different layouts for IPCs deployment. We want to understand if covering every tree in a block is necessary or if there are situations in which some trees can remain uncovered, adjusting to different psyllid pressure and geographical features of the grove. This research hinges on the edge effect concept, based on which psyllids are more abundant in the periphery of a grove. In summary, having part of the trees uncovered in a grove without a significant increase in psyllid colonization would result in more targeted management and substantial savings for the grower.

In this article we report on the first year of fruit production in Valencia trees grown under IPCs with special emphasis on internal fruit quality and fruit drop

A rational-based process was adopted for repurposing pyrrolidine-based 3-deoxysphingosylphosphorylcholine analogs bearing variable acyl chains, different stereochemical configuration and/or positional relationships. Structural features were highly influential on activity. Amongst, enantiomer 1e having 1,2-vicinal relationship for the -CH2O- and the N-acyl moieties, a saturated palmitoyl chain and an opposite stereochemical configuration to natural sphingolipids was the most potent hit compound against promastigotes showing IC50 value of 28.32 µM. The corresponding enantiomer 1a was 2-fold less potent showing a eudismic ratio of 0.54 in promastigotes. Compounds 1a and 1e inhibited the growth of amastigotes more potently relative to promastigotes. Amongst, enantiomer 1a as the more selective and safer. In silico docking study using a homology model of Leishmania donovani inositol phosphoceramide synthase (IPCS) provided plausible reasoning for the molecular factors underlying the found activity. Collectively, this study suggests compounds 1a and 1e as potential hit compounds for further development of new antileishmanial agents. [ABSTRACT FROM AUTHOR]

Xing-Hua Xiao,* Qi-Yuan Huang,* Xian-Ling Qian,* Jing Duan, Xue-Qiao Jiao, Long-Yuan Wu, Qing-Yun Huang, Jun Li, Xing-Ning Lai, Yu-Bo Shi, Li-Xia Xiong Department of Pathophysiology, Medical College, Nanchang University, Nanchang 330006, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-Xia XiongDepartment of Pathophysiology, Medical College, Nanchang University, 461 Bayi Road, Nanchang 330006, People’s Republic of ChinaTel +86-791-8636-0556Email xionglixia@ncu.edu.cnPurpose: Type 1 diabetes mellitus (T1DM) is characterized by irreversible islet β cell destruction. Accumulative evidence indicated that Cdc42 and Wnt/β-catenin signaling both play a critical role in the pathogenesis and development of T1DM. Further, bio-molecular mechanisms in adipose-derived mesenchymal stem cells (ADSCs)-derived insulin-producing cells (IPCs) remain largely unknown. Our aim was to investigate the underlying mechanism of Cdc42/Wnt/β-catenin pathway in ADSC-derived IPCs, which may provide new insights into the therapeutic strategy for T1DM patients.Methods: ADSC induction was accomplished with DMSO under high-glucose condition. ML141 (Cdc42 inhibitor) and Wnt-3a (Wnt signaling activator) were administered to ADSCs from day 2 until the induction finished. Morphological changes were determined by an inverted microscope. Dithizone staining was employed to evaluate the induction of ADSC-derived IPCs. qPCR and Western blotting were employed to measure the mRNA and protein expression level of islet cell development-related genes and Wnt signaling-related genes. The proliferation ability of ADSC-derived IPCs was also detected with a cell counting kit (CCK) assay. The expression and secretion of Insulin were detected with immunofluorescence test and enzyme-linked immunosorbent assay (ELISA) respectively.Results: During induction, morphological characters of ADSCs changed into spindle and round shape, and formed islet-line cell clusters, with brown dithizone–stained cytoplasm. Expression levels of islet cell development-related genes were up-regulated in ADSC-derived IPCs. Wnt-3a promoted Wnt signaling markers and islet cell development-related gene expression at mRNA and protein levels, while ML141 played a negative effect. Wnt-3a promoted ADSC-derived IPC proliferation and glucose-stimulated insulin secretion (GSIS), while ML141 played a negative effect.Conclusion: Our research demonstrated that DMSO and high-glucose condition can induce ADSCs into IPCs, and Wnt signaling promotes the induction. Cdc42 may promote IPC induction, IPC proliferation and insulin secretion via Wnt/β-catenin pathway, meaning that Cdc42 may be regarded as a potential target in the treatment of T1DM.Keywords: Cdc42, ML141, ADSCs, IPCs, Wnt signaling, insulin

Science, propelled forward by noble aspirations and, at times, human hubris, has the capacity to affect lives and alter the world in unanticipated ways. Even seemingly minor discoveries have repeatedly proven to have far reaching implications that experts within their respective fields could not have predicted. Nuclear technology is both a source of energy and a potential means of annihilation. The internet has both seamlessly connected the world but has also opened society to the misuse and manipulation of information. Both exemplify how new technologies have the potential for positive and negative outcomes that often go beyond what was initially intended. This is not a fault of science and innovation but rather an inherent occupational hazard as new discoveries exist within a gray zone between ignorance and comprehension. These gaps in our knowledge can only be filled over time as our knowledge expands. Innovations that were once seen as fringe, over time, become mainstream and that which was once revolutionary becomes a part of everyday life. Occasionally, a scientific advancement comes along that challenges societal norms and causes us to question what is feasible, acceptable, and ethical. Nowhere in the twenty-first century has this been more evident than within the fields of genetics and genetic engineering. As we gain a deeper understanding of the source code of life, from individual base pairs to epigenetic influences, the implications of new discoveries will go far beyond curing genetic diseases, and the possibilities will be endless. Reproductive endocrinology and infertility (REI) specialists utilize many tools including expanded carrier screening, preimplantation genetic testing, and embryo selection and have become some of the experts at the forefront of the ongoing genetic revolution. Now more than ever, there is a need for REIs to be trained in the fundamentals of genetics, exposed to novel gene sequencing and editing techniques, and involved in the coming ethical discussions in order to be prepared for the genetically engineered future. [ABSTRACT FROM AUTHOR]

Huntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the exon-1 of the IT15 gene encoding the protein Huntingtin. Expression of mutated Huntingtin in humans leads to dysfunction and ultimately degeneration of selected neuronal populations of the striatum and cerebral cortex. Current available HD therapy relies on drugs to treat chorea and control psychiatric symptoms, however, no therapy has been proven to slow down disease progression or prevent disease onset. Thus, although 24 years have passed since HD gene identification, HD remains a relentless progressive disease characterized by cognitive dysfunction and motor disability that leads to death of the majority of patients, on average 10–20 years after its onset. Up to now several molecular pathways have been implicated in the process of neurodegeneration involved in HD and have provided potential therapeutic targets. Based on these data, approaches currently under investigation for HD therapy aim on the one hand at getting insight into the mechanisms of disease progression in a human-based context and on the other hand at silencing mHTT expression by using antisense oligonucleotides. An innovative and still poorly investigated approach is to identify new factors that increase neurogenesis and/or induce reprogramming of endogenous neuroblasts and parenchymal astrocytes to generate new healthy neurons to replace lost ones and/or enforce neuroprotection of pre-existent striatal and cortical neurons. Here, we review studies that use human disease-in-a-dish models to recapitulate HD pathogenesis or are focused on promoting in vivo neurogenesis of endogenous striatal neuroblasts and direct neuronal reprogramming of parenchymal astrocytes, which combined with neuroprotective protocols bear the potential to re-establish brain homeostasis lost in HD.

Huntington's Disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the exon-1 of the IT15 gene encoding the protein Huntingtin. Expression of mutated Huntingtin in humans leads to dysfunction and ultimately degeneration of selected neuronal populations of the striatum and cerebral cortex. Current available HD therapy relies on drugs to treat chorea and control psychiatric symptoms, however, no therapy has been proven to slow down disease progression or prevent disease onset. Thus, although 24 years have passed since HD gene identification, HD remains a relentless progressive disease characterized by cognitive dysfunction and motor disability that leads to death of the majority of patients, on average 10–20 years after its onset. Up to now several molecular pathways have been implicated in the process of neurodegeneration involved in HD and have provided potential therapeutic targets. Based on these data, approaches currently under investigation for HD therapy aim on the one hand at getting insight into the mechanisms of disease progression in a human-based context and on the other hand at silencing mHTT expression by using antisense oligonucleotides. An innovative and still poorly investigated approach is to identify new factors that increase neurogenesis and/or induce reprogramming of endogenous neuroblasts and parenchymal astrocytes to generate new healthy neurons to replace lost ones and/or enforce neuroprotection of pre-existent striatal and cortical neurons. Here, we review studies that use human disease-in-a-dish models to recapitulate HD pathogenesis or are focused on promoting in vivo neurogenesis of endogenous striatal neuroblasts and direct neuronal reprogramming of parenchymal astrocytes, which combined with neuroprotective protocols bear the potential to re-establish brain homeostasis lost in HD. [ABSTRACT FROM AUTHOR]

Generation of new β cells is an important approach in the treatment of type 1 diabetes mellitus (type 1 DM). Adipose tissue-derived stem cells (ADSCs) might be one of the best sources for cell replacement therapy for diabetes. Therefore, this work aimed to test the possible role of transplanted insulin-producing cells (IPCs) differentiated from ADSCs in treatment of streptozotocin (STZ) induced type I DM in rats. Type 1 DM was induced by single intra peritoneal injection with STZ (50 mg/kg BW). Half of the diabetic rats were left without treatment and the other half were injected with differentiated IPCs directly into the pancreas. ADSCs were harvested, cultured and identified by testing their phenotypes through flow cytometry. They were further subjected to differentiation into IPCs using differentiation medium. mRNA expression of pancreatic transcription factors (pdx1), insulin and glucose transporter-2 genes by real time PCR was done to detect the cellular differentiation and confirmed by stimulated insulin secretion. The pancreatic tissues from all groups were examined 2 months after IPC transplantation and were subjected to histological, Immunohistochemical and morphometric study. The differentiated IPCs showed significant expression of pancreatic β cell markers and insulin secretion in glucose dependent manner. Treatment with IPCs induced apparent regeneration, diffused proliferated islet cells and significant increase in C-peptide immune reaction. We concluded that transplantation of differentiated IPCs improved function and morphology of Islet cells in diabetic rats. Consequently, this therapy option may be a promising therapeutic approach to patient with type 1 DM if proven to be effective and safe. [ABSTRACT FROM AUTHOR]

As a potential cure for diabetes, more and more attentions have been paid to organ transplants to replace insulin therapy. As a result, many researchers have explored out many programs to get insulin-producing cells (IPCs) to replace the defective β cells. Currently, more and more new induction methods are being proposed, and at the same time, more and more possible induction molecular mechanisms are being revealed. The purpose of this study was to explore whether and how the two factors pdx-1 and myocardin affected the differentiation of rat mesenchymal stem cells (rMSCs) into IPCs. In this study, we investigated the process of transfecting myocardin and/or pdx-1 in rMSCs in vitro. The results showed that rMSCs were able to secrete insulin after cotransfected with myocardin and pdx-1. At the same time, we explored the possible mechanism that myocardin and pdx-1 coinduced rMSCs into IPCs by forming a complex to promote the transcriptional activity of insulin. Our results may provide a theoretical basis to the study of islet transplantation in the future. [ABSTRACT FROM AUTHOR]

Background: The expansion of malaria prevention and control to school-aged children is receiving increasing attention, but there are still limited data on the costs of intervention. This paper analyses the costs of a comprehensive school-based intervention strategy, delivered by teachers, that included participatory malaria educational activities, distribution of long lasting insecticide-treated nets (LLIN), and Intermittent Parasite Clearance in schools (IPCs) in southern Mali.Methods: Costs were collected alongside a randomised controlled trial conducted in 80 primary schools in Sikasso Region in Mali in 2010-2012. Cost data were compiled between November 2011 and March 2012 for the 40 intervention schools (6413 children). A provider perspective was adopted. Using an ingredients approach, costs were classified by cost category and by activity. Total costs and cost per child were estimated for the actual intervention, as well as for a simpler version of the programme more suited for scale-up by the government. Univariate sensitivity analysis was performed.Results: The economic cost of the comprehensive intervention was estimated to $10.38 per child (financial cost $8.41) with malaria education, LLIN distribution and IPCs costing $2.13 (20.5%), $5.53 (53.3%) and $2.72 (26.2%) per child respectively. Human resources were found to be the key cost driver, and training costs were the greatest contributor to overall programme costs. Sensitivity analysis showed that an adapted intervention delivering one LLIN instead of two would lower the economic cost to $8.66 per child; and that excluding LLIN distribution in schools altogether, for example in settings where malaria control already includes universal distribution of LLINs at community-level, would reduce costs to $4.89 per child.Conclusions: A comprehensive school-based control strategy may be a feasible and affordable way to address the burden of malaria among schoolchildren in the Sahel. [ABSTRACT FROM AUTHOR]

Building circuits and studying their behavior in cells is a major goal of systems and synthetic biology. Synthetic biology enables the precise control of cellular states for systems studies, the discovery of novel parts, control strategies, and interactions for the design of robust synthetic systems. To the best of our knowledge, there are no literature reports for the synthetic circuit construction for protozoan parasites. This paper describes the construction of genetic circuit for the targeted enzyme inositol phosphorylceramide synthase belonging to the protozoan parasite Leishmania. To explore the dynamic nature of the circuit designed, simulation was done followed by circuit validation by qualitative and quantitative approaches. The genetic circuit designed for inositol phosphorylceramide synthase (Biomodels Database-MODEL1208030000) shows responsiveness, oscillatory and bistable behavior, together with intrinsic robustness. [ABSTRACT FROM AUTHOR]

The International Society for Exposure Analysis (ISEA) and its Nomenclature Committee have been involved since the mid-1990s in an intermittent but ongoing effort to develop an official ISEA glossary. Several related activities have stimulated greater interest and discussion nationally and internationally on a common exposure language. Among these activites are a 1997 Journal of Exposure Analysis and Environmental Epidemiology feature article on exposure and dose definitions and a 1999-initiated project of the International Programme on Chemical Safety (IPCS) (WHO/ILO/UNEP) to confront terminology issues hindering harmonization in the area of exposure assessment. Recently, the ISEA members voted in support of adopting the IPCS glossary as the official ISEA glossary, and the ISEA Executive Board agreed to accept this recommendation. In this feature article, we (1) describe the process through which the ISEA adopted the IPCS glossary as the official ISEA glossary, (2) present the joint IPCS/ISEA glossary of terms and their definitions, and (3) discuss plans for how the glossary can be used by ISEA and updated over time by ISEA and IPCS. The glossary is intended to be a living document that reflects the latest usage and maintains international harmonization of exposure terminology that can be practically applied to improve communication in exposure and related fields.Journal of Exposure Analysis and Environmental Epidemiology (2005) 15, 1-5. doi:10.1038/sj.jea.7500411 Published online 24 November 2004 [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) have been extensively explored over the past decade, including mice and humans. However, their impact on the transdifferentiation of canine bone marrow mesenchymal stem cells (cBMSCs) into insulin-producing cells (IPCs) is largely unknown. In this study, we used a three-step induction procedure to induce cBMSCs into IPCs, and samples (two biological replicates each) were obtained after each step; the samples consisted of "BMSCs" (B), "stage 1" (S1), "stage 2" (S2), "stage 3" (S3), and "islets" (I). After sequencing, 15,091 lncRNAs were identified, and we screened 110, 41, 23, and 686 differentially expressed lncRNAs (padjusted < 0.05) in B vs. S1, S1 vs. S2, S2 vs. S3, and I vs. S3 pairwise comparisons, respectively. In lncRNA target prediction, there were 166,623 colocalized targets and 2,976,362 correlated targets. Gene Ontology (GO) analysis showed that binding represented the main molecular functions of both the cis- and trans-modes. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the insulin signaling pathway, Rap1 signaling pathway, tight junctions, MAPK signaling pathway, and cell cycle were enriched for these relative genes. The expression of lncRNAs was verified using qRT-PCR. This study provides a lncRNA catalog for future research concerning the mechanism of the transdifferentiation of cBMSCs into IPCs. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus (T1DM), a multisystem disease with both biochemical and anatomical/structural consequences, is a major health concern worldwide. Pancreatic islet transplantation provides a promising treatment for T1DM. However, the limited availability of islet tissue or new sources of insulin producing cells (IPCs) that are responsive to glucose hinder this promising approach. Though slow, the development of pancreatic beta-cell lines from rodent or human origin has been steadily progressing. Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent, culture-expanded, non-hematopoietic cells that are currently being investigated as a novel cellular therapy. The in vitro differentiation potential of IPCs has raised hopes for a treatment of clinical diseases associated with autoimmunity. We screened for small molecules that induce pancreatic differentiation of IPCs. There are some compounds which showed positive effects on the DTZ staining. The aminopyrrole derivative compound XW4.4 which shows the best activity among them was found to induce pancreatic differentiation of rat MSCs (rMSCs). The in vitro studies indicated that treatment of rMSCs with compound XW4.4 resulted in differentiated cells with characteristics of IPCs including islet-like clusters, spherical, grape-like morphology, insulin secretion, positive for dithizone, glucose stimulation and expression of pancreatic endocrine cell marker genes. The data has also suggested that hepatocyte nuclear factor 3β (HNF 3β) may be involved in pancreatic differentiation of rMSCs when treated with XW4.4. Results indicate that XW4.4 induced rMSCs support the efforts to derive functional IPCs and serve as a means to alleviate limitations surrounding islet cell transplantation in the treatment of T1DM., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

To assess the potential risk of human exposure to carcinogenic leucomalachite green (LMG) due to fish consumption, the probabilistic risk assessment was conducted for adolescent, adult and senior adult consumers in Taiwan. The residues of LMG with the mean concentration of 13.378±20.56 μg kg(-1) (BFDA, 2009) in fish was converted into dose, considering fish intake reported for three consumer groups by NAHSIT (1993-1996) and body weight of an average individual of the group. The lifetime average and high 95th percentile dietary intakes of LMG from fish consumption for Taiwanese consumers were estimated at up to 0.0135 and 0.0451 μg kg-bw(-1) day(-1), respectively. Human equivalent dose (HED) of 2.875 mg kg-bw(-1) day(-1) obtained from a lower-bound benchmark dose (BMDL10) in mice by interspecies extrapolation was linearly extrapolated to oral cancer slope factor (CSF) of 0.035 (mgkg-bw(-1)day(-1))(-1) for humans. Although, the assumptions and methods are different, the results of lifetime cancer risk varying from 3×10(-7) to 1.6×10(-6) were comparable to those of margin of exposures (MOEs) varying from 410,000 to 4,800,000. In conclusions, Taiwanese fish consumers with the 95th percentile LADD of LMG have greater risk of liver cancer and need to an action of risk management in Taiwan., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Limited testing resources, the need to limit animal use, and the demand for better knowledge about carcinogenic hazards require that the carcinogenicity testing paradigm based on lifetime cancer bioassays in rats and mice should be as efficient and reliable as possible. We have therefore reevaluated the rodent bioassay, particularly for nongenotoxic chemicals and conducted a rigorous examination of the 710 substances listed in the Carcinogenic Potency Database (CPDB) that were tested in both mice and rats. The CPDB is a web-based database that provides access to the literature and the results of 6540 bioassays on 1547 chemicals that have been published in the general literature through 2001 and by the National Cancer Institute/National Toxicology Program through 2004. Only three chemicals (o-benzyl-p-chlorophenol, Elmiron®, p-tolylurea) were identified as unequivocally non-genotoxic, mouse non-liver carcinogens. A careful analysis showed that their carcinogenicity in mice is irrelevant for assessment of human cancer hazards. This is consistent with data showing, with a few well-known exceptions, that non-genotoxic carcinogens in rodents are considered to be non-carcinogenic to humans. As a result, we propose that the inclusion of the mouse bioassay in the standard assessment scheme for non-genotoxic chemicals is no longer necessary., (Copyright © 2013. Published by Elsevier Ltd.)

To understand the role of mitochondrial uncoupling protein (UCP) in regulating insulin signaling and glucose homeostasis, we created transgenicDrosophila lines with targeted UCP expression in insulin producing cells (IPCs). Increased UCP activity in IPCs results in decreased steady state Ca(2+) levels in IPCs as well as decreased PI3K activity and increased FoxO nuclear localization in periphery. This reduced systemic insulin signaling is accompanied by a mild hyperglycemia and extended life span. To test the hypothesis that ATP-sensitive potassium (K(ATP)) channels may link changes in metabolic activity (e.g., glucose mediated ATP production or UCP-mediated ATP reduction) with insulin secretion, we characterized the effects of glucose and a specific K(ATP) channel blocker, glibenclamide on membrane potential in adult IPCs. Exposure to glucose depolarizes membrane potential of IPCs and this effect is mimicked with glibenclamide, suggesting that K(ATP) channels contribute to the mechanism whereby IPCs sense changes in circulating sugar. Further, as demonstrated in mammalian beta-pancreatic cells, high glucose initiates a robust Ca(2+) influx in adult IPCs. The presence of functional K(ATP) channels in adult IPCs is further substantiated by in situ hybridization detecting the transcript for the sulfonylurea receptor (Sur) subunit of the K(ATP) channel in those cells. Quantitative expression analysis demon-strates a reduction in transcripts for both Sur and the inward rectifying potassium channel (Kir) subunits when IPCs are partially ablated. In summary, we have demonstrated a role for UCP in adult Drosophila IPCs in influencing systemic insulin signaling and longevity by a mechanism that may involve K(ATP) channels.