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Advances in molecular biology and toxicology are paving the way for major improvements in the evaluation of the hazards posed by the large number of chemicals found at low levels in the environment. The National Research Council was asked by the U.S. Environmental Protection Agency to review the state of the science and create a far-reaching vision for the future of toxicity testing. The book finds that developing, improving, and validating new laboratory tools based on recent scientific advances could significantly improve our ability to understand the hazards and risks posed by chemicals. This new knowledge would lead to much more informed environmental regulations and dramatically reduce the need for animal testing because the new tests would be based on human cells and cell components. Substantial scientific efforts and resources will be required to leverage these new technologies to realize the vision, but the result will be a more efficient, informative and less costly system for assessing the hazards posed by industrial chemicals and pesticides.

A single species of fly, Drosophila melanogaster, has been the subject of scientific research for more than one hundred years. Why does this tiny insect merit such intense scrutiny? Drosophila's importance as a research organism began with its short life cycle, ability to reproduce in large numbers, and easy-to-see mutant phenotypes. Over time, laboratory investigation revealed surprising similarities between flies and other animals at the level of genes, gene networks, cell interactions, physiology, immunity, and behavior. Like humans, flies learn and remember, fight microbial infection, and slow down as they age. Scientists use Drosophila to investigate complex biological activities in a simple but intact living system. Fly research provides answers to some of the most challenging questions in biology and biomedicine, including how cells transmit signals and form ordered structures, how we can interpret the wealth of human genome data now available, and how we can develop effective treatments for cancer, diabetes, and neurodegenerative diseases. Written by a leader in the Drosophila research community, First in Fly celebrates key insights uncovered by investigators using this model organism. Stephanie Elizabeth Mohr draws on these \"first in fly\" findings to introduce fundamental biological concepts gained over the last century and explore how research in the common fruit fly has expanded our understanding of human health and disease.-- Provided by publisher

Traumatic optic neuropathy (TON) is a common cause of irreversible blindness following head injury. TON is characterized by axon damage in the optic nerve followed by retinal ganglion cell death in the days and weeks following injury. At present, no therapeutic or surgical approach has been found to offer any benefit beyond observation alone. This is due in part to the lack of translational animal models suitable for understanding mechanisms and evaluating candidate treatments. In this study, we developed a rat model of TON in which the eye is rapidly rotated, inflicting mechanical stress on the optic nerve and leading to significant visual deficits. These functional deficits were thoroughly characterized up to one week after injury using electrophysiology and immunohistochemistry. The photopic negative response (PhNR) of the light adapted full field electroretinogram (LA ffERG) was significantly altered following injury. This correlated with increased biomarkers of retinal stress, axon disruption, and cell death. Together, this evidence suggests the utility of our model for mimicking clinically relevant TON and that the PhNR may be an early diagnostic for TON. Future studies will utilize this animal model for evaluation of candidate treatments.

Glucose Metabolism In Vivo in Four Commonly Used Inbred Mouse Strains Eric D. Berglund 1 , Candice Y. Li 1 2 , Greg Poffenberger 3 , Julio E. Ayala 1 2 , Patrick T. Fueger 4 , Shannon E. Willis 3 , Marybeth M. Jewell 3 , Alvin C. Powers 1 3 5 and David H. Wasserman 1 2 1 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 2 Vanderbilt University–NIH Mouse Metabolic Phenotyping Center, Vanderbilt University School of Medicine, Nashville, Tennessee 3 Department of Medicine, Division of Diabetes, Endocrinology, and Metabolism, Vanderbilt University School of Medicine, Nashville, Tennessee 4 Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 5 VA Tennessee Valley Healthcare System, Nashville, Tennessee Corresponding author: Eric Berglund, eric.d.berglund{at}vanderbilt.edu Abstract OBJECTIVE —To characterize differences in whole-body glucose metabolism between commonly used inbred mouse strains. RESEARCH DESIGN AND METHODS —Hyperinsulinemic-euglycemic (∼8.5 mmol/l) and -hypoglycemic (∼3.0 mmol/l) clamps were done in catheterized, 5-h-fasted mice to assess insulin action and hypoglycemic counter-regulatory responsiveness. Hyperglycemic clamps (∼15 mmol/l) were done to assess insulin secretion and compared with results in perifused islets. RESULTS —Insulin action and hypoglycemic counter-regulatory and insulin secretory phenotypes varied considerably in four inbred mouse strains. In vivo insulin secretion was greatest in 129X1/Sv mice, but the counter-regulatory response to hypoglycemia was blunted. FVB/N mice in vivo showed no increase in glucose-stimulated insulin secretion, relative hepatic insulin resistance, and the highest counter-regulatory response to hypoglycemia. In DBA/2 mice, insulin action was lowest among the strains, and islets isolated had the greatest glucose-stimulated insulin secretion in vitro. In C57BL/6 mice, in vivo physiological responses to hyperinsulinemia at euglycemia and hypoglycemia were intermediate relative to other strains. Insulin secretion by C57BL/6 mice was similar to that in other strains in contrast to the blunted glucose-stimulated insulin secretion from isolated islets. CONCLUSIONS —Strain-dependent differences exist in four inbred mouse strains frequently used for genetic manipulation and study of glucose metabolism. These results are important for selecting inbred mice to study glucose metabolism and for interpreting and designing experiments. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 8 April 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit,and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted April 3, 2008. Received November 15, 2007. DIABETES

Humans have a long history of using animal models to learn about ourselves. The first records of animal model usage date back to ancient Greece. In the fifth century BCE, Alcmaeon of Croton observed connections between the brain and sensory organs in dogs. A couple of centuries later, Aristotle studied embryo growth in chicks. Since then, animal models have played an indispensable role in biomedical research, leading to many of the biggest medical breakthroughs. William Harvey, founder of modern physiology, discovered blood circulation in the early 1600s after studying the anatomy of several species of animals. Surgeon Frederick Banting and his student Charles Best found that injections of pancreatic cell extracts relieved diabetic symptoms in dogs, leading to the discovery of insulin in the 1920s. The Salk and Sabin polio vaccine was developed based on more than 40 years of experiments using monkey, rat, and mouse models, leading to a successful double-blind trial on 1.8 million children in 1954.

The establishing of the first cancer models created a new perspective on the identification and evaluation of new anti-cancer therapies in preclinical studies. Patient-derived xenograft models are created by tumor tissue engraftment. These models accurately represent the biology and heterogeneity of different cancers and recapitulate tumor microenvironment. These features have made it a reliable model along with the development of humanized models. Therefore, they are used in many studies, such as the development of anti-cancer drugs, co-clinical trials, personalized medicine, immunotherapy, and PDX biobanks. This review summarizes patient-derived xenograft models development procedures, drug development applications in various cancers, challenges and limitations.

Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting is vital to this process; it allows readers to assess the reliability of the findings and repeat or build upon the work of other researchers. The ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) were developed in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of ARRIVE on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This explanation and elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2.0, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature. This document also covers advice and best practice in the design and conduct of animal studies to support researchers in improving standards from the start of the experimental design process through to publication.

Regeneration of the Pancreas in Adult Zebrafish Jennifer B. Moss 1 , Punita Koustubhan 2 , Melanie Greenman 1 , Michael J. Parsons 4 , Ingrid Walter 3 and Larry G. Moss 1 1 Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina; 2 Tufts Center for Regenerative and Developmental Biology, Tufts University, Medford, Massachusetts; 3 Department of Pathobiology, Institute of Anatomy, University of Veterinary Medicine, Vienna, Austria; 4 Department of Surgery, Johns Hopkins University, Baltimore, Maryland. Corresponding author: Jennifer B. Moss, jennifer.b.moss{at}duke.edu . Abstract OBJECTIVE Regenerating organs in diverse biological systems have provided clues to processes that can be harnessed to repair damaged tissue. Adult mammalian β-cells have a limited capacity to regenerate, resulting in diabetes and lifelong reliance on insulin. Zebrafish have been used as a model for the regeneration of many organs. We demonstrate the regeneration of adult zebrafish pancreatic β-cells. This nonmammalian model can be used to define pathways for islet-cell regeneration in humans. RESEARCH DESIGN AND METHODS Adult transgenic zebrafish were injected with a single high dose of streptozotocin or metronidazole and anesthetized at 3, 7, or 14 days or pancreatectomized. Blood glucose measurements were determined and gut sections were analyzed using specific endocrine, exocrine, and duct cell markers as well as markers for dividing cells. RESULTS Zebrafish recovered rapidly without the need for insulin injections, and normoglycemia was attained within 2 weeks. Although few proliferating cells were present in vehicles, ablation caused islet destruction and a striking increase of proliferating cells, some of which were Pdx1 positive. Dividing cells were primarily associated with affected islets and ducts but, with the exception of surgical partial pancreatectomy, were not extensively β-cells. CONCLUSIONS The ability of the zebrafish to regenerate a functional pancreas using chemical, genetic, and surgical approaches enabled us to identify patterns of cell proliferation in islets and ducts. Further study of the origin and contribution of proliferating cells in reestablishing islet function could provide strategies for treating human diseases. Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Received May 9, 2008. Accepted May 14, 2009. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. © 2009 by the American Diabetes Association.