A substantial and increasing proportion of death and disability in the EU (and elsewhere) is attributable to diseases associated with insulin resistance (i.e., decreased insulin sensitivity). Beside type II diabetes, other diseases like obesity, hypertension, atherosclerosis, hyperlipidaemia, polycystic ovarian syndrome, and acromegaly are indeed associated with insulin resistance [1].

Stephane Schurmans

The Insulin-Sensitive Side of SHIP2

A long-held hypothesis in neuroscience holds that learning and memory mechanisms involve lasting changes in synaptic weights. Multiple mechanisms for producing such changes exist, of which NMDA-receptor&#x2013;dependent long-term potentiation (LTP) is the most widely studied. Curiously, the relatively simple hypothesis that LTP plays a role in learning and memory has proven difficult to test. A current experimental strategy is to generate genetically altered mice with mutations in genes thought to be involved in LTP and assess the effects of these mutations both on LTP and animal behavior[1,2]. A difficulty associated with these approaches has been that they are not temporally or spatially refined. To alleviate this problem, Dr. Isabelle Mansuy and colleagues used an inducible and reversible transgene expression system in which transgene expression could be controlled on a week-to-week timescale to assess the effects of genetic reduction of the activity of a protein phosphatase known as calcineurin or PP2B in adult mouse forebrain[3,4].

Carl Weitlauf

Danny Winder

Calcineurin, Synaptic Plasticity, and Memory

The efficient organization of the actin cytoskeleton is important for many cellular functions. However, how the local actin organization is regulated in a cell is not well understood. By using yeast mutants defective in actin organization and secretion, we demonstrated that exocytosis plays a role in the spatial regulation of actin organization. Our findings suggest that the actin cytoskeleton, exocytosis, and perhaps endocytosis, may depend on each other for efficiency and reinforce each other.

Xiang-Dong Gao

Stefan Albert

A Role for Exocytosis in the Spatial Regulationof Actin Organization

More than one million Americans have Type 1 diabetes. This disease &#x2014; also known as autoimmune or juvenile diabetes &#x2014; strikes children suddenly, makes them dependent on insulin injections for life, and carries the constant threat of devastating complications. While it can and does strike adults, nearly half of all new cases are diagnosed in children. A child is diagnosed with Type 1 diabetes every hour. Type 1 diabetes is caused by the inability of a person&#x2019;s pancreas to produce sufficient amounts of insulin to control their blood sugar levels and sustain life. While insulin injections allow affected individuals to control their blood sugar and stay alive, it is not a cure nor does it prevent the devastating complications of this disease, which include kidney failure, blindness, amputations, heart attack, and stroke. In Type 1 diabetes, the body&#x2019;s own immune system goes awry, attacking and destroying insulin-producing cells in the pancreas.

Luc Van Kaer

Drugs from the Sea: A Marine Sponge-Derived Compound Prevents Type 1 Diabetes

Several species of frogs and toads are in serious decline in the Sierra Nevada Mountains of California. These species include the threatened red-legged frog (Rana aurora), foothill yellow-legged frog (R. boylii), mountain yellow-legged frog (R. muscosa), Cascades frog (Rana cascadae), western toad (Bufo boreas) and Yosemite toad (B. canorus). For many of these species current distributions are down to 10% of historical ranges [1,2]. Several factors including introduced predators [3,4,5], habitat loss [2], and ultraviolet radiation [6] have been suggested as causes of these declines. Another probable cause is air-borne pesticides from the Central Valley of California. The Central Valley, especially the San Joaquin Valley, is a major agricultural region where millions of pounds of active ingredient pesticides are applied each year (http://www.cdpr.ca.gov/dprdatabase.htm). Prevailing westerly winds from the Pacific Coast transport these pesticides into the Sierras [7,8].

Donald W. Sparling

Gary Fellers

Laura McConnell

Pesticides Are Involved With Population Declines of Amphibians in the California Sierra Nevadas

Angina, the prototypic vasoocclusive pain, is a radiating chest pain that occurs when heart muscle gets insufficient blood because of coronary artery disease. Other examples of vasoocclusive pain include the acute pain of heart attack and the intermittent pains that accompany sickle cell anemia and peripheral artery disease. All these conditions cause ischemia � insufficient oxygen delivery for local metabolic demand &#x2014; and this releases lactic acid as cells switch to anaerobic metabolism. Recent discoveries demonstrate that sensory neurons innervating the heart are richly endowed with an ion channel that is opened by, and perfectly tuned for, the lactic acid released by muscle ischemia[1,2].

D.C. Immke

E.W. McCleskey

ASIC3: A Lactic Acid Sensor for Cardiac Pain

As first line of defense against the majority of infections and primary site for their transmission, mucosal surfaces of the oral cavity and genitourinary, gastrointestinal, and respiratory tracts represent the most suitable sites to deliver protective agents for the prevention of infectious diseases. Mucosal protection is important not only for life threatening diseases but also for opportunistic infections which currently represent a serious burden in terms of morbidity, mortality, and cost of cures. Candida albicans is among the most prevalent causes of mucosal infections not only in immuno- compromised patients, such as HIV-infected subjects who are frequently affected by oral and esophageal candidiasis, but also in otherwise healthy individuals, as in the case of acute vaginitis. Unfortunately, current strategies for mucosal protection against candidiasis are severely limited by the lack of effective vaccines and the relative paucity and toxicity of commercially available antifungal drugs. An additional option has been reported in a recent

Luciano Polonelli

Transgenic Killer Commensal Bacteria as Mucosal Protectants

Malignant gliomas are the most common primary brain tumors. They are highly aggressive tumors characterized by a recurrence rate of virtually 100%. Despite significant advances in neuroimaging and neurosurgical techniques, the median survival time of patients with glioblastoma multiforme remains 12 to 18 months. Malignant gliomas are characterized by rapidly dividing cells, which invade into the normal brain, and a high degree of vascularity. Recent experimental evidence indicates that tumor-related angiogenesis contributes significantly to the malignant phenotype.

Rona S. Carroll

Marcelle Machluf

Bioreactors for Decreasing the Growth of Brain Tumors

Endocrine disrupting chemicals (EDCs) include organochlorine pesticides, plastics manufacturing by-products, and certain herbicides[1]. These chemicals have been shown to disrupt hormonal signaling in exposed wildlife, lab animals, and mammalian cell culture by binding to estrogen receptors (ER-&#x3b1; and ER-&#x3B2;) and affecting the expression of estrogen responsive genes[2,3]. Additionally, certain plant chemicals, termed phytoestrogens, are also able to bind to estrogen receptors and modulate gene expression, and as such also may be considered EDCs[4]. One example of phytoestrogen action is genistein, a phytochemical produced by soybeans, binding estrogen receptors, and changing expression of estrogen responsive genes which certain studies have linked to a lower incidence of hormonally related cancers in Japanese populations[5]. Why would plants make compounds that are able to act as estrogens in the human body? Obviously, soybeans do not intentionally produce phytoestrogens to prevent breast cancer in Japanese women.

Jennifer E. Fox

Matthew E. Burow

John A. McLachlan

Symbiotic Gene Activation is Interrupted by Endocrine Disrupting Chemicals

It is not known what causes type 1 diabetes (T1D), which affects over 1 million people in the U.S. alone. Each year, 30,000 young people in the U.S. develop this disease and depend on insulin injections thereafter. Because of the huge cost to the individual, the family, and to society in increased health care costs, it is important to find what makes these people susceptible. The disease process itself is clear: the individual&#x2019;s immune system &#x2014; T lymphocytes in particular &#x2014; attack and destroy the body&#x2019;s insulin-producing cells. But how and why this autoimmune process starts or proceeds unregulated is still not known.

Grant Morahan

Identification of a T1D Susceptibility Gene

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