The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

Tests of the helix dipole model for stabilization of alpha-helices

Charged groups play a critical role in the stability of the helix formed by the isolated C-peptide (residues 1-13 of ribonuclease A) in aqueous solution. One charged-group effect may arise from interactions between charged residues at either end of the helix and the helix dipole. We report here that studies of C-peptide analogues support the helix dipole model, and provide further evidence for the importance of electrostatic interactions not included in the Zimm-Bragg model for alpha-helix formation.     

Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.     

Four-terminal resistance of a ballistic quantum wire

The electrical resistance of a conductor is intimately related to the relaxation of the momentum of charge carriers. In a simple model, the accelerating force exerted on electrons by an applied electric field is balanced by a frictional force arising from their frequent collisions with obstacles such as impurities, grain boundaries or other deviations from a perfect crystalline order. Thus, in the absence of any scattering, the electrical resistance should vanish altogether. Here, we observe such vanishing four-terminal resistance in a single-mode ballistic quantum wire. This result contrasts the value of the standard two-probe resistance measurements of h/2e2 approximately 13 kOmega. The measurements are conducted in the highly controlled geometry afforded by epitaxial growth onto the cleaved edge of a high-quality GaAs/AlGaAs heterostructure. Two weakly invasive voltage probes are attached to the central section of a ballistic quantum wire to measure the inherent resistance of this clean one-dimensional conductor.     

"Curing" of Nicotiana attenuata leaves by small mammals does not decrease nicotine contents

Basal leaves of Nicotiana attenuata are frequently found neatly excised at the petiole and piled on rocks or soil in the sun until dry, after which they disappear, sometimes to be found again in the nests of Neotoma lepida . In response to herbivore attack, N. attenuata increases the concentration of nicotine in its leaves, where it functions as an induced defense. Since excision of leaves at the petiole allows for leaf removal without substantially activating this induced defense, and air-drying at high temperatures can volatilize nicotine, we examined the hypothesis that the observed leaf ""curing"" behavior decreased nicotine contents. In a natural population, replicate bundles of excised leaves were allowed to dry in the sun for up to 96 hours and harvested in 10 intervals. Even though surface temperatures reached 63° C during drying, no significant loss of nicotine was observed. In the laboratory, significant losses of nicotine were not observed until leaves were dried at 100° C. Nicotine contents of naturally ""cured"" leaf piles at 4 populations were found to be marginally higher than those of neighboring intact plants from which the leaves were likely harvested. We conclude that mammalian ""curing"" behavior does not reduce nicotine contents and may allow the leaves to be used for insect repellant purposes.     

Muscle-specific gene expression controlled by a regulatory element lacking a MyoD1-binding site

Muscle-specific expression of the gene encoding the delta subunit of the acetylcholine receptor is controlled by a 54-base-pair region that does not contain a binding site for MyoD1, a protein involved in activation of the myogenic program. A MyoD1-binding site is present in the proximal promoter region of the gene encoding the delta-subunit, but is neither sufficient nor necessary for muscle-specific expression in transfected muscle cells.     

Denning chronology of black bears in eastern Rocky Mountain National Park, Colorado

Understanding factors influencing the timing of den entrance and emergence of black bears ( Ursus americanus ) provides insight for bear management. We determined den entrance and emergence dates for bears in Rocky Mountain National Park (RMNP) and related these dates to vegetative productivity, weather, habitat, and demographic factors to assess the influence of these factors on denning chronology. Date of den entrance was most strongly influenced by age class, precipitation, and proportion of human-use areas in annual home ranges. Den entrance was typically later for adult bears during wetter years and when annual home ranges contained a greater proportion of human-use areas. Sex and presence of human-use areas were most strongly related to den emergence. Male bears typically emerged from dens before females, and bears emerged from dens earlier when human-use areas composed a greater proportion of annual home ranges. Collectively, our results suggest that denning behavior of black bears in RMNP was strongly influenced by presence of human-use areas, likely because of foods associated with such areas. Managers of black bears in RMNP can use precipitation to predict relative dates of den entrance, thereby allowing for more efficient strategies to combat potentially negative human–black bear encounters.     

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.     

Antihypertensive and other cardiovascular effects of 2-(3-pyridyl)- and 2-(4-pyridyl)-4-trifluoromethylimidazoles

Summary 2 new 4-trifluoromethylimidazole derivatives were found which lowered mean arterial pressure in renal and spontaneously hypertensive (SH) rats by the oral route. In SH rats, compounds A and B were 0.1 and 0.3 times, respectively, as potent as hydralazine. No tolerance development was observed in SH rats with either compound over a 1-week period. In anesthetized dogs, both compounds lowered arterial pressure and peripheral vascular resistance but increased cardiac output. By intraarterial administration, both compounds increased femoral arterial blood flow. These findings represent discovery of a new class of vasodilator drugs.Deceased, May 31, 1978.