A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity.

Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs). It has been proposed that NSAIDs exert their beneficial effects in part by reducing neurotoxic inflammatory responses in the brain, although this mechanism has not been proved. Here we report that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Abeta42 peptide (the 42-residue isoform of the amyloid-beta peptide) produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seems not to be mediated by inhibition of cyclooxygenase (COX) activity, the principal pharmacological target of NSAIDs. Furthermore, short-term administration of ibuprofen to mice that produce mutant beta-amyloid precursor protein (APP) lowered their brain levels of Abeta42. In cultured cells, the decrease in Abeta42 secretion was accompanied by an increase in the Abeta(1-38) isoform, indicating that NSAIDs subtly alter gamma-secretase activity without significantly perturbing other APP processing pathways or Notch cleavage. Our findings suggest that NSAIDs directly affect amyloid pathology in the brain by reducing Abeta42 peptide levels independently of COX activity and that this Abeta42-lowering activity could be optimized to selectively target the pathogenic Abeta42 species.     

Butterflies of the Toquima Range, Nevada: distribution, natural history, and comparison to the Toiyabe Range

Studies of Great Basin faunas can provide information for landscape-level adaptive management by federal agencies and shed light on potential effects of climate change in continental interior landscapes. To provide such information, we characterized the butterfly fauna of the Toquima Range, a mountain range in the heart of the Great Basin with topography typical of the region. We also compared the butterfly fauna of the Toquima Range to that of the adjacent Toiyabe Range, which is more topographically complex and species rich but less representative of the Great Basin on the whole. We explicitly addressed the effects of area and water availability on butterfly species richness. Butterfly species presence data were compiled for 14 canons and 1 peak in the Toquima Range. Data from 11 canyons that we inventoried systematically were amenable to statistical analysis. Eighty butterfly species (59 residents) have been recorded from the Toquima Range since 1935. By comparison, 99 species have been recorded from the Toiyabe Range. Mean canyon-level butterfly species richness was significantly lower in the Toquima Range than in the Toiyabe Range. This difference cannot be explained by differences in canyon size between mountain ranges. Within the Toquima Range water availability seems to have a dominant effect on butterfly species richness. Between mountain ranges species richness is influenced by interactions among areas, moisture, and topography. These data should assist managers in developing guidelines for conservation planning in the Great Basin.     

A diverse range of gene products are effectors of the type I interferon antiviral response

The type I interferon response protects cells against invading viral pathogens. The cellular factors that mediate this defence are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified since their discovery more than 25 years ago, only a few have been characterized with respect to antiviral activity. For most ISG products, little is known about their antiviral potential, their target specificity and their mechanisms of action. Using an overexpression screening approach, here we show that different viruses are targeted by unique sets of ISGs. We find that each viral species is susceptible to multiple antiviral genes, which together encompass a range of inhibitory activities. To conduct the screen, more than 380 human ISGs were tested for their ability to inhibit the replication of several important human and animal viruses, including hepatitis C virus, yellow fever virus, West Nile virus, chikungunya virus, Venezuelan equine encephalitis virus and human immunodeficiency virus type-1. Broadly acting effectors included IRF1, C6orf150 (also known as MB21D1), HPSE, RIG-I (also known as DDX58), MDA5 (also known as IFIH1) and IFITM3, whereas more targeted antiviral specificity was observed with DDX60, IFI44L, IFI6, IFITM2, MAP3K14, MOV10, NAMPT (also known as PBEF1), OASL, RTP4, TREX1 and UNC84B (also known as SUN2). Combined expression of pairs of ISGs showed additive antiviral effects similar to those of moderate type I interferon doses. Mechanistic studies uncovered a common theme of translational inhibition for numerous effectors. Several ISGs, including ADAR, FAM46C, LY6E and MCOLN2, enhanced the replication of certain viruses, highlighting another layer of complexity in the highly pleiotropic type I interferon system.     

A comparative evaluation of objective and subjective weather forecasts in the united states

This paper is concerned primarily with the evaluation and comparison of objective and subjective weather forecasts. Operational forecasts of three weather elements are considered: (1) probability forecasts of precipitation occurrence, (2) categorical (i.e. non-probabilistic) forecasts of maximum and minimum temperatures and (3) categorical forecasts of cloud amount. The objective forecasts are prepared by numerical-statistical procedures, whereas the subjective forecasts are based on the judgements of individual forecasters. In formulating the latter, the forecasters consult information from a variety of sources, including the objective forecasts themselves. The precipitation probability forecasts are found to be both reliable and skilful, and evaluation of the temperature/cloud amount forecasts reveals that they are quite accurate/skilful. Comparison of the objective and subjective forecasts of precipitation occurrence indicates that the latter are generally more skilful than the former for shorter lead times (e.g. 12–24 hours), whereas the two types of forecasts are of approximately equal skill for longer lead times (e.g. 36–48 hours). Similar results are obtained for the maximum and minimum temperature forecasts. Objective cloud amount forecasts are more skilful than subjective cloud amount forecasts for all lead times. Examination of trends in performance over the last decade reveals that both types of forecasts for all three elements increased in skill (or accuracy) over the period, with improvements in objective forecasts equalling or exceeding improvements in subjective forecasts. The role and impact of the objective forecasts in the subjective weather forecasting process are discussed in some detail. The need to conduct controlled experiments and other studies of this process, with particular reference to the assimilation of information from different sources, is emphasized. Important characteristics of the forecasting system in meteorology are identified, and they are used to describe similarities and differences between weather forecasting and forecasting in other fields. Acquisition of some of these characteristics may be beneficial to other forecasting systems.     

Segment-specific expression of a homoeobox-containing gene in the mouse hindbrain

The process of segmentation, in which the developing embryo is divided into repetitive structures along its antero-posterior (A-P) axis, as a means of organizing and coordinating the body plan is found in a wide range of organisms. In Drosophila, homoeotic genes are involved in all levels of segmental organization and in determining segment identity. The roles of these genes in segmentation have been found mainly by mutational studies, but also by in situ hybridization, which has shown their domains of expression. In contrast to Drosophila, however, embryonic expression of homoeobox-containing genes in vertebrate organisms has not been found to follow a segmental pattern. Vertebrate segmentation can be clearly seen in the mesodermal somites, but repetitive morphological structures in the central nervous system (neuromeres) have only recently been shown to have developmental significance. Neuromeres in the hindbrain (rhombomeres) have been defined as segmental units by their pattern of nerve formation in the developing chick and by the alternating expression of Krox-20, a gene encoding a zinc-finger DNA-binding protein, in the 9.5-day-old mouse. Here we report that a mouse homoeobox-containing gene, Hox-2.9, is expressed in a segment-specific manner in the developing mouse hindbrain. This expression is in a region which is flanked by the regions of expression of Krox-20, and is precisely contained within a single neuromere, rhombomere 4.     

Quality/value relationships for imperfect weather forecasts in a prototype multistage decision-making model

Some theoretical results concerning the nature of the relationship between the scientific quality and economic value of imperfect weather forecasts are obtained. A prototype multistage decision-making model is considered, involving only two possible actions and two possible states of weather. This particular form of model is motivated by a real-world application known as the fruit-frost problem. For an infinite-horizon, discounted version of this model it is shown that economic value remains zero below a forecast quality threshold and then rises monotonically but nonlinearly above this threshold. In particular, the relative sensitivity of economic value to changes in the quality of forecasts increases as perfect information is approached. This curve is compared with quality/value relationships that have been obtained for other versions of the model; namely, a single-stage model and a multistage, finite-horizon model.     

Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites

A 12 amino-acid synthetic peptide (NANP)3 comprising the immunodominant epitope of Plasmodium falciparum circumsporozoite protein was conjugated to tetanus toxoid (TT), adjuvanted with aluminium hydroxide, and administered intramuscularly in three doses at monthly intervals to 35 healthy males as a malaria vaccine. No significant adverse reactions were noted, with mild soreness at the injection site the only common symptom. Seroconversions against NANP occurred in 53% and 71% of recipients of 100 or 160 micrograms, respectively, measured by enzyme-linked immunosorbent assay (ELISA). Most ELISA-positive sera reacted with sporozoites by indirect immunofluorescence (IFA). Three vaccinees with the highest ELISA and IFA titres and four unimmunized controls were challenged with P. falciparum sporozoites introduced via the bites of infective Anopheles mosquitoes. Blood stage parasites were detected in all controls by 10 days (mean 8.5 days, range 7-10). In contrast, the two vaccinees who became infected did not manifest parasitaemia until day 11 and the third vacinee showed neither parasites nor symptoms during the 29 day observation period. This first synthetic peptide parenteral vaccine against a communicable disease tested in man is safe and stimulates biologically active antibodies. These observations encourage the development of improved vaccine formulations which, by enhancing immunogenicity, may lead to practical vaccines to assist in the control of falciparum malaria.     

Corticofugal feedback influences the generation of length tuning in the visual pathway

In the feline visual system, neurons exhibiting sensitivity to the length of a moving contour were first observed in the cortex and described as 'hypercomplex cells'. In these cells an increase in stimulus length beyond an optimal value leads to a rapid decline in response. This decline has been attributed to an intracortical inhibitory input which may be driven by layer VI cells with very long receptive fields. It is now clear, however, that cells in the dorsal lateral geniculate nucleus (dLGN), exhibit a degree of length tuning similar to that of cortical 'hypercomplex cells', suggesting that this response property could be generated subcortically. Alternatively, as the dLGN receives a massive corticofugal projection from layer VI cells in the visual cortex, it is possible that this input has a function in generating length tuning in the dLGN. We have investigated this issue by comparing the length tuning of dLGN cells with and without corticofugal feedback. The data show that corticofugal feedback makes a highly significant contribution to the length tuning of dLGN cells. This raises the possibility that length tuning is an emergent property of the geniculo-cortical loop.     

Incorporation of uridine diphospho-N-acetyl-D-glucosamine in the resting sporangium wall ofSynchytrium endobioticum

Summary The microfibrils that constitute the walls ofSynchytrium endobioticum resting sporangia are laid down at the periphery of developing walls and are packed in discrete orientation. Incorporation of uridine diphospho-N-acetyl-D-glucosamine, a precursor of chitin, is restricted to the periphery of the developing wall of the resting sporangium.     

A multi-component Fermi surface in the vortex state of an underdoped high-Tc superconductor

To understand the origin of superconductivity, it is crucial to ascertain the nature and origin of the primary carriers available to participate in pairing. Recent quantum oscillation experiments on high-transition-temperature (high-T(c)) copper oxide superconductors have revealed the existence of a Fermi surface akin to that in normal metals, comprising fermionic carriers that undergo orbital quantization. The unexpectedly small size of the observed carrier pocket, however, leaves open a variety of possibilities for the existence or form of any underlying magnetic order, and its relation to d-wave superconductivity. Here we report experiments on quantum oscillations in the magnetization (the de Haas-van Alphen effect) in superconducting YBa(2)Cu(3)O(6.51) that reveal more than one carrier pocket. In particular, we find evidence for the existence of a much larger pocket of heavier mass carriers playing a thermodynamically dominant role in this hole-doped superconductor. Importantly, characteristics of the multiple pockets within this more complete Fermi surface impose constraints on the wavevector of any underlying order and the location of the carriers in momentum space. These constraints enable us to construct a possible density-wave model with spiral or related modulated magnetic order, consistent with experimental observations.