Statistics of Neutron Stars at the Stage of Supersonic Propeller

We analyze the statistical distribution of neutron stars at the stage of a supersonic propeller. An important point of our analysis is allowance for the evolution of the angle of inclination of the magnetic axis to the spin axis of the neutron star for the boundary of the transition to the supersonic propeller stage for two models: the model with hindered particle escape from the stellar surface and the model with free particle escape. As a result, we have shown that a consistent allowance for the evolution of the inclination angle in the region of extinct radio pulsars for the two models leads to an increase in the total number of neutron stars at the supersonic propeller stage. This increase stems from he fact that when allowing for the evolution of the inclination angle $\chi$ for neutron stars in the region of extinct radio pulsars and, hence, for the boundary of the transition to the propeller stage, this transition is possible at shorter spin periods (P~5-10 s) than assumed in the standard model.Comment: 15 pages, 6 figures; scale corrected for figures 3-

Transthyretin Protects against A-Beta Peptide Toxicity by Proteolytic Cleavage of the Peptide: A Mechanism Sensitive to the Kunitz Protease Inhibitor

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid β-peptide (A-Beta) in the brain. Transthyretin (TTR) is a tetrameric protein of about 55 kDa mainly produced in the liver and choroid plexus of the brain. The known physiological functions of TTR are the transport of thyroid hormone T4 and retinol, through binding to the retinol binding protein. TTR has also been established as a cryptic protease able to cleave ApoA-I in vitro. It has been described that TTR is involved in preventing A-Beta fibrilization, both by inhibiting and disrupting A-Beta fibrils, with consequent abrogation of toxicity. We further characterized the nature of the TTR/A-Beta interaction and found that TTR, both recombinant or isolated from human sera, was able to proteolytically process A-Beta, cleaving the peptide after aminoacid residues 1, 2, 3, 10, 13, 14,16, 19 and 27, as determined by mass spectrometry, and reversed phase chromatography followed by N-terminal sequencing. A-Beta peptides (1–14) and (15–42) showed lower amyloidogenic potential than the full length counterpart, as assessed by thioflavin binding assay and ultrastructural analysis by transmission electron microscopy. A-Beta cleavage by TTR was inhibited in the presence of an αAPP peptide containing the Kunitz Protease Inhibitor (KPI) domain but not in the presence of the secreted αAPP derived from the APP isoform 695 without the KPI domain. TTR was also able to degrade aggregated forms of A-Beta peptide. Our results confirmed TTR as a protective molecule in AD, and prompted A-Beta proteolysis by TTR as a protective mechanism in this disease. TTR may prove to be a useful therapeutic agent for preventing or retarding the cerebral amyloid plaque formation implicated in AD pathology

Cosmology and Neutrino Properties

This is a brief review for particle physicists on cosmological impact of neutrinos and on restrictions on neutrino properties from cosmology. The paper includes discussion of upper bounds on neutrino mass and possible ways to relax them, methods to observe the cosmic neutrino background, bounds on the cosmological lepton asymmetry which are strongly improved by neutrino oscillations, cosmological effects of breaking of spin-statistics theorem for neutrinos, bounds on mixing parameters of active and possible sterile neutrinos with the account of active neutrino oscillations, bounds on right-handed currents and neutrino magnetic moments, and some more.Comment: Talk presented at the meeting of Nuclear Physics Division of Russian Academy of Sci., November, 2007, Moscow. 21 pages, 3 figures. One reference is added and some numbers are slightly correcte

Amyloid Oligomer Conformation in a Group of Natively Folded Proteins

Recent in vitro and in vivo studies suggest that destabilized proteins with defective folding induce aggregation and toxicity in protein-misfolding diseases. One such unstable protein state is called amyloid oligomer, a precursor of fully aggregated forms of amyloid. Detection of various amyloid oligomers with A11, an anti-amyloid oligomer conformation-specific antibody, revealed that the amyloid oligomer represents a generic conformation and suggested that toxic β-aggregation processes possess a common mechanism. By using A11 antibody as a probe in combination with mass spectrometric analysis, we identified GroEL in bacterial lysates as a protein that may potentially have an amyloid oligomer conformation. Surprisingly, A11 reacted not only with purified GroEL but also with several purified heat shock proteins, including human Hsp27, 40, 70, 90; yeast Hsp104; and bovine Hsc70. The native folds of A11-reactive proteins in purified samples were characterized by their anti-β-aggregation activity in terms of both functionality and in contrast to the β-aggregation promoting activity of misfolded pathogenic amyloid oligomers. The conformation-dependent binding of A11 with natively folded Hsp27 was supported by the concurrent loss of A11 reactivity and anti-β-aggregation activity of heat-treated Hsp27 samples. Moreover, we observed consistent anti-β-aggregation activity not only by chaperones containing an amyloid oligomer conformation but also by several A11-immunoreactive non-chaperone proteins. From these results, we suggest that the amyloid oligomer conformation is present in a group of natively folded proteins. The inhibitory effects of A11 antibody on both GroEL/ES-assisted luciferase refolding and Hsp70-mediated decelerated nucleation of Aβ aggregation suggested that the A11-binding sites on these chaperones might be functionally important. Finally, we employed a computational approach to uncover possible A11-binding sites on these targets. Since the β-sheet edge was a common structural motif having the most similar physicochemical properties in the A11-reactive proteins we analyzed, we propose that the β-sheet edge in some natively folded amyloid oligomers is designed positively to prevent β aggregation

Alzheimer disease models and human neuropathology: similarities and differences

Animal models aim to replicate the symptoms, the lesions or the cause(s) of Alzheimer disease. Numerous mouse transgenic lines have now succeeded in partially reproducing its lesions: the extracellular deposits of Aβ peptide and the intracellular accumulation of tau protein. Mutated human APP transgenes result in the deposition of Aβ peptide, similar but not identical to the Aβ peptide of human senile plaque. Amyloid angiopathy is common. Besides the deposition of Aβ, axon dystrophy and alteration of dendrites have been observed. All of the mutations cause an increase in Aβ 42 levels, except for the Arctic mutation, which alters the Aβ sequence itself. Overexpressing wild-type APP alone (as in the murine models of human trisomy 21) causes no Aβ deposition in most mouse lines. Doubly (APP × mutated PS1) transgenic mice develop the lesions earlier. Transgenic mice in which BACE1 has been knocked out or overexpressed have been produced, as well as lines with altered expression of neprilysin, the main degrading enzyme of Aβ. The APP transgenic mice have raised new questions concerning the mechanisms of neuronal loss, the accumulation of Aβ in the cell body of the neurons, inflammation and gliosis, and the dendritic alterations. They have allowed some insight to be gained into the kinetics of the changes. The connection between the symptoms, the lesions and the increase in Aβ oligomers has been found to be difficult to unravel. Neurofibrillary tangles are only found in mouse lines that overexpress mutated tau or human tau on a murine tau −/− background. A triply transgenic model (mutated APP, PS1 and tau) recapitulates the alterations seen in AD but its physiological relevance may be discussed. A number of modulators of Aβ or of tau accumulation have been tested. A transgenic model may be analyzed at three levels at least (symptoms, lesions, cause of the disease), and a reading key is proposed to summarize this analysis

Identifying Toxic Consumer Products: A Novel Data Set Reveals Air Emissions of Potent Carcinogens, Reproductive Toxicants, and Developmental Toxicants.

Consumer products are important sources of exposure to harmful chemicals. Product composition is often a mystery to users, however, due to gaps in the laws governing ingredient disclosure. A unique data set that the California Air Resources Board (CARB) uses to determine how volatile organic chemicals (VOCs) from consumer products affect smog formation holds a partial solution. By analyzing CARB data on VOCs in consumer products, we identified and quantified emissions of volatile chemicals regulated under the California Safe Drinking Water and Toxic Enforcement Act ("Prop 65"). We here highlight individual chemicals as well as consumer product categories that people are likely to be exposed to as individual consumers, in the workplace, and at the population level. Of the 33 Prop 65-listed chemicals that appear in the CARB emissions inventory, we classified 18 as "top tier priorities for elimination". Among these, methylene chloride and N-methyl-2-pyrrolidone were most prevalent in products across all three population groups. Of 172 consumer product categories, 105 contained Prop 65-listed chemicals. Although these chemicals are known carcinogens and reproductive/developmental toxicants, they remain in widespread use. Manufacturers and regulators should prioritize product categories containing Prop 65-listed chemicals for reformulation or redesign to reduce human exposures and associated health risks

The role of chemical policy in improving supply chain knowledge and product safety

Although the US government has made important improvements in chemical management since the 1970s, these advances have not kept pace with scientific knowledge about chemical hazards. While US federal chemical policy reform is being debated for the first time since 1976, some US businesses have voluntarily sought to improve their knowledge of chemical hazards in their supply chains, and several US states, the European Union, China, and other countries have moved forward with chemical policy reforms. Until policy reforms occur in the USA, the US chemical market will continue to experience problems associated with poor information on hazardous chemicals in supply chains. These market conditions make it difficult for consumer product companies to identify hazards and create safer products. Results from interviews with consumer product company representatives demonstrate that challenges in obtaining chemical-related information exist across sectors, and information on chemical hazards and uses can be conflicting, protected by trade secrets, lost in supply chains, or nonexistent. Interview results illustrate how some consumer product companies are exceeding regulatory requirements by voluntarily restricting from their products chemicals that could harm human health or the environment. Understanding the motivations behind—and barriers to—these actions could inform efforts to modernize US chemicals policies in ways that promote effective chemical management in supply chains. Using examples from the European Union and some US states, we introduce policy suggestions that would increase knowledge, market transparency, and information flows regarding hazardous chemicals and their uses; these would support the efforts of companies to develop and market safer products