Prediction of "aggregation-prone" and "aggregation-susceptible" regions in proteins associated with neurodegenerative diseases

Increasing evidence indicates that many peptides and proteins can be converted in vitro into highly organised amyloid structures, provided that the appropriate experimental conditions can be found. In this work, we define intrinsic propensities for the aggregation of individual amino acids and develop a method for identifying the regions of the sequence of an unfolded peptide or protein that are most important for promoting amyloid formation. This method is applied to the study of three polypeptides associated with neurodegenerative diseases, Abeta42, alpha-synuclein and tau. In order to validate the approach, we compare the regions of proteins that are predicted to be most important in driving aggregation, either intrinsically or as the result of mutations, with those determined experimentally. The knowledge of the location and the type of the "sensitive regions" for aggregation is important both for rationalising the effects of sequence changes on the aggregation of polypeptide chains and for the development of targeted strategies to combat diseases associated with amyloid formation.     

"Timer" and "scanner" neurons in the cat visual cortex with low stimulus-background contrast

The response pattern and orientation detection of "timer" and "scanner" neurons were investigated in awake, immobilized cats with reduced contrast (2.3 and 10.0) between the light stimulus and the background. These two divisions had already been made [3, 5] at a high contrast level of 100. During this action, all scanners were found to retain their properties: they did not change into timers. The number of timers, however, dropped to 40% of their original total. The relationship between the properties of neurons belonging to these groups remained as it was during maximum contrast: with timers, response began and peaked earlier; it was also of higher frequency and briefer, while its capacity for orientation detection was far inferior to that of scanners. The neurons leaving the timer group following a reduction in contrast manifested a pattern somewhere between timer and scanner cells, resembling the latter in a number of parameters. Findings confirmed the deduction that both timer and scanner neurons are present and operate consistently under a wide range of conductions in the cat visual cortex; the former fulfill the functions of synchronizers and the latter of directional filters which are rearranged in time [5].Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 18, No. 6, pp. 805–812, November–December, 1986.     

Unilateral absent scaphoid in a patient with "Holt-Oram" syndrome

The absence of the scaphold in a patient with Holt-Oram syndrome is reported. Only a few similar cases have been published.     

An analysis of unstirred layers in series with "tight" and "porous" lipid bilayer membranes

The present experiments were designed to evaluate the effective thickness of the unstirred layers in series with native and porous (i.e., in the presence of amphotericin B) lipid bilayer membranes and, concomitantly, the respective contributions of membranes and unstirred layers to the observed resistances to the diffusion of water and nonelectrolytes between aqueous phases. The method depended on measuring the tracer permeability coefficients for the diffusion of water and nonelectrolytes (P_DDi, cm sec^-1) when the aqueous phase viscosity (η) was increased with solutes having a unity reflection coefficient, such as sucrose or dextran. The effective thickness of the unstirred layers (α^t, cm) and the true, or membrane, permeability coefficients for diffusion of water and nonelectrolytes (P_mmi, cm sec^-1) were computed from, respectively, the slope and intercept of the linear regression of 1/P_DDi on η. In both the native and porous membranes, α^t was approximately 110 x 10^-4 cm. The ratio of P_f, the osmotic water permeability coefficient (cm sec^-1) to P_mmH2O was 1.22 in the native membranes and 3.75 in the porous membranes. For the latter, the effective pore radius, computed from Poiseuille's law, was approximately 5.6 A. A comparison of P_mmi and P_DDi, indicated that the porous membranes accounted for 16, 25, and 66% of the total resistance to the diffusion of, respectively, H₂O, urea, and glycerol, while the remainder was referable to the unstirred layers.     

Associations with Vitamin D deficiency in "at risk" Australians

In a study of 185 elderly living in assisted care and 192 frail aged living in the community in the Sydney metropolitan area, nursing home residents were found to be at a 3-fold and hostel dwellers at a 2-fold risk of Vitamin D [25(OH)D] deficiency (<25 nmol/L) compared to self care residents. Middle Eastern people were found to be at 4-fold risk and Vietnamese a 3-fold risk of deficiency compared to their Australian counterparts. In recently arrived Chinese immigrants, Vitamin D deficiency, was found in 28%, and marginal levels (<37 nmol/L) in 60%, compared to the 34 and 76% found in our nursing home population, and 25 and 57% in hostel care residents. Of the Middle Eastern elderly, 58% were deficient and 83% marginal; although only 18% of Vietnamese were deficient, 68% had marginal Vitamin D status. Other factors associated with Vitamin D deficiency were mobility and sun exposure in assisted care, and low dietary Vitamin D and calcium intake, reduced exercise levels and high % body fat levels in the immigrant groups.     

Heavy chain loss after treatment with Melphalan in a patient with "nonsecretory" myeloma

A case of "nonsecretory" myeloma is described. The patient had typical osteolytic lesions and marked infiltration of myeloma cells in the bone marrow, and plasma cell leukemia. A good partial remission was obtained with Melphalan, but the patient relapsed and died one year later. Immunofluorescent and immunoelectroscopic studies on the myeloma cells demonstrated the presence of cytoplasmic gamma-and kappa-chains at the initial stage and of only kappa-chains at a relapse. The electron microscopic method for polysome analysis indicated that both L-and H-chains were synthesized on membrane-bound polysomes initially, but the ability to produce H-chain was missing at the relapse.     

The "beggar's" hand and the "unshakable" hand in children with total obstetric brachial plexus palsy

A total 12 consecutive children with secondary deformities following total obstetric brachial plexus palsy were included in this retrospective study. In all patients, the main complaints were two socially disabling hand postures: the "beggar's" hand and/or the "unshakable" hand. All children had a supinated forearm with no active pronation and were teased by their friends, who called them "beggars." When the impairment was severe and involved the right hand and wrist, children also complained that they were not able to shake hands. The management approach to these children was described, with the main aim of surgery being the correction of the abnormal posture. Other simultaneous tendon transfers were also performed to improve hand function if there were suitable musculotendinous units. Successful reconstruction was accomplished in all patients. Preoperatively, some children refused to go to school because of teasing, and most did not want to interact socially. After surgery, all children attended school regularly, and parents reported much better social interaction. However, the functional gain was never enough to dramatically improve the daily use of the limb. The contralateral normal limb remained the dominant one for all daily activities, including writing and eating.     

A cost-effectiveness analysis of "test" versus "treat" patients hospitalized with suspected influenza in Hong Kong

Background

Seasonal and 2009 H1N1 influenza viruses may cause severe diseases and result in excess hospitalization and mortality in the older and younger adults, respectively. Early antiviral treatment may improve clinical outcomes. We examined potential outcomes and costs of test-guided versus empirical treatment in patients hospitalized for suspected influenza in Hong Kong.

Methods

We designed a decision tree to simulate potential outcomes of four management strategies in adults hospitalized for severe respiratory infection suspected of influenza: “immunofluorescence-assay” (IFA) or “polymerase-chain-reaction” (PCR)-guided oseltamivir treatment, “empirical treatment plus PCR” and “empirical treatment alone”. Model inputs were derived from literature. The average prevalence (11%) of influenza in 2010–2011 (58% being 2009 H1N1) among cases of respiratory infections was used in the base-case analysis. Primary outcome simulated was cost per quality-adjusted life-year (QALY) expected (ICER) from the Hong Kong healthcare providers'' perspective.

Results

In base-case analysis, “empirical treatment alone” was shown to be the most cost-effective strategy and dominated the other three options. Sensitivity analyses showed that “PCR-guided treatment” would dominate “empirical treatment alone” when the daily cost of oseltamivir exceeded USD18, or when influenza prevalence was <2.5% and the predominant circulating viruses were not 2009 H1N1. Using USD50,000 as the threshold of willingness-to-pay, “empirical treatment alone” and “PCR-guided treatment” were cost-effective 97% and 3% of time, respectively, in 10,000 Monte-Carlo simulations.

Conclusions

During influenza epidemics, empirical antiviral treatment appears to be a cost-effective strategy in managing patients hospitalized with severe respiratory infection suspected of influenza, from the perspective of healthcare providers in Hong Kong.     

Rethinking Ancient Maya Social Organization: Replacing "Lineage" with "House"

Long-standing disagreements concerning prehispanic Maya kinship and social organization have focused on the nature of their corporate groups, generally presumed to have been lineages. Specific debates center on whether the lineages were patrilineal or incorporated some kind of double-descent reckoning, how descent was combined with locality to define a group, and the status of lineage-outsiders within a group. It is argued here that Maya social organization is better approached within the contemporary critique of kinship, replacing "lineage" with Lévi-Strauss's model of the "house"—a corporate group maintaining an estate perpetuated by the recruitment of members whose relationships are expressed "in the language" of kinship and affinity and affirmed by purposeful actions. In this perspective, the operation of corporate groups is the primary concern, and relationships construed in terms of consanguinity and affinity are seen as strategies pursued to enhance and perpetuate the group, [ancestor veneration, house society, kinship, Maya, social organization]     

"Endless" viral DNA in cells infected with channel catfish virus

The state of intracellular viral DNA in cells infected with channel catfish virus has been studied by the Hirt selective extraction procedure and by restriction endonuclease digestion. The sedimentation properties and restriction patterns of viral DNA in the Hirt supernatant fraction indicate that the majority, if not all, of the DNA is in the form of linear unit-length (Mr approximately equal to 85 x 10(6)) molecules. However, restriction digests of viral DNA in the pellet fraction lacked two fragments corresponding to the molecular ends of unit-length DNA. In addition, there appeared in HpaI digests of pellet DNA a new restriction fragment interpretable as the product of fusion between the ends of unit-length molecules. The size of the new fragment requires that fusion occur in such a way that one copy of the terminally repeated sequences (Mr approximately equal to 12.3 x 10(6)) of the unit-length DNA is lost in the process. In pulse-chase experiments, radioactivity flowed from the pellet fraction to the supernatant fraction, suggesting a precursor-product relationship for these DNA species. The results are easily understood if unit-length virion DNA is generated by excision from concatemeric structures.