Specificity of amino acid sequence and its role in secondary and supersecondary structure generation

Schematic presentation of loops (7 aa) linking two β-strands (fragments of β-sheets). The left one – helical form represents fuzzy oil drop distribution of hydrophobicity. The right one not able to generate the helical form represents the status recognized as amyloid seed in amyloids discussed in this work

Nicotinic Acetylcholine Receptor Agonists Attenuate Septic Acute Kidney Injury in Mice by Suppressing Inflammation and Proteasome Activity

Sepsis is one of the leading causes of acute kidney injury (AKI). Septic patients who develop acute kidney injury (AKI) are at increased risk of death. To date there is no effective treatment for AKI or septic AKI. Based on their anti-inflammatory properties, we examined the effects of nicotinic acetylcholine receptor agonists on renal damage using a mouse model of lipopolysaccharide (LPS)-induced AKI where localized LPS promotes inflammation-mediated kidney damage. Administration of nicotine (1 mg/kg) or GTS-21 (4 mg/kg) significantly abrogated renal leukocyte infiltration (by 40%) and attenuated kidney injury. These renoprotective effects were accompanied by reduced systemic and localized kidney inflammation during LPS-induced AKI. Consistent with these observations, nicotinic agonist treatment significantly decreased renal IκBα degradation and NFκB activation during LPS-induced AKI. Treatment of human kidney cells with nicotinic agonists, an NFκB inhibitor (Bay11), or a proteasome inhibitor (MG132) effectively inhibited their inflammatory responses following stimulation with LPS or TNFα. Renal proteasome activity, a major regulator of NFκB-mediated inflammation, was enhanced by approximately 50% during LPS-induced AKI and elevated proteasome activity was significantly blunted by nicotinic agonist administration in vivo. Taken together, our results identify enhanced renal proteasome activity during LPS-induced AKI and the suppression of both proteasome activity and inflammation by nicotinic agonists to attenuate LPS-induced kidney injury

A Recombinant Blood-Stage Malaria Vaccine Reduces Plasmodium falciparum Density and Exerts Selective Pressure on Parasite Populations in a Phase 1-2b Trial in Papua New Guinea

The malaria vaccine Combination B comprises recombinant Plasmodium falciparum ring-infected erythrocyte surface antigen and 2 merozoite surface proteins (MSP1 and MSP2) formulated in oil-based adjuvant. A phase 1-2b double-blind, randomized, placebo-controlled trial in 120 children (5-9 years old) in Papua New Guinea demonstrated a 62% (95% confidence limits: 13%, 84%) reduction in parasite density in children not pretreated with sulfadoxine-pyrimethamine. Vaccinees had a lower prevalence of parasites carrying the MSP2-3D7 allelic form (corresponding to that in the vaccine) and a higher incidence of morbid episodes associated with FC27-type parasites. These results demonstrate functional activity of Combination B against P. falciparum in individuals with previous malaria exposure. The specific effects on parasites with particular msp2 genotypes suggest that the MSP2 component, at least in part, accounted for the activity. The vaccine-induced selection pressure exerted on the parasites and its consequences for morbidity strongly argue for developing vaccines comprising conserved antigens and/or multiple components covering all important allelic type

Adaptive Filtering Enhances Information Transmission in Visual Cortex

Sensory neuroscience seeks to understand how the brain encodes natural environments. However, neural coding has largely been studied using simplified stimuli. In order to assess whether the brain's coding strategy depend on the stimulus ensemble, we apply a new information-theoretic method that allows unbiased calculation of neural filters (receptive fields) from responses to natural scenes or other complex signals with strong multipoint correlations. In the cat primary visual cortex we compare responses to natural inputs with those to noise inputs matched for luminance and contrast. We find that neural filters adaptively change with the input ensemble so as to increase the information carried by the neural response about the filtered stimulus. Adaptation affects the spatial frequency composition of the filter, enhancing sensitivity to under-represented frequencies in agreement with optimal encoding arguments. Adaptation occurs over 40 s to many minutes, longer than most previously reported forms of adaptation.Comment: 20 pages, 11 figures, includes supplementary informatio

Screening for Chronic Conditions Using a Patient Internet Portal: Recruitment for an Internet-based Primary Care Intervention

Background: Patient Internet portals have created new opportunities for assessment and management of chronic conditions. Objective: To conduct an online screening survey for a study recruitment using a secure patient Internet portal to identify primary care patients with untreated depression, chronic pain, or mobility difficulty before nonurgent office visits. Design: Internet-based screening survey for a randomized trial. Participants: Patients who were registered portal users who had scheduled primary care appointments. Approach: Electronic study invitations via the portal were sent to 4,047 patients with scheduled visits to 34 primary care physicians participating in the study. After clicking on a link in the study invitation, patients were consecutively shown the study description, consent form, and lastly, the screening survey to determine final eligibility for study participation. Results: Of the 2,113 (52%) patients who opened the study invitation, 1,001 consented online to join the study and 981 (98%) of these completed the screening survey. Of the respondents, 319 (33%) screened positive for 1 or more of the 3 conditions. Conclusions: The online screening survey conducted through the patient portal was effective in identifying patients with chronic conditions in advance of scheduled primary care visits for participation in an intervention study

Nutritional supplements and infection in the elderly: why do the findings conflict?

BACKGROUND: Most of the randomized placebo-controlled trials that have examined the clinical effects of multivitamin-mineral supplements on infection in the elderly have shown no significant effect. The exceptions are three such trials, all using a supplement with the same composition, and all claiming dramatic benefits: a frequently cited study published in 1992, which reported a 50% reduction in the number of days of infection (NDI), and two 2002 replication studies. Questions have been raised about the 1992 report; a second report in 2001 based on the same trial, but describing effects of the supplement on cognitive functions, has been retracted by Nutrition. The primary purpose of the present paper is to evaluate the claims about the effects of supplements on NDI in the two replication reports. METHODS: Examination of internal consistency (outcomes of statistical tests versus reported data); comparison of variability of NDI across individuals in these two reports with variability in other trials; estimation of the probability of achieving the reported close agreement with the original finding. RESULTS: The standard deviations of NDI and levels of statistical significance reported are profoundly inconsistent. The reported standard deviations of NDI are consistently below what other studies have found. The reported percent reductions in NDI agree too closely with the original study. CONCLUSION: The claims of reduced NDI in the two replication reports should be questioned, which also adds to concerns about the 1992 study. It follows that there is currently no trustworthy evidence from randomized placebo-controlled clinical trials that favors the use of vitamin-mineral supplements to reduce infection in the elderly

DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice

In humans, DOCK8 immunodeficiency syndrome is characterized by severe cutaneous viral infections. Thus, CD8 T cell function may be compromised in the absence of DOCK8. In this study, by analyzing mutant mice and humans, we demonstrate a critical, intrinsic role for DOCK8 in peripheral CD8 T cell survival and function. DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA+CCR7? phenotype. Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic. DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division. Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they showed greatly reduced memory cell persistence and recall. These findings highlight a key role for DOCK8 in the survival and function of human and mouse CD8 T cells

Algal biomass and diesel emulsions: An alternative approach for utilizing the energy content of microalgal biomass in diesel engines

The use of algal biomass for the production of sustainable biofuels has attracted significant interest due to the fast reproduction rates and high lipid content of many microalgal species. However, existing methods of extracting algal cellular lipids are complex and expensive, with regards to both energy input and economic costs. This work explores an alternative method of utilizing the energy content of microalgae through the preparation of wet algal biomass slurry/fossil diesel emulsions containing up to 6.6% wt/wt algae biomass, using a specific surfactant combination, for direct injection diesel engine combustion of microalgae without prior biomass drying or lipid extraction. A high lipid containing green microalgae, Chlorella sorokiniana, was used to produce algal biomass for the study. The preparation of wet algal slurry/diesel emulsions from algae grown under standard conditions, and also those under conditions intended to increase cellular lipid content or growth rates was investigated, and in all cases a surfactant pack of Span80, CTAB and butanol was found to produce a stable emulsion. A correlation between the engine work produced during combustion of the emulsions in a modern direct injection compression ignition and the lower heating value of the wet slurry emulsions was found, with no evidence of individual algae cells persisting to the engine exhaust. Engine exhaust emissions of nitrogen oxides (NOx) and particulate matter were lower for all of the wet algal slurry/diesel emulsions relative to a reference fossil diesel tested under similar conditions, while in the case of the emulsion prepared from algal biomass to which a flocculating agent had been added, emissions of carbon monoxide (CO) were found to increase significantly

A simple method to assess freezing of gait in Parkinson's disease patients

Freezing of gait (FOG) can be assessed by clinical and instrumental methods. Clinical examination has the advantage of being available to most clinicians; however, it requires experience and may not reveal FOG even for cases confirmed by the medical history. Instrumental methods have an advantage in that they may be used for ambulatory monitoring. The aim of the present study was to describe and evaluate a new instrumental method based on a force sensitive resistor and Pearson's correlation coefficient (Pcc) for the assessment of FOG. Nine patients with Parkinson's disease in the "on" state walked through a corridor, passed through a doorway and made a U-turn. We analyzed 24 FOG episodes by computing the Pcc between one "regular/normal" step and the rest of the steps. The Pcc reached +/- 1 for "normal" locomotion, while correlation diminished due to the lack of periodicity during FOG episodes. Gait was assessed in parallel with video. FOG episodes determined from the video were all detected with the proposed method. The computed duration of the FOG episodes was compared with those estimated from the video. The method was sensitive to various types of freezing; although no differences due to different types of freezing were detected. The study showed that Pcc analysis permitted the computerized detection of FOG in a simple manner analogous to human visual judgment, and its automation may be useful in clinical practice to provide a record of the history of FOG

Angiomyolipoma Have Common Mutations in TSC2 but No Other Common Genetic Events

Renal angiomyolipoma are part of the PEComa family of neoplasms, and occur both in association with Tuberous Sclerosis Complex (TSC) and independent of that disorder. Previous studies on the molecular genetic alterations that occur in angiomyolipoma are very limited. We evaluated 9 angiomyolipoma for which frozen tissue was available from a consecutive surgical series. Seven of 8 samples subjected to RT-PCR-cDNA sequencing showed mutations in TSC2; none showed mutations in TSC1 or RHEB. Six of the seven mutations were deletions. We searched for 983 activating and inactivating mutations in 115 genes, and found none in these tumors. Similarly analysis for genomic regions of loss or gain, assessed by Affymetrix SNP6.0 analysis, showed no abnormalities. Loss of heterozygosity in the TSC2 region was commonly seen, except in patients with low frequency TSC2 mutations. We conclude that sporadic renal angiomyolipoma usually have mutations in TSC2, but not TSC1 or RHEB, and have no other common genomic events, among those we searched for. However, chromosomal translocations and gene fusion events were not assessed here. TSC2 inactivation by mutation is a consistent and likely necessary genetic event in the pathogenesis of most angiomyolipoma