APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to analyze factors influencing the risk and timing of Alzheimer's disease (AD) in central Norway. The <it>APOE </it>ε4 allele is the only consistently identified risk factor for late onset Alzheimer's disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (<it>APOE</it>) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the <it>APOE </it>ε4 allele on the risk and the age at onset of AD in this population.</p> <p>Methods</p> <p>376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the <it>APOE </it>alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated.</p> <p>Results</p> <p>Odds Ratio (OR) for developing AD was significantly increased in carriers of the <it>APOE </it>ε4 allele compared to individuals with the <it>APOE </it>ε3/ε3 genotype. Individuals carrying <it>APOE </it>ε4/ε4 had OR of 12.9 for developing AD, while carriers of <it>APOE </it>ε2/ε4 and <it>APOE </it>ε3/ε4 had OR of 3.2 and 4.2 respectively. The effect of the <it>APOE </it>ε4 allele was weaker with increasing age. Carrying the <it>APOE </it>ε2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the <it>APOE </it>ε4 allele, to 75.3 in carriers of one <it>APOE </it>ε4 allele and 72.9 in carriers of two <it>APOE </it>ε4 alleles. Age at onset in early onset AD (EOAD) was not influenced by <it>APOE </it>ε4 alleles.</p> <p>Conclusion</p> <p><it>APOE </it>ε4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.</p

An Expanded Set of Amino Acid Analogs for the Ribosomal Translation of Unnatural Peptides

BACKGROUND: The application of in vitro translation to the synthesis of unnatural peptides may allow the production of extremely large libraries of highly modified peptides, which are a potential source of lead compounds in the search for new pharmaceutical agents. The specificity of the translation apparatus, however, limits the diversity of unnatural amino acids that can be incorporated into peptides by ribosomal translation. We have previously shown that over 90 unnatural amino acids can be enzymatically loaded onto tRNA. METHODOLOGY/PRINCIPAL FINDINGS: We have now used a competition assay to assess the efficiency of tRNA-aminoacylation of these analogs. We have also used a series of peptide translation assays to measure the efficiency with which these analogs are incorporated into peptides. The translation apparatus tolerates most side chain derivatives, a few alpha,alpha disubstituted, N-methyl and alpha-hydroxy derivatives, but no beta-amino acids. We show that over 50 unnatural amino acids can be incorporated into peptides by ribosomal translation. Using a set of analogs that are efficiently charged and translated we were able to prepare individual peptides containing up to 13 different unnatural amino acids. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that a diverse array of unnatural building blocks can be translationally incorporated into peptides. These building blocks provide new opportunities for in vitro selections with highly modified drug-like peptides

Optical biosensors in drug discovery

Optical biosensors that exploit surface plasmon resonance, waveguides and resonant mirrors have been used widely over the past decade to analyse biomolecular interactions. These sensors allow the determination of the affinity and kinetics of a wide variety of molecular interactions in real time, without the need for a molecular tag or label. Advances in instrumentation and experimental design have led to the increasing application of optical biosensors in many areas of drug discovery, including target identification, ligand fishing, assay development, lead selection, early ADME and manufacturing quality control. This article reviews important advances in optical-biosensor instrumentation and applications, and also highlights some exciting developments, such as highly multiplexed optical-biosensor arrays

Marine Sclerobiofacies: Encrusting and Endolithic Communities on Shells Through Time and Space

The concept of sclerobiofacies is defined herein as suites of sclerobiont encrusters and endiont borers (collectively sclerobionts) preserved on skeletons that characterize particular facies/environments. Skeletal components provide biologically standardized substrates; when possible, comparison of encrusting assemblages on fossil shells of the same or closely related eurytopic species provides a degree of substrate control comparable to modern experimentally deployed shells. Taxonomic composition of sclerobiont suites varies rather predictably among marine environments (e.g., based upon depth) but is primarily useful for comparisons of environments within local areas and limited time frames. Parameters that may be used to compare sclerobiofacies across broader spatial and temporal dimensions include: per shell and cumulative species richness (diversity), frequency of encrustation, areal coverage, and guild structure of encrusting taxa. Herein, we summarize characteristic sclerobiofacies in a series of Recent and ancient examples. Modern subtropical marine encrusters, documented on experimentally deployed molluscan shells at sites ranging from 15 to over 200 m, show high biont richness in shallow subtidal areas. Maximal areal coverages in Bahamian samples occur at about 20–30 m, whereas species richness increases downward to the deeper euphotic zone (∼75–80 m). Below this level, rapid decline in both richness and percent coverage results in deeper Dysphotic–Aphotic zone samples yielding only a few species with coverage rarely exceeding 5%. Burial is also a key factor such that rapidly buried shells in the Shallow Euphotic zone have species coverages, richnesses, and taxonomic compositions resembling long-exposed shells in deeper areas below the euphotic zone. Shelly substrates from the Cambrian to Early Ordovician exhibit only minor encrustation by solitary attached taxa, especially echinoderms; however, by the Late Ordovician various solitary (e.g., cornulitids, craniid brachiopods) and colonial forms (e.g., trepostome and tubuliporate bryozoans) form distinctive sclerobiofacies. Photic zone-related environments, judged independently on the basis of microendoliths, show overall lower taxonomic richness than modern counterparts. However, they also show common patterns, including a general decrease of richness and percent encrustation from Shallow Euphotic to Dysphotic/Aphotic zones. Comparable trends are seen in Middle Devonian exemplars from New York State. Not only were there consistent trends toward lowered diversity/coverage into deep-water settings but also an additional factor related to turbidity and/or sedimentation rate was identified from assemblages at comparable depths arrayed along a distal to proximal gradient with respect to siliciclastic input sources. Carboniferous sclerobiont suites from varied sites in North America show many of the same traits as their Devonian counterparts, although detailed depth zonations are not documented at present. The Permo-Triassic extinctions appear to have had a strong impact on the taxonomic composition of marine sclerobiofacies, although a paucity of studies obscures details of Mesozoic and Cenozoic sclerobiofacies. In general, they appear to have taxonomic compositions and patterns similar to those observed in the Recent. The concept of sclerobiofacies provides another tool for paleoenvironmental analysis. Together with litho-, ichno-, bio-, and taphofacies, the properties of shell encrusting assemblages will yield detailed further insights into ancient environmental gradients