Alzheimer's disease therapeutics: new approaches to an ageing problem

Abnormal proteinaceous deposits are found in the brain of patients with many different neurodegenerative diseases. In many of these diseases, the production of the deposits is probably associated with disease pathogenesis. In Alzheimer's disease (AD), the amyloid protein (A beta), is produced by the action of enzymes known as secretases, which cleave the beta-amyloid protein precursor. A beta is secreted from cells in the brain, after which it oligomerizes and is deposited in the extracellular compartment of the brain to form amyloid plaques and amyloid angiopathy. Targeting the production of A beta and its aggregation is now a key strategy in the development of novel therapeutic agents for the treatment of AD. This review examines the potential of immunization strategies, cholesterol-lowering drugs, protease inhibitors and nicotinic drugs for the treatment of AD.     

Using new tools to solve an old problem: the evolution of endothermy in vertebrates

During the past 30 years, the evolution of endothermy has been a topic of keen interest to palaeontologists and evolutionary physiologists. While palaeontologists have found abundant Permian and Triassic fossils, suggesting important clues regarding the timing of origin of endothermy, physiologists have proposed several plausible hypotheses of how the metabolic elevation leading to endothermy could have occurred. More recently, molecular biologists have developed powerful tools to infer past adaptive processes, and gene expression mechanisms that describe the organization of genomes into phenotypes. Here, we argue that the evolution of endothermy could now be elucidated based on a joint, and perhaps unprecedented, effort of researchers from the fields of genomics, physiology and evolution.     

Numerical approaches to the species problem

The use of numbers by systematists is not new. Measurements to describe individuals and formal taxa have been used since the beginnings of our science. But the advent of electronic computers now permits a much more accurate understanding of the phenotypic relationships within and among populations and taxa. Furthermore, estimates of cladistic relationship also are being attempted with the help of computers. Computers can increase our understanding of speciation, but this requires us to think intelligently about the meaning of their results.Presented at the symposium Speciation and the Species Concept during the XIIth International Botanical Congress, Leningrad, July 8, 1975.     

Evolution of genome size: new approaches to an old problem

Eukaryotic genomes come in a wide variety of sizes. Haploid DNA contents (C values) range > 80,000-fold without an apparent correlation with either the complexity of the organism or the number of genes. This puzzling observation, the C-value paradox, has remained a mystery for almost half a century, despite much progress in the elucidation of the structure and function of genomes. Here I argue that new approaches focussing on the genetic mechanisms that generate genome-size differences could shed much light on the evolution of genome size.     

Two new phragmotic ant species from Africa: morphology and next-generation sequencing solve a caste association problem in the genus Carebara Westwood

Phragmotic or “door head” ants have evolved independently in several ant genera across the world, but in Africa only one case has been documented until now. Carebara elmenteitae (Patrizi) is known from only a single phragmotic major worker collected from sifted leaf-litter near Lake Elmenteita in Kenya, but here the worker castes of two species collected from Kakamega Forest, a small rainforest in Western Kenya, are studied. Phragmotic major workers were previously identified as Carebara elmenteitae and non-phragmotic major and minor workers were assigned to Carebara thoracica (Weber). Using evidence of both morphological and next-generation sequencing analysis, it is shown that phragmotic and non-phragmotic workers of the two different species are actually the same and that neither name – Carebara elmenteitae or Carebara thoracica – correctly applies to them. Instead, this and another closey related species from Ivory Coast are both morphologically different from Carebara elmenteitae, and thus they are described as the new species Carebara phragmotica sp. n. and Carebara lilith sp. n.     

A general strategy to solve the phase problem in RNA crystallography

X-ray crystallography of biologically important RNA molecules has been hampered by technical challenges, including finding heavy-atom derivatives to obtain high-quality experimental phase information. Existing techniques have drawbacks, limiting the rate at which important new structures are solved. To address this, we have developed a reliable means to localize heavy atoms specifically to virtually any RNA. By solving the crystal structures of thirteen variants of the G*U wobble pair cation binding motif, we have identified a version that when inserted into an RNA helix introduces a high-occupancy cation binding site suitable for phasing. This "directed soaking" strategy can be integrated fully into existing RNA crystallography methods, potentially increasing the rate at which important structures are solved and facilitating routine solving of structures using Cu-Kalpha radiation. This method already has been used to solve several crystal structures.     

Hypothesis testing approaches to the exon prediction problem

MOTIVATION: Many gene identification methods assign scores to gene elements prior to their assembly into predicted genes. The scoring system is often based on log-likelihood ratios. These methods usually perform well but it is difficult to interpret how significant a score is. RESULTS: We have developed several tests of significance for the scores: (1) a sum-of-scores test (SST), (2) an intersection-union test (IUT), based on a multiple hypothesis testing interpretation of an exon's score and (3) a meta-analytical approach (MA), which combines several P-values, corresponding to the exon's parts, to yield a global P-value. We performed simulation studies, which show that the MA has better sensitivity and specificity than other methods and is easier to interpret by non-expert users. This is an improvement over other methods and is especially relevant for users who would like to predict incomplete gene sequences.     

New approaches to an age-old problem

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New approaches to the problem of macronuclear assortment

Macronuclear assortment is a vegetative (somatic) process in the ciliate protozoan genus Tetrahymena which leads to the production of “homozygous” phenotypes from sexually-produced heterozygotes. The appearance of pure types follows a model of 45 randomly distributed and replicating subunits in the polyploid macronucleus. Models for the organization of macronuclear chromatin must explain the following: (1) haploid genomes are distributed at each fission; (2) not all loci assort; (3) different loci begin assortment at different times following conjugation. Therefore, either haploid subunits distributed at fission must frequently exchange parts (by somatic recombination, gene conversion, or progressive chromosome fragmentation), or they may actually disintegrate between fissions. Some of these possibilities can be distinguished by considering the kinetics of the appearance of pure types at two or more loci simultaneously. Conditions which give optimum discrimination between hypotheses of limited recombination and complete scrambling (by disintegration of haploid units between fissions) have been developed. A method for determining the number of assorting subunits in very young macronuclei is also given.     

Animal cognition: rooks team up to solve a problem

A recent study has found that rooks team up to get food in a cooperative instrumental task, but they may have difficulties in understanding when cooperation is necessary and how it works.     

DNA computation model to solve 0-1 programming problem

0-1 programming problem is an important problem in opsearch with very widespread applications. In this paper, a new DNA computation model utilizing solution-based and surface-based methods is presented to solve the 0-1 programming problem. This model contains the major benefits of both solution-based and surface-based methods; including vast parallelism, extraordinary information density and ease of operation. The result, verified by biological experimentation, revealed the potential of DNA computation in solving complex programming problem.     

Two approaches to the synthesis of 3-beta-D-glucopyranosyl-D-glucitol

Glycosidation of 1,2:5,6-di-O-isopropylidene-D-glucose with tetra-O-acetyl-glucosyl bromide in 1:1 benzene-MeNO2 afforded approximately equal amounts of the 3-O-beta-D-glycoside and the rearranged 6-O-beta-D-glycoside, while in MeCN only the latter was formed. When tetra-O-acetyl-beta-thiophenylglucoside was used as donor in CH2Cl2 in the presence of NIS/TfOH as activator, the 6-O-beta-D-glycoside and a 3-O-orthoester were formed in a 1:2 ratio at -20 degrees C, while at 20 degrees C only the former could be isolated. Glycosidation of 1-O-benzoyl-2,4-O-benzylidene-5,6-O-isopropylidene-d-glucitol with tetra-O-acetyl-glucosyl bromide in MeCN in the presence of Hg(CN)2 afforded the corresponding 3-O-alpha- and 3-O-beta-glycopyranoside in a 1:4 ratio in MeCN and 1:5 in 1:1 benzene-MeNO2, respectively. When Hg(CN)2/HgBr2 was used as promoter, the corresponding orthoester was also formed. When tetra-O-acetyl-beta-thiophenylglucoside was used as donor, the 3-O-beta-anomer and the orthoester were obtained predominantly in a 3:2 ratio together with traces of the 3-O-alpha-glycoside. Both beta-glycosides could be smoothly converted into 3-beta-D-glucopyranosyl-D-glucitol.     

Mathematical approaches to the problem of generating immunoglobulin diversity

The frequency of mutations necessary for maintenance in the organism of the existing diversity of immunoglobulin for specificity of active centres is estimated using a mathematical model. The calculation shows the mutation frequency to be approx. 10(-2) per cell in a generation.     

Synthetic approaches to the 2009 new drugs

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009.     

Synthetic approaches to the 2010 new drugs

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 15 NCEs that were launched anywhere in the world in 2010.     

Synthetic approaches to the 2014 new drugs

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of thirty-seven NCEs that were approved for the first time in 2014 and one drug which was approved in 2013 and was not covered in a previous edition of this review.     

Synthetic approaches to the 2012 new drugs

New drugs introduced to the market every year represent a privileged structure for a particular biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011.