Are rates of species diversification correlated with rates of morphological evolution?

Some major evolutionary theories predict a relationship between rates of proliferation of new species (species diversification) and rates of morphological divergence between them. However, this relationship has not been rigorously tested using phylogeny-based approaches. Here, we test this relationship with morphological and phylogenetic data from 190 species of plethodontid salamanders. Surprisingly, we find that rates of species diversification and morphological evolution are not significantly correlated, such that rapid diversification can occur with little morphological change, and vice versa. We also find that most clades have undergone remarkably similar patterns of morphological evolution (despite extensive sympatry) and that those relatively novel phenotypes are not associated with rapid diversification. Finally, we find a strong relationship between rates of size and shape evolution, which has not been previously tested.     

Complex of repair DNA polymerase β with autonomous 3′→5′ exonuclease shows increased accuracy of DNA synthesis

The complexes of repair DNA polymerase β with 3′-exonuclease and some other proteins were isolated from the chromatin of hepatocytes of normal rats for the first time. Biopolymers were extracted from the chromatin by the solution of NaCl and Triton X-100. The extract was fractionated by gel-filtration on Sephacryl S-300 columns successively in low and high ionic strength solutions, on hydroxyapatite, and on Sephadex G-100 columns. The complexes have molecular weights of 100 and 300 kDa. They dissociate to DNA polymerase and exonuclease in the course of chromatography on a DNA-cellulose column or after gel-filtration in the presence of 1 M NaCl. The co-purification of the polymerase and exonuclease is reconstituted in 0.1 M NaCl. The fidelity of monomeric and composite DNA polymerase β was measured using phase ?X174 amber 3 as a primer/template. The products of the synthesis were transfected into Escherichia coli spheroplasts, and the frequency of reverse mutations was determined. The complex of DNA polymerase β with 3′-exonuclease was shown to be 30 times more accurate than the monomeric polymerase, which can decrease the probability of repair mutagenesis and carcinogenesis.     

Whole body synthesis rates of DHA from α-linolenic acid are greater than brain DHA accretion and uptake rates in adult rats

Docosahexaenoic acid (DHA) is important for brain function, however, the exact amount required for the brain is not agreed upon. While it is believed that the synthesis rate of DHA from α-linolenic acid (ALA) is low, how this synthesis rate compares with the amount of DHA required to maintain brain DHA levels is unknown. The objective of this work was to assess whether DHA synthesis from ALA is sufficient for the brain. To test this, rats consumed a diet low in n-3 PUFAs, or a diet containing ALA or DHA for 15 weeks. Over the 15 weeks, whole body and brain DHA accretion was measured, while at the end of the study, whole body DHA synthesis rates, brain gene expression, and DHA uptake rates were measured. Despite large differences in body DHA accretion, there was no difference in brain DHA accretion between rats fed ALA and DHA. In rats fed ALA, DHA synthesis and accretion was 100-fold higher than brain DHA accretion of rats fed DHA. Also, ALA-fed rats synthesized approximately 3-fold more DHA than the DHA uptake rate into the brain. This work indicates that DHA synthesis from ALA may be sufficient to supply the brain.     

N-terminal acetylation of α-synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomer

The conformational properties of soluble α-synuclein, the primary protein found in patients with Parkinson's disease, are thought to play a key role in the structural transition to amyloid fibrils. In this work, we report that recombinant 100% N-terminal acetylated α-synuclein purified under mild physiological conditions presents as a primarily monomeric protein, and that the N-terminal acetyl group affects the transient secondary structure and fibril assembly rates of the protein. Residue-specific NMR chemical shift analysis indicates substantial increase in transient helical propensity in the first 9 N-terminal residues, as well as smaller long-range changes in residues 28-31, 43-46, and 50-66: regions in which the three familial mutations currently known to be causative of early onset disease are found. In addition, we show that the N-terminal acetylated protein forms fibrils that are morphologically similar to those formed from nonacetylated α-synuclein, but that their growth rates are slower. Our results highlight that N-terminal acetylation does not form significant numbers of dimers, tetramers, or higher molecular weight species, but does alter the conformational distributions of monomeric α-synuclein species in regions known to be important in metal binding, in association with membranes, and in regions known to affect fibril formation rates.     

Human recombination rates are increased around accelerated conserved regions--evidence for continued selection?

MOTIVATION: We hypothesized that recombination rates might be increased at genetic loci that are subject to more intense selection. Here, we test this hypothesis by using a recently published set of accelerated conserved regions and fine-scale recombination rate estimates provided by the HapMap project. RESULTS: We observed that fine-scale recombination rates are increased around conserved noncoding regions that show accelerated evolution in human or chimp, as compared to noncoding regions showing accelerated evolution in mouse and those being conserved between human and fugu. Recombination rates around hominid accelerated conserved regions (ACRs) are furthermore increased as compared to exonic regions. On the other hand, GC-content is reduced around ACRs, excluding a major confounding influence of GC-content on the observed variation in recombination rate. Conclusion: Our observations indicate that selection intensity could be an important determinant of local recombination rate variation and that continued positive selection might act at many ACR loci. Alternatively, a confounding factor needs to be found that causes a congruent signal in recombination rate estimates based on human polymorphism data and in the comparative genomic data. Researchers who consider the explanation involving selection as more likely may expect more common functional sequence variants at ACRs in genetic association studies.     

Method for the synthesis of phosphinic acids from hypophosphites V. The synthesis of pseudo-α,α-dipeptides

Summary. Neurolathyrisim is a motor neuron disease characterized by spastic paraparesis in the hind legs, and is caused by grass pea, Lathyrus sativus, which contains the excitotoxic amino acid, 3-N-oxalyl-L-2,3-diaminopropanoic acid (L--ODAP), an -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamatergic receptor agonist. In an attempt to make a useful model of this disease, the CNS distribution and toxicity of L--ODAP was studied in rat neonates after parenteral administration. L--ODAP was detected in the spinal cord as well as in the pons/medulla oblongata, though only small amounts in the latter. Repeated injection of L--ODAP resulted in rats with paraparesis of the legs, though at a low incidence rate of 0.032. These paralyzed rats displayed the severe atrophy of the ventral root of the lumbar cord as well as degenerations of motor neuron. The rats were useful models for the study of motor neuron degeneration in the spinal cord.     

Design, synthesis and pharmacological evaluation of spirocyclic σ(1) receptor ligands with exocyclic amino moiety (increased distance 1)

Various pharmacophore models for potent σ(1) ligands specify a basic amino group flanked by two different hydrophobic regions in defined distances to the basic amine (distance 1 and distance 2, respectively). According to these models distance 1 of the potent spirocyclic σ(1) ligand 1 is too short. In order to find a new class of more potent σ(1) ligands and to verify the distance hypothesis of the pharmacophore models spirocyclic compounds 2 with an exocyclic amino group were designed and synthesized. The secondary amines 8 and 9 with N-benzyl residues are >100-fold less potent than the spirocyclic piperidine 1. However, the tertiary methylamines trans-11 and cis-11 represent potent σ(1) ligands with K(i)-values of 43 and 24 nM, respectively. Whereas one large benzyl moiety is required for high σ(1) receptor binding, a second large N-substituent is not tolerated by the σ(1) receptor protein. As a rule, cis-configured diastereomers with a longer distance 1 (predominantly 7.16-7.23 ?) show higher σ(1) affinities than their trans-configured counterparts (distance 1 is predominantly 5.88-6.26 ?).     

Down's syndrome,Edwards' syndrome,Patau's syndrome —synthesis of glycosaminoglycans

Synthesis of glycosaminoglycans (GAGS) by fibroblasts derived from seven patients with Down's syndrome, five patients with Edwards' syndrome, and two patients with Patau's syndrome were studied in cell culture. The aneuploid strains were compared with diploid fibroblasts from age-matched controls. In terms of hyaluronic acid and sulfated GAG synthesis, the amount of synthesized hyaluronic acid was not significantly different between postnatal aneuploid strains and controls.     

Evidence for increased de novo synthesis of NAD in immune-activated RAW264.7 macrophages: a self-protective mechanism?

Chondrogenesis in cartilage development and repair and cartilage degeneration in arthritis can be regulated by mechanical-load-induced physical factors such as tissue deformation, interstitial fluid flow and pressure, and electrical fields or streaming potentials. Previous animal and tissue explant studies have shown that time-varying dynamic tissue loading can increase the synthesis and deposition of matrix molecules in an amplitude-, frequency-, and spatially dependent manner. To provide information on the cell-level physical factors which may stimulate chondrocytes to increase production and export of aggrecan, the main proteoglycan component of the cartilage matrix, we characterized local changes in aggrecan synthesis within cyclically loaded tissue explant disks and compared those changes to values of predicted local physical factors. Aggrecan synthesis following a 23-h compression/radiolabel protocol was measured with a spatial resolution of approximately 0.1 mm across the 1.5-mm radius of explanted disks using a quantitative autoradiography method. A uniform stimulation of aggrecan synthesis was observed at an intermediate frequency of 0.01 Hz, while, at a higher frequency of 0.1 Hz, stimulation was only seen at peripheral radial positions. Profiles of radial solid matrix deformation and interstitial fluid pressure and velocity predicted to be occurring across the radius of the disk during sinusoidal loading were estimated using a composite poroelastic model. Tissue regions experiencing high interstitial fluid velocities corresponded to those displaying increased aggrecan synthesis. These results reinforce the role of load-induced flow of interstitial fluid in the stimulation of aggrecan production during dynamic loading of cartilage.     

What are the relative costs,limits and correlates of increased degree of serotiny?

There is variability in the period that serotinous species retain seeds in protective closed cones and in the sizes of the cones. Seed predation and inter‐fire recruitment have been suggested to be reasons for this variability. I argue against these two reasons. Variation in annual rates of increase in fecundity and in numbers of flowering episodes before fire should be correlated with the degree of serotiny. These two attributes are a consequence of cone size, plant architecture and degree of serotiny.     

Design, synthesis, and evaluation of a novel class of 2,3-disubstituted-tetrahydro-β-carboline derivatives

Several novel tetrahydro-β-carboline derivatives with amino acid residues at the 2-position and a glucosamine group at the 3-position of the tetrahydro-β-carboline nucleus were synthesized from a readily available starting material, tryptophane, and were evaluated for their anti-inflammatory activity in the present study. Our results showed that all of the derivatives tested exhibited a significant inhibition of xylene-induced inflammation in mice.     

Commodity specific rates of temporal discounting: Does metabolic function underlie differences in rates of discounting?

Discounting rates vary as a function of commodity type. Previous studies suggest five potential characteristics of the commodity that could explain these differences: type of reinforcer (primary or secondary), if the commodity is perishable, if the commodity is satiable, if the commodity can be directly consumed, and immediacy of consumption. This paper suggests that these characteristics may best be viewed as related to a more fundamental characteristic: metabolic processing. In order to explore the possibility that metabolic processing underlies changes in discount rates, the difference in discounting between food, money, music CDs, DVDs, and books are compared. Music CDs, DVDs, and books share many characteristics in common with food, including gaining value through a physiological process, but are not directly metabolized. Results are consistent with previous findings of commodity specific discount rates and show that metabolic function plays a role in determining discount rates with those commodities that are metabolized being discounted at a higher rate. These results are interpreted as evidence that the discount rate for different commodities lies along a continuum with those that serve an exchange function rather than a direct function (money) anchoring the low end and those that serve a direct metabolic function capping the high end (food, alcohol, drugs).     

Rifampicin-induced protein synthesis: A pre-requisite for increased expression of the ββ′ operon in Escherichia coli

Summary In a rif ^S/rif^R heterodiploid strain of E. coli, a 4 minute pulse of rifampicin can induce a prolonged (>60 min) increase in the rate of synthesis of the RNA polymerase subunits, and . The application of a constraint on the fidelity of protein synthesis during, but not after, the rifampicin pulse partially arrests the development of this capacity for subunit synthesis. I discuss the implications of these findings in relation to the control of the operon in E. coli.     

Reproductive rates of ringed seals and survival of pups in Northwestern Hudson Bay, Canada, 1991–2000

Reproductive parameters were determined from a sample of ringed seals collected by Inuit hunters during their annual open water harvest in autumn at Arviat, Nunavut, on the western coast of Hudson Bay, Canada, in 1991–1992 and 1998–2000. Ovulation rates of adult females were high and similar to rates recorded from studies of ringed seals in other geographic areas. However, pregnancy rates averaged only 55% and were significantly lower than in other studies, and the proportions of young-of-the-year were only 4.8, 4.2, 7.5, 4.1, and 23% for the mentioned years, respectively, instead of being >30% as expected. These results appear to indicate that reproductive parameters of ringed seals and survival of their young are exhibiting long-term shifts rather than short-term fluctuations, and that the trend is downward. Furthermore, these downward trends in reproduction, in conjunction with changes in the proportions of different seal species in the diet of polar bears, climatic warming in western Hudson Bay, and progressively earlier breakup of sea ice over the last 25 years, suggest that major changes are occurring in the marine ecosystem of Hudson Bay. The pathways involved are poorly understood and merit further study.     

Design,synthesis and anticancer evaluation of tetrahydro-β-carboline-hydantoin hybrids

A series of new tetrahydro-β-carboline-hydantoin hybrids have been designed and synthesized based on the structure of the known Eg5 inhibitor HR22C16. These compounds have been evaluated for their anticancer activity against lung (A549), cervical (ME180, HeLa), prostate (PC-3) and breast (MCF-7) cancer cell lines by MTT assay. These hybrids have displayed significant in vitro cytotoxicity in comparison to etoposide against PC-3, A549, and MCF-7 cell lines. The hybrids 3a, 3b, 3c, 3e, 3f, 3g, 4b, 4c, 4e and 4f appear to be more effective against the PC-3 cell line, among which compound 4b displayed the highest cytotoxicity (6.08 ± 0.2, IC₅₀ μM). Based on these results, an attempt was made to rationalize their mechanism of action through cell cycle analysis studies. The flow-cytometric analysis of compound 4b in PC-3 cells indicated a G2/M cell cycle arrest. Molecular docking studies substantiate that these compounds indeed bind to the allosteric site of Eg5 formed from Glu116, Gly117, Glu118, Trp127, Ala133, Ile136, Pro137, Tyr211, Leu214, and Glu215 residues with the most potent compound 4b showing the most favorable interaction.     

Design,synthesis and anticholinesterase activity of some new α-aminobisphosphonates

Some new α-aminomethylenephosphonic acids 1–11 were synthesised and characterised by ¹H, ¹³C, ³¹P NMR, IR spectroscopy and elemental analysis. The potencies of these compounds to inhibit human erythrocyte acetylcholinesterase (hAChE, EC 3.1.1.7) were studied by a modified Ellman’s method. In addition, the log P values were computed by Hyperchem software. Here, alendronate was used as a reference inhibitor. Results showed that the IC₅₀ values ranged from 9.11 to 28.72?mM. The half maximal inhibitory concentration (IC₅₀) value decreased with an increasing number of carbon atoms of the amine group in compounds 1–5. Also, in most cases, increasing the number of carbon atoms led to enhancement of the toxicity as predicted by the log P values. Using Lineweaver-Burk and Dixon analysis, it was indicated that compounds 1–10 are mixed inhibitors while compound 11 is a coupling or uncompetitive inhibitor. The results showed that the electronic changes have ignorable effects, steric influence is important in some cases, but the lipophilicity parameter is the most significant factor in hAChE inhibition by bisphosphonates.