Free-energy landscape of a chameleon sequence in explicit water and its inherent alpha/beta bifacial property

A sequence in yeast MATalpha2/MCM1/DNA complex that folds into alpha-helix or beta-hairpin depending on the surroundings has been known as "chameleon" sequence. We obtained the free-energy landscape of this sequence by using a generalized-ensemble method, multicanonical molecular dynamics simulation, to sample the conformational space. The system was expressed with an all-atom model in explicit water, and the initial conformation for the simulation was a random one. The free-energy landscape demonstrated that this sequence inherently has an ability to form either alpha or beta structure: The conformational distribution in the landscape consisted of two alpha-helical clusters with different packing patterns of hydrophobic residues, and four beta-hairpin clusters with different strand-strand interaction patterns. Narrow pathways connecting the clusters were found, and analysis on the pathways showed that a compact structure formed at the N-terminal root of the chameleon sequence controls the cluster-cluster transitions. The free-energy landscape indicates that a small conditional change induces alpha-beta transitions. Additional unfolding simulations done with replacing amino acids showed that the chameleon sequence has an advantage to form an alpha-helix. Current study may be useful to understand the mechanism of diseases resulting from abnormal chain folding, such as amyloid disease.     

Differential strength of sex-biased hybrid inferiority in impeding gene flow may be a cause of Haldane's rule

Abstract In animals, if one sex of the F₁ hybrid between two species is sterile or inviable, it is usually the heterogametic (XY or WZ) sex. This phenomenon, known as Haldane's rule, is currently thought to be coincidentally caused by different mechanisms in separate entities. The following questions have never been asked: Are heterogametic and homogametic inferiority (sterility or inviability) equivalent as isolating mechanisms? Could discrepancies between them, if existing, produce Haldane's rule? Here I consider sex‐biased hybrid inferiority strictly as an isolating mechanism, and quantitatively evaluate its strength in impeding gene flow. The comparison reveals that the ability of sex‐biased inferiority to impede gene flow varies according to the sex and chromosome involved. Heterogametic inferiority is a weaker barrier when unidirectional and a much stronger one when in compound reciprocal directions, compared with homogametic inferiority. Such differential strength may affect divergence in speciation and produce Haldane's rule.     

代谢性谷氨酸受体配体(s)-4C3HPG对大鼠脑缺血耐受性诱导的影响

目的：观察侧脑室注射代谢型谷氨酸受体1／5亚型（mGluR1/5)配体（s)-4C3HPG对海马脑缺血耐受（BIT）诱导的影响,以探讨mGLUR1/5在BIT诱导中的作用。方法：采用大鼠四血管闭塞全脑缺血模型（4－vessel occlusion,4VO),应用硫堇染色和GFAP免疫组化法。36只大鼠椎动脉凝闭后分为sham组、单纯缺血组、BIT组和（s)-4C3HPG组,其中（s)-4C3HPG组又按所给药物剂量不同,分为0．2、0．04和0．008mg三个亚组。所有动物均在手术后或末次缺血后7d处死取材观察。结果：（1）单纯8min缺血可使海马CA1区组织学分级升高、锥体神经元密度降低和胶质纤维酸性蛋白（glial fibrillary acidic protein,GFAP)阳性表达增加（P＜0．05vs sham）.(2)BIT组未见单纯缺血组的上述变化,表明CIP可防止后续8min缺血造成的神经元损伤。（3）CIP的这种保护作用可被（s)-4C3HPG阻断,表现为海马CA1区组织学分级升高和锥体神经元密度降低（P＜0．05 vs sham)。这种变化与（s)-4C3HPG的剂量呈现明显的相关性,即剂量越大,上述改变越明显。结论：（s)-4C3HPG可阻断CIP诱导BIT的作用,提示mGluR1/5参与BIT的诱导。     

Isofurans,but not F2-isoprostanes,are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease

F2-isoprostanes (F2-IsoPs) are well-established sensitive and specific markers of oxidative stress in vivo. Isofurans (IsoFs) are also products of lipid peroxidation, but in contrast to F2-IsoPs, their formation is favored when oxygen tension is increased in vitro or in vivo. Mitochondrial dysfunction in Parkinson's disease (PD) may not only lead to oxidative damage to brain tissue but also potentially result in increased intracellular oxygen tension, thereby influencing relative concentrations of F2-IsoPs and IsoFs. In this study, we attempted to compare the levels of F2-IsoPs and IsoFs esterified in phospholipids in the substantia nigra (SN) from patients with PD to those of age-matched controls as well as patients with other neurodegenerative diseases, including dementia with Lewy body disease (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). The results demonstrated that IsoFs but not F2-IsoPs in the SN of patients with PD and DLB were significantly higher than those of controls. Levels of IsoFs and F2-IsoPs in the SN of patients with MSA and AD were indistinguishable from those of age-matched controls. This preferential increase in IsoFs in the SN of patients with PD or DLB not only indicates a unique mode of oxidant injury in these two diseases but also suggests different underlying mechanisms of dopaminergic neurodegeneration in PD and DLB from those of MSA.     

A study of prey-predator relations for mammals

In this paper, we present a prey-predator nonlinear model for mammals, consisting of large- and small-size prey species with group defence, in a partially protected habitat. If the prey size is small, then it is more prone to the predator at higher densities. Conversely, large prey size at higher densities tend to develop group defence. Therefore, the predator will be attracted towards that area where prey are less in number. A new physical constant has been introduced into the radiation-type condition on that part of the boundary where interaction between prey and predator takes place. This constant allows us to efficiently model group defence capabilities of the herds and its numerical values have to be determined for different pairs of prey-predator species from field observations. A way of measuring the constants involved in the model is suggested. Numerical results are provided and thoroughly discussed for a habitat of circular shape. The obtained results show that in the region away from the protected area, the density of large-size prey species is higher than that of small-size prey species, a fact that is in accordance with observations.     

Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's beta-secretase

Cleavage of amyloid precursor protein (APP) by the Alzheimer's beta-secretase (BACE1) is a key step in generating amyloid beta-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with beta-site APP-cleaving enzyme (BACE) 1 and regulates its cleavage of APP. We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates. Inhibitory activity is dependent on saccharide size and specific structural characteristics, and the mechanism of action involves blocking access of substrate to the active site. In cellular assays, HS specifically inhibits BACE1 cleavage of APP but not alternative cleavage by alpha-secretase. Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action. Furthermore, inhibition of cellular HS synthesis results in enhanced BACE1 activity. Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing.     

APP processing is regulated by cytoplasmic phosphorylation

Amyloid-beta peptide (Abeta) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the beta-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by alpha-secretase. The production of Abeta is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Abeta generation.     

Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity

Although NH2-terminal mutant huntingtin (htt) fragments cause neurological disorders in Huntington's disease (HD), it is unclear how toxic htt fragments are generated and contribute to the disease process. Here, we report that complex NH2-terminal mutant htt fragments smaller than the first 508 amino acids were generated in htt-transfected cells and HD knockin mouse brains. These fragments constituted neuronal nuclear inclusions and appeared before neurological symptoms. The accumulation and aggregation of these htt fragments were associated with an age-dependent decrease in proteasome activity and were promoted by inhibition of proteasome activity. These results suggest that decreased proteasome activity contributes to late onset htt toxicity and that restoring the ability to remove NH2-terminal fragments will provide a more effective therapy for HD than inhibiting their production.     

On Parametric Stability of Gene Networks Controlling Ontogenetic Processes

The problem of evaluation of parametric stability of three models of pro- and eukaryotic gene networks controlling ontogenetic processes has been defined and solved. Experimental schemes of testing gene networks for parametric stability based on the method of generalized threshold models were developed and realized as a software application. We studied the sensitivity of the functioning modes to random variations of the parameters in three model systems: phage development control system, Arabidopsis thaliana flower morphogenesis control subsystem, and gene subnetwork controlling early ontogeny of Drosophila melanogaster. The parametric stability was quantitatively assessed for these models.     

Molar absorption coefficients for the reduced Ellman reagent: reassessment

The Ellman method for assaying thiols is based on the reaction of thiols with the chromogenic DTNB (5,5'-dithiobis-2-nitrobenzoate) whereby formation of the yellow dianion of 5-thio-2-nitrobenzoic acid (TNB) is measured. The TNB molar absorption coefficient, 13.6 x 10(3)M(-1)cm(-1), as published by Ellman in 1959 has been almost universally used until now. Over the years, however, slightly different values have been published, and it has further been shown that TNB reveals thermochromic properties. This should be taken into account when the Ellman method is used for determination of enzyme activities, such as in cholinesterase assays. Our data show that the absorbance spectra of TNB are shifted to longer wavelengths when temperature increases, while absorbance maxima decrease. Our recommended molar absorption coefficients at 412 nm are 14.15 x 10(3)M(-1)cm(-1) at 25 degrees C and 13.8 x 10(3)M(-1)cm(-1) at 37 degrees C (0.1M phosphate buffer, pH 7.4). Molar absorption coefficients for other temperatures and wavelengths are included in the paper.