Inhibition of amyloid fibril formation and cytotoxicity by hydroxyindole derivatives

Gaining insight into the mechanism of amyloid fibril formation, the hallmark of multiple degenerative syndromes of unrelated origin, and exploring novel directions of inhibition are crucial for preventing disease development. Specific interactions between aromatic moieties were suggested to have a key role in the recognition and self-assembly processes leading to the formation of amyloid fibrils by several amyloidogenic polypeptides, including the beta-amyloid polypeptide associated with Alzheimer's disease. Our finding of the high-affinity molecular recognition and intense amyloidogenic potential of tryptophan-containing peptide fragments led to the hypothesis that screening for indole derivatives might lead to the identification of potential inhibitors of amyloid formation. Such inhibitors could mediate specific recognition processes without allowing further growth of the well-ordered amyloid chain. Using fluorescence spectroscopy, atomic force microscopy, and electron microscopy to screen 29 indole derivatives, we identified three potent inhibitors: indole-3-carbinol (I3C), 3-hydroxyindole (3HI), and 4-hydroxyindole (4HI). The latter, a simple low-molecular weight aromatic compound, was the most effective, completely abrogating not only the formation of aggregated structures by Abeta but also the cytotoxic activity of aggregated Abeta toward cultured cells. The results of this study provide further experimental support for the paradigm of amyloid inhibition by heteroaromatic interaction and point to indole derivatives as a simple molecular platform for the development of novel fibrillization inhibitors.     

Primary Colonization of Volcanic Rocks by Plants in Arid Baja California, Mexico

Abstract: In an arid region of Baja California Sur, Mexico, field observations, combined with chemical and physical analyses, mineral analysis and scanning electron microscopy of unweathered and weathered volcanic rocks, revealed the presence of rock-colonizing plants (most are tree-shaped cacti, possibly rock weathering), growing in volcanic rocks without benefit of soil. Many are at the seedling stage. At least four cactus species ( Pachycereus pringlei [S. Wats] Britt. and Ross, Stenocereus thurberi [Engelm.] Buxb. subsp. thurberi, Mamillaria fraileana [Britt. and Rose] Boed., Opuntia cholla F. A. C. Weber), and one tree (wild fig, Ficus palmeri [S. Wats]) were capable of cracking, growing in and colonizing cliffs and rocks formed from ancient lava flows and, consequently, forming soil for succession by other plant species. This study shows that plant colonization of volcanic rocks may assist soil formation, which eventually leads to accumulation of soil, water and nutrients in a desert terrestrial ecosystem that otherwise lacks these essential plant-growth variables.     

Fine with heat,problems with water: microclimate alters water loss in a thermally adapted insular lizard

Global change, including habitat isolation and climate change, has both short‐ and long‐term impacts on wildlife populations. For example, genetic drift and inbreeding result in genetic impoverishment in small, isolated populations, while species undergo range shifts or adaptive phenotypic change in response to shifts in environmental temperatures. In this study, we utilize a model system in which Holocene landscape changes have occurred to examine long‐term effects of population isolation. To examine how isolation may constrain responses to climate change, we characterized ecophysiology across land‐bridge island populations of Erhard's wall lizard Podarcis erhardii. We hypothesized that 1) small, isolated populations that are likely genetically depauperate would exhibit lower phenotypic variability; and 2) populations would be adapted to local microhabitat conditions. We compared a population at a low elevation site on the large island of Naxos with two small populations on nearby islets to determine the effects of population fragmentation. We further compared the low elevation Naxos population with two high elevation sites characterized by disparate microclimates to examine the effects of microclimate. To assess the thermal biology and ecophysiological limits of the study species we measured operative body temperatures (T_e), field body temperatures (T_b), preferred temperatures (T_p), thermal tolerances (CT_max and CT_min), and evaporative water loss (EWL). Our results indicate that small, isolated populations did not exhibit thermal biology or evaporative water loss, while EWL and thermoregulatory effort varied according to microhabitat characteristics. This study integrates fine‐scale measurements with environmental data to provide a holistic view of the relationships between ecophysiology, fragmentation, and microclimate. Our methods can be applied to other ectotherms to gain a better understanding of potential impacts of global change on natural populations.     

Evolution of homo‐oligomerization of methionine S‐adenosyltransferases is replete with structure–function constrains

Homomers are prevalent in bacterial proteomes, particularly among core metabolic enzymes. Homomerization is often key to function and regulation, and interfaces that facilitate the formation of homomeric enzymes are subject to intense evolutionary change. However, our understanding of the molecular mechanisms that drive evolutionary variation in homomeric complexes is still lacking. How is the diversification of protein interfaces linked to variation in functional regulation and structural integrity of homomeric complexes? To address this question, we studied quaternary structure evolution of bacterial methionine S‐adenosyltransferases (MATs)—dihedral homotetramers formed along a large and conserved dimeric interface harboring two active sites, and a small, recently evolved, interdimeric interface. Here, we show that diversity in the physicochemical properties of small interfaces is directly linked to variability in the kinetic stability of MAT quaternary complexes and in modes of their functional regulation. Specifically, hydrophobic interactions within the small interface of Escherichia coli MAT render the functional homotetramer kinetically stable yet impose severe aggregation constraints on complex assembly. These constraints are alleviated by electrostatic interactions that accelerate dimer‐dimer assembly. In contrast, Neisseria gonorrhoeae MAT adopts a nonfunctional dimeric state due to the low hydrophobicity of its small interface and the high flexibility of its active site loops, which perturbs small interface integrity. Remarkably, in the presence of methionine and ATP, N. gonorrhoeae MAT undergoes substrate‐induced assembly into a functional tetrameric state. We suggest that evolution acts on the interdimeric interfaces of MATs to tailor the regulation of their activity and stability to unique organismal needs.     

High resolution structure of the large ribosomal subunit from a mesophilic eubacterium.

We describe the high resolution structure of the large ribosomal subunit from Deinococcus radiodurans (D50S), a gram-positive mesophile suitable for binding of antibiotics and functionally relevant ligands. The over-all structure of D50S is similar to that from the archae bacterium Haloarcula marismortui (H50S); however, a detailed comparison revealed significant differences, for example, in the orientation of nucleotides in peptidyl transferase center and in the structures of many ribosomal proteins. Analysis of ribosomal features involved in dynamic aspects of protein biosynthesis that are partially or fully disordered in H50S revealed the conformations of intersubunit bridges in unbound subunits, suggesting how they may change upon subunit association and how movements of the L1-stalk may facilitate the exit of tRNA.     

A high-density microsatellite map of the ataxia-telangiectasia locus

The locus of the autosomal recessive disorder ataxia-telangiectasia (A-T) has been assigned by linkage analysis with biallelic markers to a 4-Mb interval on chromosome 11q22-23, between GRIA4 and D11S1897. We have undertaken to saturate the A-T region with highly polymorphic microsatellite markers. To this end, we have identified seven new polymorphic CA-repeats in this region, and have mapped to it five new markers generated by Genethon and the Cooperative Human Linkage Center. These markers are in addition to 12 others that we have previously mapped or generated at the A-T locus. All 24 markers have been integrated into a high-density microsatellite map spanning some 6 Mb DNA. This map, which contains the A-T locus and flanking sequences, allows the construction of extensive, highly informative haplotypes.     

Biofilm control in water by a UV-based advanced oxidation process

An ultraviolet (UV)-based advanced oxidation process (AOP), with hydrogen peroxide and medium-pressure (MP) UV light (H₂O₂/UV), was used as a pretreatment strategy for biofilm control in water. Suspended Pseudomonas aeruginosa cells were exposed to UV-based AOP treatment, and the adherent biofilm formed by the surviving cells was monitored. Control experiments using H₂O₂ or MP UV irradiation alone could inhibit biofilm formation for only short periods of time (<24 h) post-treatment. In a H₂O₂/filtered-UV (>295 nm) system, an additive effect on biofilm control was shown vs filtered-UV irradiation alone, probably due to activity of the added hydroxyl radical (OH?). In a H₂O₂/full-UV (ie full UV spectrum, not filtered) system, this result was not obtained, possibly due to the germicidal UV photons overwhelming the AOP system. Generally, however, H₂O₂/UV prevented biofilm formation for longer periods (days) only when maintained with residual H₂O₂. The ratio of surviving bacterial concentration post-treatment to residual H₂O₂ concentration played an important role in biofilm prevention and bacterial regrowth. H₂O₂ treatments alone resulted in poorer biofilm control compared to UV-based AOP treatments maintained with similar levels of residual H₂O₂, indicating a possible advantage of AOP.     

Remodeling of Proteostasis Upon Transition to Adulthood is Linked to Reproduction Onset

Protein folding and clearance networks sense and respond to misfolded and aggregation-prone proteins by activating cytoprotective cell stress responses that safeguard the proteome against damage, maintain the health of the cell, and enhance lifespan. Surprisingly, cellular proteostasis undergoes a sudden and widespread failure early in Caenorhabditis elegans adulthood, with marked consequences on proteostasis functions later in life. These changes in the regulation of quality control systems, such as chaperones, the ubiquitin proteasome system and cellular stress responses, are controlled cell-nonautonomously by the proliferation of germline stem cells. Here, we review recent studies examining changes in proteostasis upon transition to adulthood and how proteostasis is modulated by reproduction onset, focusing on C. elegans. Based on these and our own findings, we propose that the regulation of quality control systems is actively remodeled at the point of transition between development and adulthood to influence the subsequent course of aging.     

Can hair steroids predict pregnancy longevity?

Maintaining pregnancy to term is important as preterm delivery is a risk factor for impaired infant development, which may have negative long-term consequences. Therefore, developing biomarkers that can predict pregnancy longevity during early gestation is essential for the prevention of preterm birth. Here we explored whether maternal hair testosterone and cortisol, representing the pre-conception and first trimester periods respectively, may be used to predict pregnancy longevity. We recruited 125 pregnant women that contributed hair samples and answered a personal information questionnaire that included pre-conception smoking. We quantified steroids using commercial enzyme-linked immunosorbent assay kits. Gestational age at delivery was obtained from medical records. We used General Linear Models to predict gestation length. The model that included first trimester cortisol, pre-conception smoking, pre-conception testosterone and the interaction between first trimester cortisol and pre-conception smoking predicted 13% of the variance in gestation length (R² = 0.130; n?=?105; p?=? 0.007). First trimester cortisol was the best predictor of gestational length. Women with high levels of cortisol in their first trimester had an increased probability of a full-term delivery. The effect of cortisol was especially pronounced in smokers (ß?=?1.69), compared to non-smokers (ß?=?0.45). Pre-conception testosterone also contributed to the model. Our study suggests that hair steroids may be used to predict pregnancy longevity, together with other contributing factors.