Genetic aberrations in macroautophagy genes leading to diseases

The catabolic process of macroautophagy, through the rapid degradation of unwanted cellular components, is involved in a multitude of cellular and organismal functions that are essential to maintain homeostasis. Those functions include adaptation to starvation, cell development and differentiation, innate and adaptive immunity, tumor suppression, autophagic cell death, and maintenance of stem cell stemness. Not surprisingly, an impairment or block of macroautophagy can lead to severe pathologies. A still increasing number of reports, in particular, have revealed that mutations in the autophagy-related (ATG) genes, encoding the key players of macroautophagy, are either the cause or represent a risk factor for the development of several illnesses. The aim of this review is to provide a comprehensive overview of the diseases and disorders currently known that are or could be caused by mutations in core ATG proteins but also in the so-called autophagy receptors, which provide specificity to the process of macroautophagy. Our compendium underlines the medical relevance of this pathway and underscores the importance of the eventual development of therapeutic approaches aimed at modulating macroautophagy.     

Natural products as modulators of the nuclear receptors and metabolic sensors LXR,FXR and RXR

Nuclear receptors (NRs) represent attractive targets for the treatment of metabolic syndrome-related diseases. In addition, natural products are an interesting pool of potential ligands since they have been refined under evolutionary pressure to interact with proteins or other biological targets.This review aims to briefly summarize current basic knowledge regarding the liver X (LXR) and farnesoid X receptors (FXR) that form permissive heterodimers with retinoid X receptors (RXR). Natural product-based ligands for these receptors are summarized and the potential of LXR, FXR and RXR as targets in precision medicine is discussed.     

Phylogenetic spread of sequence data affects fitness of SOD1 consensus enzymes: Insights from sequence statistics and structural analyses

Non‐natural protein sequences with native‐like structures and functions can be constructed successfully using consensus design. This design strategy is relatively well understood in repeat proteins with simple binding function, however detailed studies are lacking in globular enzymes. The SOD1 family is a good model for such studies due to the availability of large amount of sequence and structure data motivated by involvement of human SOD1 in the fatal motor neuron disease amyotrophic lateral sclerosis (ALS). We constructed two consensus SOD1 enzymes from multiple sequence alignments from all organisms and eukaryotic organisms. A significant difference in their catalytic activities shows that the phylogenetic spread of the sequences used affects the fitness of the construct obtained. A mutation in an electrostatic loop and overall design incompatibilities between bacterial and eukaryotic sequences were implicated in this disparity. Based on this analysis, a bioinformatics approach was used to classify mutations thought to cause familial ALS providing a unique high level view of the physical basis of disease‐causing aggregation of human SOD1.     

The effects of substrate and vertebral number on locomotion in the garter snake Thamnophis elegans

1. Locomotor performance of limbless vertebrates depends on the substrate through which individuals move and may result in selection on vertebral number in different habitats. To evaluate the effect of push-point density on snake locomotion, the density of vegetation and other potential push-points was quantified at two sites in California (coastal and inland), where conspecific snakes differed greatly in vertebral number (230 and 256 average total vertebrae, respectively; Arnold 1988). The coastal site had significantly higher push-point densities than the inland site.
2. Five experimental push-point densities that fell within the natural range of push-point densities were employed in laboratory trials of juvenile snake locomotion. Density of push-points significantly affected both crawling speed and head-to-tail distance (HTD), an indirect measure of lateral bending. The fastest speed was achieved at an intermediate push-point density. The shortest HTD occurred when snakes moved through the lowest push-point density.
3. Sex, total number of vertebrae and total length significantly affected HTD, regardless of push-point density. Snakes with relatively more vertebrae had a shorter HTD, suggesting they were able to achieve greater lateral bending than snakes with fewer vertebrae. Coastal and inland populations did not differ in HTD during locomotion.
4. Numbers of body and tail vertebrae significantly influenced speed at different push-point densities. In general, snakes with more body vertebrae were slower than those with fewer, while snakes with more tail vertebrae were faster than those with fewer. Snakes of greater total length were faster at all densities. Coastal snakes crawled faster than inland snakes at all push-point densities.     

Novel mutations in an otherwise strictly conserved domain of CuZn superoxide dismutase

All mutations in the human gene for CuZn superoxide dismutase (CuZnSOD) reported to date are associated with the disease amyotrophic lateral sclerosis (ALS). These mutations, mostly of a familial nature (ALS 1, MIM 105400), span all of the coding region of this enzyme except for a highly conserved centrally located domain that includes all of exon III. We describe the identification and characterization of two mutations in this region, both found in mice. One mutation, a glutamate to lysine amino acid substitution was found in position 77 (E77K) of the strain SOD1/Ei distributed by the Jackson Laboratory. The other mutation, a lysine to glutamate substitution at position 70 (K70E) of a human transgene, was discovered in mouse line TgHS/SF-155. Enzyme activity measurements and heterodimer analysis of the CuZn SOD variant in SOD1/Ei suggest a mild loss of activity, which differs from the enzyme activity losses detected in patients with autosomal dominant ALS 1. Similarly, the presence of the mutant transgene in TgHS/SF 155 does not produce any phenotypic manifestations.     

Concepts and terminology of apical dominance

Apical dominance is the control exerted by the shoot apex over lateral bud outgrowth. The concepts and terminology associated with apical dominance as used by various plant scientists sometimes differ, which may lead to significant misconceptions. Apical dominance and its release may be divided into four developmental stages: (I) lateral bud formation, (II) imposition of inhibition on lateral bud growth, (III) release of apical dominance following decapitation, and (IV) branch shoot development. Particular emphasis is given to discriminating between Stage III, which is accompanied by initial bud outgrowth during the first few hours of release and may be promoted by cytokinin and inhibited by auxin, and Stage IV, which is accompanied by subsequent bud outgrowth occurring days or weeks after decapitation and which may be promoted by auxin and gibberellin. The importance of not interpreting data measured in Stage IV on the basis of conditions and processes occurring in Stage III is discussed as well as the correlation between degree of branching and endogenous auxin content, branching mutants, the quantification of apical dominance in various species (including Arabidopsis ), and apical control in trees.     

Shoot inversion-induced ethylene in pharbitis nil induces the release of apical dominance by restricting shoot elongation

Shoot inversion induces outgrowth of the highest lateral bud (HLB) adjacent to the bend in the stem in Pharbitis nil. In order to determine whether or not ethylene produced by shoot inversion plays a direct role in promoting or inhibiting bud outgrowth, comparisons were made of endogenous levels of ethylene in the HLB and HLB node of plants with and without inverted shoots. That no changes were found suggests that the control of apical dominance does not involve the direct action of ethylene. This conclusion is further supported by evidence that the direct application of ethylene inhibitors or ethrel to inactive or induced lateral buds has no significant effect on bud outgrowth. The hypothesis that ethylene evolved during shoot inversion indirectly promotes the outgrowth of the highest lateral bud (HLB) by restricting terminal bud (TB) growth is found to be supported by the following observations: (1) the restriction of TB growth appears to occur before the beginning of HLB outgrowth; (2) the treatment of the inverted portion of the shoot with AgNO₃, an inhibitor of ethylene action, dramatically eliminates both the restriction of TB growth and the promotion of HLB outgrowth which usually accompany shoot inversion; and (3) the treatment of the upper shoot of an upright plant with ethrel mimics shoot inversion by retarding upper shoot growth and inducing outgrowth of the lateral bud basipetal to the treated region.     

Copigments in the blueing of sepal colour of Hydrangea macrophylla

From blue sepals of Hydrangea macrophylla, copigments which show a blueing effect on the hydrangea anthocyanin were isolated and identified as 3-p-coumaroylquinic acid and 3-caffeoylquinic acid. 5-Caffeoylquinic acid (chlorogenic acid) which was also found in the blue sepals, however, did not show such a blueing effect though it acted as a copigment. Likewise, the 4-esters of p-coumaroyl- and caffeoylquinic acids (not found in sepals) produced purple rather than blue colours. The facts suggest that the stereostructures of 3-p-coumaroyl- and 3-caffeoylquinic acids are effective for molecular interaction between the p-coumaroyl or caffeoyl residue in the compounds and the anthocyanin. The anthocyanin in red and blue sepals of hydrangea was confirmed to be delphinidin 3-monoglucoside.