Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation,SUMOylation and Ubiquitination

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the nigrostriatal pathway. The etiology of PD remains unclear and most cases are sporadic, however genetic mutations in more than 20 proteins have been shown to cause inherited forms of PD. Many of these proteins are linked to mitochondrial function, defects in which are a central characteristic of PD. Post-translational modifications (PTMs) allow rapid and reversible control over protein function. Largely focussing on mitochondrial dysfunction in PD, here we review findings on the PTMs phosphorylation, SUMOylation and ubiquitination that have been shown to affect PD-related proteins.     

Floral nectaries in Sapindaceae <Emphasis Type="Italic">s.s.</Emphasis>: morphological and structural diversity,and their systematic implications

We investigated the morphology and structure of the floral nectary in 11 Neotropical genera belonging to the subfamilies Dodonaeoideae and Paullinioideae (Sapindaceae) from southern South America representing three tribes (Dodonaeaeae, Paullinieae, and Melicocceae), in relation to other floral traits in species with contrasting morphological flower characteristics. Nectary organization was analyzed under light, stereoscopic, and scanning electron microscopes; Diplokeleba floribunda N.E. Br. was also observed using transmission electron microscopy. Our comparative data may contribute to the understanding of floral nectary evolution and systematic value in this family. The nectaries were studied in both staminate and pistillate flowers. All the floral nectaries are typical of Sapindaceae: extrastaminal, receptacular, structured, and persistent. The anatomical analysis revealed a differentiated secretory parenchyma and an inner non-secretory parenchyma; the nectary is supplied by phloem traces and, less frequently, by phloem and xylem traces. Nectar is secreted through nectarostomata of anomocytic type. The anatomical analysis showed the absence of nectary in the three morphs of Dodonaea viscosa flowers. Nectary ultrastructure is described in D. floribunda. In this species, the change in nectary color is related to progressive accumulation of anthocyanins during the functional phase. We found relatively small variation in the nectary structural characteristics compared with large variation in nectary morphology. The latter aspect agreed with the main infrafamilial groupings revealed by recent phylogenetic studies, so it is of current valuable systematic importance for Sapindaceae. In representatives of Paullinieae, the reduction of the floral nectary to 4–2 posterior lobes should be interpreted as a derived character state.     

Diversification of <Emphasis Type="Italic">Caiophora</Emphasis> (Loasaceae subfam. Loasoideae) during the uplift of the Central Andes

Andean orogeny and the ecological changes that followed promoted diversification in plant and animal lineages since the Early Miocene. The angiosperm genus Caiophora (Loasaceae, subfam. Loasoideae) comprises around 50 species that are endemic to South America. These are distributed from southern Ecuador to Central Chile and Argentina. Bee pollination and distribution at low-intermediate elevations probably represent the ancestral condition in the lineage that includes Caiophora and its allied genera. The majority of Caiophora species grow at high elevations in the Andes, where some depend on vertebrate pollination. Previous studies did not resolve phylogenetic relationships within Caiophora, which precluded the dating of the origin and divergence of this group. We used markers of one nuclear (ITS) and one plastid region (trnS ^GCU -trnG ^UUC ) to solve phylogenetic relationships among 19 Caiophora species (including different accessions). We also included 10 species of the allied genera Blumenbachia and Loasa. Aosa rostrata and Xylopodia klaprothioides were used as outgroups. Phylogenetic reconstruction strongly supports the monophyly of Caiophora, and although several clades within this genus are poorly supported, our study yielded a better infra-generic resolution than previous studies. The origin of Caiophora is dated to the Early-Middle Miocene and can be related to the uplift of the Cordilleras Frontal and Principal and to Pacific marine transgressions. According to our estimations, Caiophora began to diversify during the Middle-Late Miocene and this unfolding proceeded eastwards during the Pliocene and the Pleistocene, in parallel to the uplift of different Andean mountain ranges.     

A new nitrobenzoxadiazole-based GSTP1-1 inhibitor with a previously unheard of mechanism of action and high stability

Context: The nitrobezoxadiazole derivative NBDHEX is a potent inhibitor of glutathione transferase P1-1 (GSTP1-1) endowed with outstanding anticancer activity in different tumor models.

Objective: To characterize by in vitro biochemical and in silico studies the NBDHEX analogues named MC2752 and MC2753.

Materials and methods: Synthesis of MC2752 and MC2753, biochemical assays and in silico docking and normal-mode analyses.

Results: The presence of a hydrophobic moiety in the side chain of MC2753 confers unique features to this molecule. Unlike its parent drug NBDHEX, MC2753 does not require GSH to trigger the dissociation of the complex between GSTP1-1 and TRAF2, and displays high stability towards the nucleophilic attack of the tripeptide under physiological conditions.

Discussion and conclusion: MC2753 may represent a lead compound for the development of novel GSTP1-1 inhibitors not affected in their anticancer action by fluctuations of cellular GSH levels, and characterized by an increased half-life in vivo.     

Climate Change Impacts on Faidherbia albida (Delile) A. Chev. Distribution in Dry Lands of Ethiopia

Given recent and projected climate change, the study of adaptation and mitigation strategies which involve ecologically and economically important plant species is urgently needed. Faidherbia albida (Delile) A. Chev. is a species of both economic and ecological importance. We use 229 locational records gathered in the dry highlands of Ethiopia, nineteen environmental variables and the modelling program MaxEnt to model both the present and possible future distributions of this species. To model future distributions, we used two emission scenarios (Representative Concentration Pathways 2.6 and 8.5) for two time slices (2050 and 2070). Mean temperature of wettest quarter was the major factor which determines the species' potential distribution. Suitable habitat for F. albida under the current climatic conditions is the mid‐highlands. However, its future distributions would shift upwards in elevation and will likely lead to some decrease in suitable areas, especially towards the end of the century. At the same time, however, other areas would become suitable for colonization, so that, overall, the species does not appear to face a significant reduction in distribution within our study region. Future studies should consider the possible effects of climate extremes, further environmental factors and of evolutionary adaptation of the species to new conditions.     

Clinical Implications of <Emphasis Type="Italic">Candida</Emphasis> Biofilms

Purpose of Review

In this review, we will assess what is currently known about Candida biofilms, its epidemiology and impact on clinical practice, and the biology underlying biofilm-related antifungal drug resistance. We also review potential antifungal lock therapies and discuss what avenues are available for future discoveries for the prevention and eradication of fungal biofilms.

Recent Findings

There is a multitude of in vitro tests of agents against Candida biofilms, but many of these studies have not demonstrated their utility against other Candida species and/or their efficacy in in vivo systems. This makes it particularly difficult to translate these findings for use in the clinical setting.

Summary

Research has helped us to understand the complexity of biofilms and its inherent antifungal resistance. The extracellular matrix remains a significant barrier for most antifungal therapy, and thus it stands to reason that agents directed at disrupting this protective barrier could be useful in antifungal lock therapies.

     

Rv0180c contributes to Mycobacterium tuberculosis cell shape and to infectivity in mice and macrophages

Mycobacterium tuberculosis, the main causative agent of human tuberculosis, is transmitted from person to person via small droplets containing very few bacteria. Optimizing the chance to seed in the lungs is therefore a major adaptation to favor survival and dissemination in the human population. Here we used TnSeq to identify genes important for the early events leading to bacterial seeding in the lungs. Beside several genes encoding known virulence factors, we found three new candidates not previously described: rv0180c, rv1779c and rv1592c. We focused on the gene, rv0180c, of unknown function. First, we found that deletion of rv0180c in M. tuberculosis substantially reduced the initiation of infection in the lungs of mice. Next, we established that Rv0180c enhances entry into macrophages through the use of complement-receptor 3 (CR3), a major phagocytic receptor for M. tuberculosis. Silencing CR3 or blocking the CR3 lectin site abolished the difference in entry between the wild-type parental strain and the Δrv0180c::km mutant. However, we detected no difference in the production of both CR3-known carbohydrate ligands (glucan, arabinomannan, mannan), CR3-modulating lipids (phthiocerol dimycocerosate), or proteins in the capsule of the Δrv0180c::km mutant in comparison to the wild-type or complemented strains. By contrast, we established that Rv0180c contributes to the functionality of the bacterial cell envelope regarding resistance to toxic molecule attack and cell shape. This alteration of bacterial shape could impair the engagement of membrane receptors that M. tuberculosis uses to invade host cells, and open a new perspective on the modulation of bacterial infectivity.     

From decision to action: Detailed modelling of frog tadpoles reveals neuronal mechanisms of decision-making and reproduces unpredictable swimming movements in response to sensory signals

How does the brain process sensory stimuli, and decide whether to initiate locomotor behaviour? To investigate this question we develop two whole body computer models of a tadpole. The “Central Nervous System” (CNS) model uses evidence from whole-cell recording to define 2300 neurons in 12 classes to study how sensory signals from the skin initiate and stop swimming. In response to skin stimulation, it generates realistic sensory pathway spiking and shows how hindbrain sensory memory populations on each side can compete to initiate reticulospinal neuron firing and start swimming. The 3-D “Virtual Tadpole” (VT) biomechanical model with realistic muscle innervation, body flexion, body-water interaction, and movement is then used to evaluate if motor nerve outputs from the CNS model can produce swimming-like movements in a volume of “water”. We find that the whole tadpole VT model generates reliable and realistic swimming. Combining these two models opens new perspectives for experiments.