Crystal Structures of Human Pyridoxal Kinase in Complex with the Neurotoxins, Ginkgotoxin and Theophylline: Insights into Pyridoxal Kinase Inhibition

Several drugs and natural compounds are known to be highly neurotoxic, triggering epileptic convulsions or seizures, and causing headaches, agitations, as well as other neuronal symptoms. The neurotoxic effects of some of these compounds, including theophylline and ginkgotoxin, have been traced to their inhibitory activity against human pyridoxal kinase (hPL kinase), resulting in deficiency of the active cofactor form of vitamin B6, pyridoxal 5′-phosphate (PLP). Pyridoxal (PL), an inactive form of vitamin B6 is converted to PLP by PL kinase. PLP is the B6 vitamer required as a cofactor for over 160 enzymatic activities essential in primary and secondary metabolism. We have performed structural and kinetic studies on hPL kinase with several potential inhibitors, including ginkgotoxin and theophylline. The structural studies show ginkgotoxin and theophylline bound at the substrate site, and are involved in similar protein interactions as the natural substrate, PL. Interestingly, the phosphorylated product of ginkgotoxin is also observed bound at the active site. This work provides insights into the molecular basis of hPL kinase inhibition and may provide a working hypothesis to quickly screen or identify neurotoxic drugs as potential hPL kinase inhibitors. Such adverse effects may be prevented by administration of an appropriate form of vitamin B6, or provide clues of how to modify these drugs to help reduce their hPL kinase inhibitory effects

Variations in plant richness, biogeographical composition, and life forms along an elevational gradient in a mediterranean mountain

Despite the increasing interest in elevational patterns in biodiversity, few studies have investigated variations in life forms and biogeographical composition, especially in the Mediterranean biome. We investigated elevational patterns in species richness, biogeographical composition (chorotypes) and life forms (Raunkiaer classification) along an elevational gradient in a Mediterranean mountain (Central Italy). We found a general hump‐shaped pattern of species richness, which can be explained by harsher conditions at the lowest and highest elevations. This pattern is distinctly related to prevalence at mid elevations of species with European and Euro‐Asiatic distribution, which are favored by a temperate climate. Phanerophytes and geophytes (which are mainly associated with woods) were concentrated at mid elevations where woodlands prevail. Hemicrypto-phytes increased with elevation, consistently with their ability to cope with high altitude climatic conditions. Mediterranean species declined with elevation because they are negatively affected by decreasing temperatures. Chamaephytes showed a U‐shaped pattern, suggesting they are able to cope with arid and cold conditions at the extremes of the gradient. Endemics increased with elevation because of their association with mountainous areas as key places for endemism evolution. These results illustrate how elevational patterns in species richness, biogeographical composition and life forms are interrelated and demonstrate reciprocal insights for understanding current vegetation settings

Fine-scale vegetation characteristics drive insect ensemble structures in a desert ecosystem: The tenebrionid beetles (coleoptera: Tenebrionidae) inhabiting the ulan buh desert (inner mongolia, china)

In community ecology, ensembles are defined as phylogenetically bounded groups of species that use a similar set of resources within a community. Tenebrionids are a conspicuous faunal component of Asian deserts, but little is known about their community ecology. We investigated if tenebrionids associated with different plant species constitute ensembles with a different ecological structure. Sampling was done with pitfall traps placed beneath the most common plant species. Tenebrionid abundance patterns were modelled by fitting rank–abundance plots. The association between tenebrionid species and plant species was tested using contingency tables. Differences in ensemble diversity were investigated by diversity profiles. All ensembles were fitted by the geometric series model. Tenebrionid species were differently associated with different plant species. Diversity profiles indicate that different ensembles have different diversity patterns, because of differences in species relative abundance. Tenebrionids form different ensembles associated with the different dominant plant species. All these ensembles are, however, characterized by similar patterns of dominance, following the “niche pre-emption” model, and a steep decline in the diversity profiles. This indicates that similar environmental conditions lead to similar insect ensemble organization, although the most abundant species may vary, which suggests a role for microhabitat selection

Carabid community stability is enhanced by carabid diversity but reduced by aridity in Chinese steppes

Carabids (Coleoptera, Carabidae) are an important arthropod component of grassland ecosystems, where they are involved in many important ecosystem services. Grasslands are the most widespread ecosystems in China, where they are under increasing degradation that turn productive grasslands into desert. We studied the relationships between carabid community stability and various community parameters (richness, diversity, dominance, evenness, and proportion of the most dominant species) in three types of steppes characterized by a different degree of aridity (desert, typical and meadow) in northern China. Carabid community stability was lowest in the most arid environment (i.e. the desert steppe). In the less arid steppe (i.e. the meadow steppe) stability was correlated positively with richness, diversity, and equitability, and negatively with dominance and proportion of the most abundant species. This supports the diversity hypothesis (i.e. that high levels diversity lead to higher levels of stability, possibly by increasing niche complementation) and falsifies the mass ratio hypothesis (i.e. that ecosystem processes, and hence their stability, are strongly influenced by the most dominant species). Current transformation of productive grasslands into arid lands will reduce carabid community stability and this might compromise ecosystem functioning even at moderate levels of degradation, as observed in the typical steppe

Novel insights on GM1 and Parkinson's disease: A critical review

GM1 is a crucial component of neuronal membrane residing both in the soma and nerve terminals. As reported in Parkinson’s disease patients, the reduction of GM1 determines the failure of fundamental functional processes leading to cumulative cell distress up to neuron death. This review reports on the role of GM1 in the pathogenesis of the disease, illustrating the current data available but also hypotheses on the additional mechanisms in which GM1 could be involved and which require further study. In the manuscript we discuss these points trying to explain the role of diminished content of brain GM1, particularly in the nigro-striatal system, in Parkinson’s disease etiology and progression

PET imaging of putative microglial activation in individuals at ultra-high risk for psychosis, recently diagnosed and chronically ill with schizophrenia

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.M A Di Biase, A Zalesky, G O'keefe, L Laskaris, B T Baune, C S Weickert, J Olver, P D McGorry, G P Amminger, B Nelson, A M Scott, I Hickie, R Banati, F Turkheimer, M Yaqub, I P Everall, C Pantelis and V Crople

GM1 Ganglioside Is A Key Factor in Maintaining the Mammalian Neuronal Functions Avoiding Neurodegeneration

Many species of ganglioside GM1, differing for the sialic acid and ceramide content, have been characterized and their physico\u2010chemical properties have been studied in detail since 1963. Scientists were immediately attracted to the GM1 molecule and have carried on an ever\u2010increasing number of studies to understand its binding properties and its neurotrophic and neuroprotective role. GM1 displays a well balanced amphiphilic behavior that allows to establish strong both hydrophobic and hydrophilic interactions. The peculiar structure of GM1 reduces the fluidity of the plasma membrane which implies a retention and enrichment of the ganglioside in specific membrane domains called lipid rafts. The dynamism of the GM1 oligosaccharide head allows it to assume different conformations and, in this way, to interact through hydrogen or ionic bonds with a wide range of membrane receptors as well as with extracellular ligands. After more than 60 years of studies, it is a milestone that GM1 is one of the main actors in determining the neuronal functions that allows humans to have an intellectual life. The progressive reduction of its biosynthesis along the lifespan is being considered as one of the causes underlying neuronal loss in aged people and severe neuronal decline in neurodegenerative diseases. In this review, we report on the main knowledge on ganglioside GM1, with an emphasis on the recent discoveries about its bioactive component

Per-Pixel Forest Attribute Mapping and Error Estimation: The Google Earth Engine and R dataDriven Tool

Remote sensing products are typically assessed using a single accuracy estimate for the entire map, despite significant variations in accuracy across different map areas or classes. Estimating per-pixel uncertainty is a major challenge for enhancing the usability and potential of remote sensing products. This paper introduces the dataDriven open access tool, a novel statistical design-based approach that specifically addresses this issue by estimating per-pixel uncertainty through a bootstrap resampling procedure. Leveraging Sentinel-2 remote sensing data as auxiliary information, the capabilities of the Google Earth Engine cloud computing platform, and the R programming language, dataDriven can be applied in any world region and variables of interest. In this study, the dataDriven tool was tested in the Rincine forest estate study area—eastern Tuscany, Italy—focusing on volume density as the variable of interest. The average volume density was 0.042, corresponding to 420 m3 per hectare. The estimated pixel errors ranged between 93 m3 and 979 m3 per hectare and were 285 m3 per hectare on average. The ability to produce error estimates for each pixel in the map is a novel aspect in the context of the current advances in remote sensing and forest monitoring and assessment. It constitutes a significant support in forest management applications and also a powerful communication tool since it informs users about areas where map estimates are unreliable, at the same time highlighting the areas where the information provided via the map is more trustworthy. In light of this, the dataDriven tool aims to support researchers and practitioners in the spatially exhaustive use of remote sensing-derived products and map validation

Polyphase folding at upper structural levels in the Borbera valley (Northern Apennines, Italy): implications for the tectonic evolution of the linkage area between Alps and Apennines

The Borbera Valley (northwestern Italy) is located in a complex geological area where the linkage between Alps and Apennines occurs. In this area the Antola Unit (Late Cretaceous–Palaeocene) is unconformably overlain by the Upper Eocene–Miocene succession of the Tertiary Piedmont Basin. The structural analysis indicates the occurrence of a folding phase of Late Oligocene–Early Miocene age, characterised by recumbent F2 folds. These folds are superposed onto D1 structures related to an early folding phase of Middle Eocene, affecting only the Antola Unit. The occurrence of map-scale D2 folding phase structures that affect the Tertiary Piedmont Basin succession suggests that the linkage area between Alps and Apennines was reactivated during the Late Oligocene–Early Miocene

Cardiovascular health in migrants: current status and issues for prevention. A collaborative multidisciplinary task force report.

OBJECTIVES: To review information on cardiovascular health and migration, to stress the attention of researchers that much needs to be done in the collection of sound data in Italy and to allow policy makers identifying this issue as an important public health concern. BACKGROUND: In Italy, the rate of immigrants in the total number of residents increased from 2.5% in 1990 to 7.4% in 2010, and currently exceeds 10% in regions such as Lombardia, Emilia Romagna and Toscana. METHODS: A consensus statement was developed by approaching relevant Italian national scientific societies involved in cardiovascular prevention. Task force members were identified by the president and/or the boards of each relevant scientific society or working group, as appropriate. To obtain a widespread consensus, drafts were merged and distributed to the scientific societies for local evaluation and revision by as many experts as possible. The ensuing final draft was finally approved by scientific societies. RESULTS: In several western European countries, the prevalence of hypertension, diabetes, chronic kidney disease, obesity and metabolic syndrome was found to be higher among immigrants than in the native population. Although migrants are often initially healthier than non-migrant populations in their host countries, genetic factors, and changing environments with lifestyle changes, social exclusion and insufficient medical control may expose them to health challenges. Cultural reasons may also hamper both the dissemination of prevention strategies and migrant communication with healthcare providers. However, great diversity exists across and within different groups of migrants, making generalizations very difficult and many countries do not collect registry or survey data for migrant's health. CONCLUSIONS: In the present economic context, the European Union is placing great attention to improve data collection for migrant health and to support the implementation of specific prevention policies aimed at limiting the future burden of cardiovascular and renal disease, and the consequent load for health systems. Wider initiatives on the topic are awaited in Italy