Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers.

The aberrant aggregation of proteins is implicated in the onset and pathogenesis of a wide range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Mounting evidence indicates that misfolded protein oligomers produced as intermediates in the aggregation process are potent neurotoxic agents in these diseases. Because of the transient and heterogeneous nature of these elusive aggregates, however, it has proven challenging to develop therapeutics that can effectively target them. Here, we review approaches aimed at reducing oligomer toxicity, including (1) modulating the oligomer populations (e.g., by altering the kinetics of aggregation by inhibiting, enhancing, or redirecting the process), (2) modulating the oligomer properties (e.g., through the size-hydrophobicity-toxicity relationship), (3) modulating the oligomer interactions (e.g., by protecting cell membranes by displacing oligomers), and (4) reducing oligomer toxicity by potentiating the protein homeostasis system. We analyze examples of these complementary approaches, which may lead to the development of compounds capable of preventing or treating neurodegenerative disorders associated with protein aggregation

Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers.

The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-β peptide (Aβ) and of α-synuclein (αS), which are associated with Alzheimer's and Parkinson's diseases. In this work, we expand our previous analyses to two squalamine derivatives, des-squalamine and α-squalamine, obtaining further insights into the mechanism by which aminosterols modulate Aβ and αS aggregation. We then characterize the ability of these small molecules to alter the physicochemical properties of stabilized oligomeric species in vitro and to suppress the toxicity of these aggregates to varying degrees toward human neuroblastoma cells. We found that, despite the fact that these aminosterols exert opposing effects on Aβ and αS aggregation under the conditions that we tested, the modifications that they induced to the toxicity of oligomers were similar. Our results indicate that the suppression of toxicity is mediated by the displacement of toxic oligomeric species from cellular membranes by the aminosterols. This study, thus, provides evidence that aminosterols could be rationally optimized in drug discovery programs to target oligomer toxicity in Alzheimer's and Parkinson's diseases

Emergent research and priorities for shark and ray conservation

Over the past 4 decades there has been a growing concern for the conservation status of elasmobranchs (sharks and rays). In 2002, the first elasmobranch species were added to Appendix II of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). Less than 20 yr later, there were 39 species on Appendix II and 5 on Appendix I. Despite growing concern, effective conservation and management remain challenged by a lack of data on population status for many species, human−wildlife interactions, threats to population viability, and the efficacy of conservation approaches. We surveyed 100 of the most frequently published and cited experts on elasmobranchs and, based on ranked responses, prioritized 20 research questions on elasmobranch conservation. To address these questions, we then convened a group of 47 experts from 35 institutions and 12 countries. The 20 questions were organized into the following broad categories: (1) status and threats, (2) population and ecology, and (3) conservation and management. For each section, we sought to synthesize existing knowledge, describe consensus or diverging views, identify gaps, and suggest promising future directions and research priorities. The resulting synthesis aggregates an array of perspectives on emergent research and priority directions for elasmobranch conservation

Transcriptome Sequencing Revealed Significant Alteration of Cortical Promoter Usage and Splicing in Schizophrenia

While hybridization based analysis of the cortical transcriptome has provided important insight into the neuropathology of schizophrenia, it represents a restricted view of disease-associated gene activity based on predetermined probes. By contrast, sequencing technology can provide un-biased analysis of transcription at nucleotide resolution. Here we use this approach to investigate schizophrenia-associated cortical gene expression.The data was generated from 76 bp reads of RNA-Seq, aligned to the reference genome and assembled into transcripts for quantification of exons, splice variants and alternative promoters in postmortem superior temporal gyrus (STG/BA22) from 9 male subjects with schizophrenia and 9 matched non-psychiatric controls. Differentially expressed genes were then subjected to further sequence and functional group analysis. The output, amounting to more than 38 Gb of sequence, revealed significant alteration of gene expression including many previously shown to be associated with schizophrenia. Gene ontology enrichment analysis followed by functional map construction identified three functional clusters highly relevant to schizophrenia including neurotransmission related functions, synaptic vesicle trafficking, and neural development. Significantly, more than 2000 genes displayed schizophrenia-associated alternative promoter usage and more than 1000 genes showed differential splicing (FDR<0.05). Both types of transcriptional isoforms were exemplified by reads aligned to the neurodevelopmentally significant doublecortin-like kinase 1 (DCLK1) gene.This study provided the first deep and un-biased analysis of schizophrenia-associated transcriptional diversity within the STG, and revealed variants with important implications for the complex pathophysiology of schizophrenia

Biological Earth observation with animal sensors

Space-based tracking technology using low-cost miniature tags is now delivering data on fine-scale animal movement at near-global scale. Linked with remotely sensed environmental data, this offers a biological lens on habitat integrity and connectivity for conservation and human health; a global network of animal sentinels of environmen-tal change

Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers

The aberrant aggregation of proteins is implicated in the onset and pathogenesis of a wide range of neurodegenerative disorders, including Alzheimer&rsquo;s and Parkinson&rsquo;s diseases. Mounting evidence indicates that misfolded protein oligomers produced as intermediates in the aggregation process are potent neurotoxic agents in these diseases. Because of the transient and heterogeneous nature of these elusive aggregates, however, it has proven challenging to develop therapeutics that can effectively target them. Here, we review approaches aimed at reducing oligomer toxicity, including (1) modulating the oligomer populations (e.g., by altering the kinetics of aggregation by inhibiting, enhancing, or redirecting the process), (2) modulating the oligomer properties (e.g., through the size&ndash;hydrophobicity&ndash;toxicity relationship), (3) modulating the oligomer interactions (e.g., by protecting cell membranes by displacing oligomers), and (4) reducing oligomer toxicity by potentiating the protein homeostasis system. We analyze examples of these complementary approaches, which may lead to the development of compounds capable of preventing or treating neurodegenerative disorders associated with protein aggregation

The effects of interrupting prolonged sitting with intermittent activity on appetite sensations and subsequent food intake in preadolescent children

<div><p>Background</p><p>Short-term and long-term exposure to prolonged sitting is associated with excess food intake and weight gain in children. Interrupting prolonged sitting with low-intensity activity has been shown to not alter hunger, satiety, or food consumption in children, however it is unclear whether interrupting sitting with high-intensity activity will alter appetite regulation in children.</p><p>Purpose</p><p>The purpose of this study was to examine the acute effects of interrupting prolonged sitting with intermittent activity performed at varying intensities on hunger, satiety, prospective food consumption (PFC), and food intake in preadolescent children.</p><p>Methods</p><p>Thirty-nine children (ages 7–11 years, 54% female, 33% overweight/obese) completed four experimental conditions in random order: 8 hours of sitting interrupted with 20, 2-minute low-, moderate-, or high-intensity activity breaks or 20, 2-minute sedentary screen time breaks. Exercise intensity corresponded with 25%, 50% and 75% of heart rate reserve, respectively. Hunger, satiety, and PFC were assessed using the Visual Analog Scale, at five time points (pre- and post-breakfast, pre- and post-lunch, and pre-dinner) during each experimental condition. Dietary compensation was assessed as total caloric intake during a post-condition dinner standardized to provide 70% of estimated daily energy requirements.</p><p>Results</p><p>There was a significant effect of time on hunger, satiety, and PFC throughout each condition day (p< 0.001). There were no differences across conditions for hunger (sedentary: 4.9±0.3 cm, low: 5.0±0.3 cm, moderate: 5.1±0.3 cm, high: 5.1±0.3 cm, p>0.05), satiety (sedentary: 4.7±0.3 cm, low: 4.4±0.3 cm, moderate: 4.6±0.3 cm, high: 4.2±0.3 cm, p>0.05), and PFC (sedentary: 4.9±0.3 cm, low: 4.7±0.3 cm, moderate: 4.9±0.3 cm, high: 5.0±0.3 cm, p>0.05). There were no significant differences in post-activity food intake across conditions (sedentary: 1071.9±53.6 kcals; low: 1092.6±43.4kcals; moderate: 996.2±54.6kcals; high: 1138.7±62.8kcals, p>0.05). However, there was a significant effect of condition on energy balance (sedentary: +61.4±65.9 kcals, low: +74.9±57.6 kcals, moderate: -58.3±62.8 kcals, high: -391.2±77.9 kcals; p<0.001). There were no significant effects of weight status on hunger, satiety, PFC, post-activity food intake, and mean energy balance across conditions (all p’s>0.05).</p><p>Conclusions</p><p>Interrupting prolonged sitting with physical activity of any intensity does not alter appetite sensations and subsequent food consumption in children. These data suggest that interventions targeting prolonged sitting with high-intensity intermittent activity may be an effective strategy to increase physical activity energy expenditure without increasing food intake, allowing for a short-term energy deficit in both healthy weight and overweight/obese children. Future studies should examine the long-term effects of interrupting prolonged sitting with activity on food consumption and weight status in preadolescent children.</p></div

Ras-association domain of sorting nexin 27 is critical for regulating expression of GIRK potassium channels

G protein-gated inwardly rectifying potassium (GIRK) channels play an important role in regulating neuronal excitability. Sorting nexin 27b (SNX27b), which reduces surface expression of GIRK channels through a PDZ domain interaction, contains a putative Ras-association (RA) domain with unknown function. Deleting the RA domain in SNX27b (SNX27b-DRA) prevents the down-regulation of GIRK2c/GIRK3 channels. Similarly, a point mutation (K305A) in the RA domain disrupts regulation of GIRK2c/GIRK3 channels and reduces H-Ras binding in vitro. Finally, the dominant-negative H-Ras (S17N) occludes the SNX27b-dependent decrease in surface expression of GIRK2c/GIRK3 channels. Thus, the presence of a functional RA domain and the interaction with Ras-like G proteins comprise a novel mechanism for modulating SNX27b control of GIRK channel surface expression and cellular excitability

Mean energy balance across conditions.

<p>Asterisk denotes a significant difference between conditions. Normal weight participant data on the left, overweight/obese participant data on the right.</p