Maintenance of Synaptic Stability Requires Calcium-Independent Phospholipase A2 Activity

Phospholipases A2 (PLA2s) represent one of the largest groups of lipid-modifying enzymes. Over the years, significant advances have been made in understanding their potential physiological and pathological functions. Depending on their calcium requirement for activation, PLA2s are classified into calcium dependent and independent. This paper mainly focuses on brain calcium-independent PLA2 (iPLA2) and on the mechanisms by which they influence neuronal function and regulate synaptic plasticity. Particular attention will be given to the iPLA2γ isoform and its role in the regulation of synaptic glutamate receptors. In particular, the paper discusses the possibility that brain iPLA2γ deficiencies could destabilise normal synaptic operation and might contribute to the aetiology of some brain disorders. In this line, the paper presents new data indicating that iPLA2γ deficiencies accentuate AMPA receptor destabilization and tau phosphorylation, which suggests that this iPLA2 isoform should be considered as a potential target for the treatment of Tau-related disorders

Revisiting the calpain hypothesis of learning and memory 40 years later

In 1984, Gary Lynch and Michel Baudry published in Science a novel biochemical hypothesis for learning and memory, in which they postulated that the calcium-dependent protease, calpain, played a critical role in regulating synaptic properties and the distribution of glutamate receptors, thereby participating in memory formation in hippocampus. Over the following 40 years, much work has been done to refine this hypothesis and to provide convincing arguments supporting what was viewed at the time as a simplistic view of synaptic biochemistry. We have now demonstrated that the two major calpain isoforms in the brain, calpain-1 and calpain-2, execute opposite functions in both synaptic plasticity/learning and memory and in neuroprotection/neurodegeneration. Thus, calpain-1 activation is required for triggering long-term potentiation (LTP) of synaptic transmission and learning of episodic memory, while calpain-2 activation limits the magnitude of LTP and the extent of learning. On the other hand, calpain-1 is neuroprotective while calpain-2 is neurodegenerative, and its prolonged activation following various types of brain insults leads to neurodegeneration. The signaling pathways responsible for these functions have been identified and involve local protein synthesis, cytoskeletal regulation, and regulation of glutamate receptors. Human families with mutations in calpain-1 have been reported to have impairment in motor and cognitive functions. Selective calpain-2 inhibitors have been synthesized and clinical studies to test their potential use to treat disorders associated with acute neuronal damage, such as traumatic brain injury, are being planned. This review will illustrate the long and difficult journey to validate a bold hypothesis

Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation

Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC) disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) and murine double minute (Mdm2) E3 ligase. Growth cone collapse induced by genetic (npc1−/−) or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK)-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1−/− mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Reliability-Based Design Optimization for Crane Metallic Structure Using ACO and AFOSM Based on China Standards

The design optimization of crane metallic structures is of great significance in reducing their weight and cost. Although it is known that uncertainties in the loads, geometry, dimensions, and materials of crane metallic structures are inherent and inevitable and that deterministic structural optimization can lead to an unreliable structure in practical applications, little amount of research on these factors has been reported. This paper considers a sensitivity analysis of uncertain variables and constructs a reliability-based design optimization model of an overhead traveling crane metallic structure. An advanced first-order second-moment method is used to calculate the reliability indices of probabilistic constraints at each design point. An effective ant colony optimization with a mutation local search is developed to achieve the global optimal solution. By applying our reliability-based design optimization to a realistic crane structure, we demonstrate that, compared with the practical design and the deterministic design optimization, the proposed method could find the lighter structure weight while satisfying the deterministic and probabilistic stress, deflection, and stiffness constraints and is therefore both feasible and effective

Contextual fear memory impairment in Angelman syndrome model mice is associated with altered transcriptional responses

Abstract Angelman syndrome (AS) is a rare neurogenetic disorder caused by UBE3A deficiency and characterized by severe developmental delay, cognitive impairment, and motor dysfunction. In the present study, we performed RNA-seq on hippocampal samples from both wildtype (WT) and AS male mice, with or without contextual fear memory recall. There were 281 recall-associated differentially expressed genes (DEGs) in WT mice and 268 DEGs in AS mice, with 129 shared by the two genotypes. Gene ontology analysis showed that extracellular matrix and stimulation-induced response genes were prominently enriched in recall-associated DEGs in WT mice, while nuclear acid metabolism and tissue development genes were highly enriched in those from AS mice. Further analyses showed that the 129 shared DEGs belonged to nuclear acid metabolism and tissue development genes. Unique recall DEGs in WT mice were enriched in biological processes critical for synaptic plasticity and learning and memory, including the extracellular matrix network clustered around fibronectin 1 and collagens. In contrast, AS-specific DEGs were not enriched in any known pathways. These results suggest that memory recall in AS mice, while altering the transcriptome, fails to recruit memory-associated transcriptional programs, which could be responsible for the memory impairment in AS mice

Stability Reinforcement of Slopes Using Vegetation Considering the Existence of Soft Rock

This study investigates the effectiveness of vegetation reinforcement on the stability of a slope with red-bed soft rock in a slope along the Xining-Chengdu railway, China. Four kinds of vegetation were considered to reinforce the soil and the slope. The rooted soil parameters were determined based on the laboratory tests. A numerical model was developed based on the actual geometry and soil layer distributions. The soils were modeled as elastic perfectly plastic materials and the vegetation reinforcement was represented as addition cohesion of a series of subsoil layers within a given depth. The effectiveness of vegetation on slope reinforcement under both dry and rainfall conditions was investigated regarding this case. The potential failure surface and corresponding factor of safety of the red-bed soft rock slope for those different conditions were analyzed and compared. It has been found that the addition of vegetation increased the safety of slope stability whether the slope is under a dry condition or a rainfall condition, while the increasing proportion of factor of safety due to vegetation reinforcement for this case is very limited. The results and findings in this study are still significant for the practitioner to evaluate the reasonability of vegetation reinforcement

Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death

Calpains are a family of soluble calcium-dependent proteases that are involved in multiple regulatory pathways. Our laboratory has focused on the understanding of the functions of two ubiquitous calpain isoforms, calpain-1 and calpain-2, in the brain. Results obtained over the last 30 years led to the remarkable conclusion that these two calpain isoforms exhibit opposite functions in the brain. Calpain-1 activation is required for certain forms of synaptic plasticity and corresponding types of learning and memory, while calpain-2 activation limits the extent of plasticity and learning. Calpain-1 is neuroprotective both during postnatal development and in adulthood, while calpain-2 is neurodegenerative. Several key protein targets participating in these opposite functions have been identified and linked to known pathways involved in synaptic plasticity and neuroprotection/neurodegeneration. We have proposed the hypothesis that the existence of different PDZ (PSD-95, DLG and ZO-1) binding domains in the C-terminal of calpain-1 and calpain-2 is responsible for their association with different signaling pathways and thereby their different functions. Results with calpain-2 knock-out mice or with mice treated with a selective calpain-2 inhibitor indicate that calpain-2 is a potential therapeutic target in various forms of neurodegeneration, including traumatic brain injury and repeated concussions