Assessment of the Probability of Collapse of Structures Under Earthquakes

Avoidance of collapse is the most important objective in earthquake resistant design, but assessing the probability of collapse of a structure during an earthquake is technically challenging and it is computationally demanding. This paper summarizes recent investigations conducted by the authors at Stanford University aimed at improving the assessment of the probability of collapse of structures. It is shown that methodologies based on estimating the probability of collapse at a single ground motion intensity, such as those that only evaluate the level of safety at the so called maximum considered earthquake are inadequate. Results are presented showing that estimating the probability of collapse using incremental dynamic analyses in which a model of the structure is subjected to ground motions scaled at increasing levels of intensity until collapse is produced may introduce significant bias in the results. An improved procedure, referred to as Enhanced Two Stripe Analysis, E2SA is presented which provides not only more accurate results compared to those obtained with an incremental dynamic analysis but can be obtained at a small fraction of the computational effort. The new approach is based on careful observation of the deaggregation the mean annual frequency of collapse that reveals that is typically dominated by earthquake ground motion intensities corresponding to the lower half of the collapse fragility curve. Therefore, rather than focusing on the estimation of the median collapse intensity as proposed in previous studies, the new method proposes to focus on intensities in the lower tail of the collapse fragility function. Furthermore, it is shown that the uncertainty in the collapse fragility curve and on the mean annual frequency of collapse is significantly reduced by increasing the number of ground motions used in the analysis, so instead of using a small ground motion set scaled at many increasing levels of intensity, the proposed method recommends conducting nonlinear response history analyses with a larger number of ground motions but only at two levels of intensity. Results indicate that using a larger number of ground motions at two intensity levels provides improved results. Finally, recent investigations conducted by the authors show that rather than selecting and scaling ground motions based on spectral accelerations at a period equal to the fundamental period of the structure alone or in combination with epsilon, a much better approach is to use an averaged spectral acceleration over a wide range of periods extending to periods shorter than the fundamental period to significantly longer than the fundamental period. Extensive studies conducted by the authors over a wide range of structures indicate that this new intensity measure is significantly better correlated with collapse and therefore leads to a more reliable estimation of the mean annual frequency of collapse while at the same time reducing the computational effort involved since the number of ground motions to be used in the analysis can be reduced

Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy.

Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis

p75 neurotrophin receptor regulates energy balance in obesity

Obesity and metabolic syndrome reflect the dysregulation of molecular pathways that control energy homeostasis. Here, we show that the p75 neurotrophin receptor (p75NTR) controls energy expenditure in obese mice on a high-fat diet (HFD). Despite no changes in food intake, p75NTR-null mice were protected from HFD-induced obesity and remained lean as a result of increased energy expenditure without developing insulin resistance or liver steatosis. p75NTR directly interacts with the catalytic subunit of protein kinase A (PKA) and regulates cAMP signaling in adipocytes, leading to decreased lipolysis and thermogenesis. Adipocyte-specific depletion of p75NTR or transplantation of p75NTR-null white adipose tissue (WAT) into wild-type mice fed a HFD protected against weight gain and insulin resistance. Our results reveal that signaling from p75NTR to cAMP/PKA regulates energy balance and suggest that non-CNS neurotrophin receptor signaling could be a target for treating obesity and the metabolic syndrome

In vivo imaging of the neurovascular unit in CNS disease.

The neurovascular unit-comprised of glia, pericytes, neurons and cerebrovasculature-is a dynamic interface that ensures physiological central nervous system (CNS) functioning. In disease dynamic remodeling of the neurovascular interface triggers a cascade of responses that determine the extent of CNS degeneration and repair. The dynamics of these processes can be adequately captured by imaging in vivo, which allows the study of cellular responses to environmental stimuli and cell-cell interactions in the living brain in real time. This perspective focuses on intravital imaging studies of the neurovascular unit in stroke, multiple sclerosis (MS) and Alzheimer disease (AD) models and discusses their potential for identifying novel therapeutic targets

Stable in vivo imaging of densely populated glia, axons and blood vessels in the mouse spinal cord using two-photon microscopy

In vivo imaging has revolutionized our understanding of biological processes in brain physiology and pathology. However, breathing-induced movement artifacts have impeded the application of this powerful tool in studies of the living spinal cord. Here we describe in detail a method to image stably and repetitively, using two-photon microscopy, the living spinal tissue in mice with dense fluorescent cells or axons, without the need for animal intubation or image post-processing. This simplified technique can greatly expand the application of in vivo imaging to study spinal cord injury, regeneration, physiology and disease

Systemic Inflammation Regulates Microglial Responses to Tissue Damage in Vivo

Microglia, the resident immune cells of the central nervous system, exist in either a “resting” state associated with physiological tissue surveillance or an “activated” state in neuroinflammation. We recently showed that ATP is the primary chemoattractor to tissue damage in vivo and elicits opposite effects on the motility of activated microglia in vitro through activation of adenosine A2A receptors. However, whether systemic inflammation affects microglial responses to tissue damage in vivo remains largely unknown. Using in vivo two-photon imaging of mice, we show that injection of lipopolysaccharide (LPS) at levels that can produce both clear neuroinflammation and some features of sepsis significantly reduced the rate of microglial response to laser-induced ablation injury in vivo. Under proinflammatory conditions, microglial processes initially retracted from the ablation site, but subsequently moved toward and engulfed the damaged area. Analyzing the process dynamics in 3D cultures of primary microglia indicated that only A2A, but not A1 or A3 receptors, mediate process retraction in LPS-activated microglia. The A2A receptor antagonists caffeine and preladenant reduced adenosine-mediated process retraction in activated microglia in vitro. Finally, administration of preladenant before induction of laser ablation in vivo accelerated the microglial response to injury following systemic inflammation. The regulation of rapid microglial responses to sites of injury by A2A receptors could have implications for their ability to respond to the neuronal death occurring under conditions of neuroinflammation in neurodegenerative disorders. GLIA 2014;62:1345–136

Oligodendrocyte precursors migrate along vasculature in the developing nervous system

Oligodendrocytesmyelinate axons in the central nervous system and develop fromoligodendrocyte precursor cells (OPCs) that must first migrate extensively during brain and spinal cord development.We showthat OPCs require the vasculature as a physical substrate for migration.We observed that OPCs of the embryonic mouse brain and spinal cord, as well as the human cortex, emerge from progenitor domains and associate with the abluminal endothelial surface of nearby blood vessels. Migrating OPCs crawl along and jump between vessels. OPC migration in vivo was disrupted in mice with defective vascular architecture but was normal in mice lacking pericytes. Thus, physical interactions with the vascular endothelium are required for OPC migration.We identifyWnt-Cxcr4 (chemokine receptor 4) signaling in regulation of OPC-endothelial interactions and propose that this signaling coordinates OPC migration with differentiation

Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium.

Breakthrough advances in intravital imaging have launched a new era for the study of dynamic interactions at the neurovascular interface in health and disease. The first Neurovascular and Immuno-Imaging Symposium was held at the Gladstone Institutes, University of California, San Francisco in March, 2015. This highly interactive symposium brought together a group of leading researchers who discussed how recent studies have unraveled fundamental biological mechanisms in diverse scientific fields such as neuroscience, immunology, and vascular biology, both under physiological and pathological conditions. These Proceedings highlight how advances in imaging technologies and their applications revolutionized our understanding of the communication between brain, immune, and vascular systems and identified novel targets for therapeutic intervention in neurological diseases