Voluntary wheel running preserves lumbar perineuronal nets, enhances motor functions and prevents hyperreflexia after spinal cord injury

Altres ajuts: Fundació La Marató-TV3 (TV3-201736-30-31)Perineuronal nets (PNN) are a promising candidate to harness neural plasticity since their activity-dependent modulation allows to either stabilize the circuits or increase plasticity. Modulation of plasticity is the basis of rehabilitation strategies to reduce maladaptive plasticity after spinal cord injuries (SCI). Hence, it is important to understand how spinal PNN are affected after SCI and rehabilitation. Thus, this work aims to describe functional and PNN changes after thoracic SCI in mice, followed by different activity-dependent therapies: enriched environment, voluntary wheel and forced treadmill running. We found that the contusion provoked thermal hyperalgesia, hyperreflexia and locomotor impairment as measured by thermal plantar test, H wave recordings and the BMS score of locomotion, respectively. In the spinal cord, SCI reduced PNN density around lumbar motoneurons. In contrast, activity-based therapies increased motoneuron activity and reversed PNN decrease. The voluntary wheel group showed full preservation of PNN which also correlated with reduced hyperreflexia and better locomotor recovery. Furthermore, both voluntary wheel and treadmill running reduced hyperalgesia, but this finding was independent of lumbar PNN levels. In the brainstem sensory nuclei, SCI did not modify PNN whereas some activity-based therapies reduced them. The results of the present study highlight the impact of SCI on decreasing PNN at caudal segments of the spinal cord and the potential of physical activity-based therapies to reverse PNN disaggregation and to improve functional recovery. As modulating plasticity is crucial for restoring damaged neural circuits, regulating PNN by activity is an encouraging target to improve the outcome after injury

Automating the application data placement in hybrid memory systems

Multi-tiered memory systems, such as those based on Intel® Xeon Phi™processors, are equipped with several memory tiers with different characteristics including, among others, capacity, access latency, bandwidth, energy consumption, and volatility. The proper distribution of the application data objects into the available memory layers is key to shorten the time– to–solution, but the way developers and end-users determine the most appropriate memory tier to place the application data objects has not been properly addressed to date.In this paper we present a novel methodology to build an extensible framework to automatically identify and place the application’s most relevant memory objects into the Intel Xeon Phi fast on-package memory. Our proposal works on top of inproduction binaries by first exploring the application behavior and then substituting the dynamic memory allocations. This makes this proposal valuable even for end-users who do not have the possibility of modifying the application source code. We demonstrate the value of a framework based in our methodology for several relevant HPC applications using different allocation strategies to help end-users improve performance with minimal intervention. The results of our evaluation reveal that our proposal is able to identify the key objects to be promoted into fast on-package memory in order to optimize performance, leading to even surpassing hardware-based solutions.This work has been performed in the Intel-BSC Exascale Lab. Antonio J. Peña is cofinanced by the Spanish Ministry of Economy and Competitiveness under Juan de la Cierva fellowship number IJCI-2015-23266. We would like to thank the Intel’s DCG HEAT team for allowing us to access their computational resources. We also want to acknowledge this team, especially Larry Meadows and Jason Sewall, as well as Pardo Keppel for the productive discussions. We thank Raphaël Léger for allowing us to access the MAXW-DGTD application and its input.Peer ReviewedPostprint (author's final draft

Nonmonotonic Response of Primary Production and Export to Changes in Mixed-Layer Depth in the Southern Ocean

International audienceOngoing and future changes in wind and temperature are predicted to alter upper ocean vertical mixing across the Southern Ocean. How these changes will affect primary production (PP) remains unclear as mixing influences the two controlling factors: light and iron. We used a large ensemble of 1‐D‐biogeochemical model simulations to explore the impacts of changes in mixed‐layer depths on PP in the Southern Ocean. In summer, shoaling mixed‐layer depth always reduced depth‐integrated PP, despite increasing production rates. In winter, shoaling mixed layers had a two‐staged impact: for moderate shoaling PP increased as light conditions improved, but more pronounced shoaling decreased iron supply, which reduced PP. The fraction of PP exported below 100 m also presented a nonmonotonic behavior. This suggests a potential future shift from a situation where reduced winter mixing increases PP and export, to a situation where PP and export may collapse if the ML shoals above a threshold depth

Evaluating Southern Ocean carbon eddy-pump from biogeochemical-Argo floats

The vertical transport of surface water and carbon into ocean's interior, known as subduction, is one of the main mechanisms through which the ocean influences Earth's climate. New instrumental approaches have shown the occurrence of localized and intermittent subduction episodes associated with small-scale ocean circulation features. These studies also revealed the importance of such events for the export of organic matter, the so-called eddy-pump. However, the transient and localized nature of episodic subduction hindered its large-scale evaluation to date. In this work, we present an approach to detect subduction events at the scale of the Southern Ocean using measurements collected by biogeochemical autonomous floats (BGCArgo). We show how subduction events can be automatically identified as anomalies of spiciness and Apparent Oxygen Utilization (AOU) below the mixed layer. Using this methodology over more than 4,000 profiles, we detected 40 subduction events unevenly distributed across the Sothern Ocean. Events were more likely found in hot spots of eddy kinetic energy (EKE), downstream major bathymetric features. Moreover, the bio-optical measurements provided by BGCArgo allowed measuring the amount of Particulate Organic Carbon (POC) being subducted and assessing the contribution of these events to the total downward carbon flux at 100 m (EP100). We estimated that the eddy-pump represents less than 19% to the EP100 in the Southern Ocean, although we observed particularly strong events able to locally duplicate the EP100. This approach provides a novel perspective on where episodic subduction occurs that will be naturally improved as BGCArgo observations continue to increase

Evaluating Southern Ocean carbon eddy-pump from biogeochemical-Argo floats

The vertical transport of surface water and carbon into ocean's interior, known as subduction, is one of the main mechanisms through which the ocean influences Earth's climate. New instrumental approaches have shown the occurrence of localized and intermittent subduction episodes associated with small-scale ocean circulation features. These studies also revealed the importance of such events for the export of organic matter, the so-called eddy-pump. However, the transient and localized nature of episodic subduction hindered its large-scale evaluation to date. In this work, we present an approach to detect subduction events at the scale of the Southern Ocean using measurements collected by biogeochemical autonomous floats (BGCArgo). We show how subduction events can be automatically identified as anomalies of spiciness and Apparent Oxygen Utilization (AOU) below the mixed layer. Using this methodology over more than 4,000 profiles, we detected 40 subduction events unevenly distributed across the Sothern Ocean. Events were more likely found in hot spots of eddy kinetic energy (EKE), downstream major bathymetric features. Moreover, the bio-optical measurements provided by BGCArgo allowed measuring the amount of Particulate Organic Carbon (POC) being subducted and assessing the contribution of these events to the total downward carbon flux at 100 m (EP100). We estimated that the eddy-pump represents less than 19% to the EP100 in the Southern Ocean, although we observed particularly strong events able to locally duplicate the EP100. This approach provides a novel perspective on where episodic subduction occurs that will be naturally improved as BGCArgo observations continue to increase

Physical exercise neuroprotects ovariectomized 3xTg-AD mice through BDNF mechanisms

Postmenopausal women may be more vulnerable to cognitive loss and Alzheimer's disease (AD) than premenopausal women because of their deficiency in estrogens, in addition to their usually older age. Aerobic physical exercise has been proposed as a therapeutic approach for maintaining health and well-being in postmenopausal women, and for improving brain health and plasticity in populations at high risk for AD. To study the neuroprotective mechanisms of physical exercise in a postmenopausal animal model, we submitted previously ovariectomized, six-month old non-transgenic and 3xTg-AD mice to three months of voluntary exercise in a running wheel. At nine months of age, we observed lower grip strength and some exacerbation of the behavioral and psychological symptoms of dementia (BPSD)-like involving active exploratory activities. A similar major cognitive impairment was observed of ovariectomized 3xTg-AD mice in comparison with sham-operated 3xTg-AD mice. A reduction of bodily fitness and lack of retention of memory were observed in the ovariectomized non-transgenic mice. Physical exercise protected against all deleterious behaviors and normalized learning and memory. It also protected against body frailty, as expected. Analyses of hippocampal key markers of antioxidant and neuroplasticity signaling pathways, showed that ovariectomy impairs the activation of CREB through physical exercise. Furthermore, molecular and behavioral correlates suggested a central role of BDNF in the neuroprotection mediated by physical exercise therapy against apathy and memory loss induced by ovariectomy and the AD-genotype. © 2014 Elsevier Ltd.This study was supported by grants: SAF2009-13093-C02-02, SAF2010-19498, SAF2012-39852-C02-02 and CSD2010-00045 from the Spanish MINECO; 2009/SGR/214 from the Generalitat and 062931 from the Fundació La Marató de TV3, of Catalonia; and 35NEURO GentxGent. Yoelvis García-Mesa acknowledges support received from the Fundació La Marató de TV3Peer Reviewe

The biogeochemical structure of Southern Ocean mesoscale eddies

Mesoscale eddies play a key role in modulating physical and biogeochemical properties across the global ocean. They also play a central role in cross‐frontal transport of heat, freshwater, and carbon, especially in the Southern Ocean. However, the role that eddies play in the biogeochemical cycles is not yet well constrained, partly due to a lack of observations below the surface. Here, we use hydrographic data from two voyages, conducted in the austral summer and autumn, to document the vertical biogeochemical structure of two mesoscale cyclonic eddies and quantify the role of these eddies in the meridional transport of nutrients across the Subantarctic Front. Our study demonstrates that the nutrient distribution is largely driven by eddy dynamics, yielding identical eddy structure below the mixed layer in both seasons. This result allowed us to relate nutrient content to dynamic height and estimate the average transport by eddies across the Subantarctic Front. We found that relative to Subantarctic Zone waters, long‐lived cold‐core eddies carry nitrate anomalies of 1.6±0.2×1010 moles and silicate anomalies of −5.5±0.7×1010 moles across the fronts each year. This cross‐frontal transport of nutrients has negligible impact on Subantarctic Zone productivity; however, it has potential to modify the nutrient content of mode waters that are exported from the Southern Ocean to lower latitudes

Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia : a genetic and functional study

Objective To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. Design A case-control study. Setting Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. Population We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. Methods The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. Main outcome measures Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. Results The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. Conclusions Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. Tweetable abstract Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.Peer reviewe

Neuroprotective effects of the multitarget agent AVCRI104P3 in brain of middle-aged mice

Molecular factors involved in neuroprotection are key in the design of novel multitarget drugs in aging and neurodegeneration. AVCRI104P3 is a huprine derivative that exhibits potent inhibitory effects on human AChE, BuChE, and BACE-1 activities, as well as on AChE-induced and self-induced Aβ aggregation. More recently, cognitive protection and anxiolytic-like effects have also been reported in mice treated with this compound. Now, we have assessed the ability of AVCRI104P3 (0.43 mg/kg, 21 days) to modulate the levels of some proteins involved in the anti-apoptotic/apoptotic processes (pAkt1, Bcl2, pGSK3β, p25/p35), inflammation (GFAP and Iba1) and neurogenesis in C57BL/6 mice. The effects of AVCRI104P3 on AChE-R/AChE-S isoforms have been also determined. We have observed that chronic treatment of C57BL/6 male mice with AVCRI104P3 results in neuroprotective effects, increasing significantly the levels of pAkt1 and pGSK3β in the hippocampus and Bcl2 in both hippocampus and cortex, but slightly decreasing synaptophysin levels. Astrogliosis and neurogenic markers GFAP and DCX remained unchanged after AVCRI104P3 treatment, whereas microgliosis was found to be significantly decreased pointing out the involvement of this compound in inflammatory processes. These results suggest that the neuroprotective mechanisms that are behind the cognitive and anxiolytic effects of AVCRI104P3 could be partly related to the potentiation of some anti-apoptotic and anti-inflammatory proteins and support the potential of AVCRI104P3 for the treatment of brain dysfunction associated with aging and/or dementia