Assessing reconstruction techniques of the Atlantic Ocean circulation variability during the last millennium

We assess the use of the meridional thermal-wind transport estimated from zonal density gradients to reconstruct the oceanic circulation variability during the last millennium in a forced simulation with the ECHO-G coupled climate model. Following a perfect-model approach, model-based pseudo-reconstructions of the Atlantic meridional overturning circulation (AMOC) and the Florida Current volume transport (FCT) are evaluated against their true simulated variability. The pseudo-FCT is additionally verified as proxy for AMOC strength and compared with the available proxy-based reconstruction. The thermal-wind component reproduces most of the simulated AMOC variability, which is mostly driven by internal climate dynamics during the preindustrial period and by increasing greenhouse gases afterwards. The pseudo-reconstructed FCT reproduces well the simulated FCT and reasonably well the variability of the AMOC strength, including the response to external forcing. The pseudo-reconstructed FCT, however, underestimates/overestimates the simulated variability at deep/shallow levels. Density changes responsible for the pseudo-reconstructed FCT are mainly driven by zonal temperature differences; salinity differences oppose but play a minor role. These results thus support the use of the thermal-wind relationship to reconstruct the oceanic circulation past variability, in particular at multidecadal timescales. Yet model-data comparison highlights important differences between the simulated and the proxy-based FCT variability. ECHO-G simulates a prominent weakening in the North Atlantic circulation that contrasts with the reconstructed enhancement. Our model results thus do not support the reconstructed FC minimum during the Little Ice Age. This points to a failure in the reconstruction, misrepresented processes in the model, or an important role of internal ocean dynamics

Bax-Induced Apoptosis in Leber's Congenital Amaurosis: A Dual Role in Rod and Cone Degeneration

Pathogenesis in the Rpe65−/− mouse model of Leber's congenital amaurosis (LCA) is characterized by a slow and progressive degeneration of the rod photoreceptors. On the opposite, cones degenerate rapidly at early ages. Retinal degeneration in Rpe65−/− mice, showing a null mutation in the gene encoding the retinal pigment epithelium 65-kDa protein (Rpe65), was previously reported to depend on continuous activation of a residual transduction cascade by unliganded opsin. However, the mechanisms of apoptotic signals triggered by abnormal phototransduction remain elusive. We previously reported that activation of a Bcl-2-dependent pathway was associated with apoptosis of rod photoreceptors in Rpe65−/− mice during the course of the disease. In this study we first assessed whether activation of Bcl-2-mediated apoptotic pathway was dependent on constitutive activation of the visual cascade through opsin apoprotein. We then challenged the direct role of pro-apoptotic Bax protein in triggering apoptosis of rod and cone photoreceptors

Neural Predictors of Gait Stability When Walking Freely in the Real-World.

Background: Gait impairments during real-world locomotion are common in neurological diseases. However, very little is currently known about the neural correlates of walking in the real world and on which regions of the brain are involved in regulating gait stability and performance. As a first step to understanding how neural control of gait may be impaired in neurological conditions such as Parkinson’s disease, we investigated how regional brain activation might predict walking performance in the urban environment and whilst engaging with secondary tasks in healthy subjects. Methods: We recorded gait characteristics including trunk acceleration and brain activation in fourteen healthy young subjects whilst they walked around the university campus freely (single task), while conversing with the experimenter and while texting with their smartphone. Neural spectral power density (PSD) was evaluated in three brain regions of interest, namely the pre-frontal cortex (PFC) and bilateral posterior parietal cortex (right/left PPC). We hypothesized that specific regional neural activation would predict trunk acceleration data obtained during the different walking conditions. Results: Vertical trunk acceleration was predicted by gait velocity and left PPC theta (4-7 Hz) band PSD in single-task walking (R-squared = 0.725, p = 0.001) and by gait velocity and left PPC alpha (8-12 Hz) band PSD in walking while conversing (R-squared = 0.727, p = 0.001). Medio-lateral trunk acceleration was predicted by left PPC beta (15-25 Hz) band PSD when walking while texting (R-squared = 0.434, p = 0.010). Conclusions: We suggest that the left PPC may be involved in the processes of sensorimotor integration and gait control during walking in real-world conditions. Frequency-specific coding was operative in different dual tasks and may be developed as biomarkers of gait deficits in neurological conditions during performance of these types of, now commonly undertaken, dual tasks

Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6

Adult skeletal tissue is composed of heterogeneous population of cells that constantly self-renew by means of a controlled process of activation and proliferation of tissue-resident stem cells named satellite cells. Many growth factors, cytokines and myokines produced by skeletal muscle cells play critical roles in local regulation of the inflammatory process and skeletal muscle regeneration during different pathological conditions. IL-6 is a pleiotropic cytokine released in large amount during infection, autoimmunity and cancer. Low levels of IL-6 can promote activation of satellite cells and myotube regeneration while chronically elevated production promote skeletal muscle wasting. These distinct effects may be explained by a crosstalk of the IL-6/IL-6 receptor and gp130 trans-signaling pathway that oppose to regenerative and anti-inflammatory of the classical IL-6 receptor signaling pathway. Here we discuss on potential therapeutic strategies using monoclonal antibodies to IL-6R for the treatment of skeletal muscle wasting and cachexia. We also highlight on the IL-6/JAK/STAT and FGF/p38αβ MAPK signaling pathways in satellite cell activation and the use of protein kinase inhibitors for tailoring and optimizing satellite cell proliferation during the skeletal muscle renewal. Future investigations on the roles of the IL-6 classical and trans-signaling pathways in both immune and non-immune cells in skeletal muscle tissue will provide new basis for therapeutic approaches to reverse atrophy and degeneration of skeletal muscles in cancer and inflammatory diseases

Estimating trends of Atlantic meridional overturning circulation from long-term hydrographic data and model simulations

The ocean meridional overturning circulation (MOC) plays a central role for the climate in the Atlantic realm. Since scenarios for future climate change indicate a significant reduction of the MOC under global warming, an assessment of variations and trends of the real MOC is important. Using observations at ocean weather ship (OWS) stations and along oceanic sections, we examine the hydrographic information that can be used to determine MOC trends via its signature in water mass properties obtained from model simulations with the climate model ECHAM5/MPI-OM. We show that temperature trends at mid-latitudes provide useful indirect measure of large-scale changes of deep circulation: A mid-depth warming is related to MOC weakening and a cooling to MOC strengthening. Based on our model experiments, we argue that a continuation of measurements at key OWS sites may contribute to a timely detection of a possible future MOC slowdown and to separate the signal from interannual-to-multidecadal MOC variability. The simulations suggest that the subsurface hydrographic information related to MOC has a lower variability than the MOC trend measured directly. Based on our model and the available long-term hydrographic data, we estimate non-significant MOC trends for the last 80 years. For the twenty-first century, however, the model simulations predict a significant MOC decline and accompanied mid-depth warming trend

RNAi-Mediated Gene Suppression in a GCAP1(L151F) Cone-Rod Dystrophy Mouse Model

Dominant mutations occurring in the high-affinity Ca(2+)-binding sites (EF-hands) of the GUCA1A gene encoding guanylate cyclase-activating protein 1 (GCAP1) cause slowly progressing cone-rod dystrophy (CORD) in a dozen families worldwide. We developed a nonallele-specific adeno-associated virus (AAV)-based RNAi knockdown strategy to rescue the retina degeneration caused by GCAP1 mutations. We generated three genomic transgenic mouse lines expressing wildtype (WT) and L151F mutant mouse GCAP1 with or without a C-terminal GFP fusion. Under control of endogenous regulatory elements, the transgenes were expressed specifically in mouse photoreceptors. GCAP1(L151F) and GCAP1(L151F)-GFP transgenic mice presented with a late onset and slowly progressive photoreceptor degeneration, similar to that observed in human GCAP1-CORD patients. Transgenic expression of WT GCAP1-EGFP in photoreceptors had no adverse effect. Toward therapy development, a highly effective anti-mGCAP1 shRNA, mG1hp4, was selected from four candidate shRNAs using an in-vitro screening assay. Subsequently a self-complementary (sc) AAV serotype 2/8 expressing mG1hp4 was delivered subretinally to GCAP1(L151F)-GFP transgenic mice. Knockdown of the GCAP1(L151F)-GFP transgene product was visualized by fluorescence live imaging in the scAAV2/8-mG1hp4-treated retinas. Concomitant with the mutant GCAP1-GFP fusion protein, endogenous GCAP1 decreased as well in treated retinas. We propose nonallele-specific RNAi knockdown of GCAP1 as a general therapeutic strategy to rescue any GCAP1-based dominant cone-rod dystrophy in human patients

Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration

The regenerative capacity of skeletal muscle declines with age. Previous studies suggest that this process can be reversed by exposure to young circulation, but systemic age-specific factors responsible for this phenomenon are largely unknown. Here we report that oxytocin- a hormone best known for its role in lactation, parturition, and social behaviors - is required for proper muscle tissue regeneration and homeostasis, and that plasma levels of oxytocin decline with age. Inhibition of oxytocin signaling in young animals reduces muscle regeneration, whereas systemic administration of oxytocin rapidly improves muscle regeneration by enhancing aged muscle stem cell activation/proliferation throughactivation of the MAPK/ERK signalling pathway. We further show that the genetic lack of oxytocin does not cause a developmental defect in muscle, but instead leads to premature sarcopenia. Considering that oxytocin is an FDA approved drug, this work reveals a potential novel and safe way to combat or prevent skeletal muscle aging