Deletion of TRAAK Potassium Channel Affects Brain Metabolism and Protects against Ischemia

Cerebral stroke is a worldwide leading cause of disability. The two-pore domain K(+) channels identified as background channels are involved in many functions in brain under physiological and pathological conditions. We addressed the hypothesis that TRAAK, a mechano-gated and lipid-sensitive two-pore domain K(+) channel, is involved in the pathophysiology of brain ischemia. We studied the effects of TRAAK deletion on brain morphology and metabolism under physiological conditions, and during temporary focal cerebral ischemia in Traak(-/-) mice using a combination of in vivo magnetic resonance imaging (MRI) techniques and multinuclear magnetic resonance spectroscopy (MRS) methods. We provide the first in vivo evidence establishing a link between TRAAK and neurometabolism. Under physiological conditions, Traak(-/-) mice showed a particular metabolic phenotype characterized by higher levels of taurine and myo-inositol than Traak(+/+) mice. Upon ischemia, Traak(-/-) mice had a smaller infarcted volume, with lower contribution of cellular edema than Traak(+/+) mice. Moreover, brain microcirculation was less damaged, and brain metabolism and pH were preserved. Our results show that expression of TRAAK strongly influences tissue levels of organic osmolytes. Traak(-/-) mice resilience to cellular edema under ischemia appears related to their physiologically high levels of myo-inositol and of taurine, an aminoacid involved in the modulation of mitochondrial activity and cell death. The beneficial effects of TRAAK deletion designate this channel as a promising pharmacological target for the treatment against stroke

Visible camera cryostat design and performance for the SuMIRe Prime Focus Spectrograph (PFS)

We describe the design and performance of the SuMIRe Prime Focus Spectrograph (PFS) visible camera cryostats. SuMIRe PFS is a massively multi-plexed ground-based spectrograph consisting of four identical spectrograph modules, each receiving roughly 600 fibers from a 2394 fiber robotic positioner at the prime focus. Each spectrograph module has three channels covering wavelength ranges 380~nm -- 640~nm, 640~nm -- 955~nm, and 955~nm -- 1.26~um, with the dispersed light being imaged in each channel by a f/1.07 vacuum Schmidt camera. The cameras are very large, having a clear aperture of 300~mm at the entrance window, and a mass of $\sim$280~kg. In this paper we describe the design of the visible camera cryostats and discuss various aspects of cryostat performance

Responders to Wide-Pulse, High-Frequency Neuromuscular Electrical Stimulation Show Reduced Metabolic Demand: A 31P-MRS Study in Humans.

Conventional (CONV) neuromuscular electrical stimulation (NMES) (i.e., short pulse duration, low frequencies) induces a higher energetic response as compared to voluntary contractions (VOL). In contrast, wide-pulse, high-frequency (WPHF) NMES might elicit-at least in some subjects (i.e., responders)-a different motor unit recruitment compared to CONV that resembles the physiological muscle activation pattern of VOL. We therefore hypothesized that for these responder subjects, the metabolic demand of WPHF would be lower than CONV and comparable to VOL. 18 healthy subjects performed isometric plantar flexions at 10% of their maximal voluntary contraction force for CONV (25 Hz, 0.05 ms), WPHF (100 Hz, 1 ms) and VOL protocols. For each protocol, force time integral (FTI) was quantified and subjects were classified as responders and non-responders to WPHF based on k-means clustering analysis. Furthermore, a fatigue index based on FTI loss at the end of each protocol compared with the beginning of the protocol was calculated. Phosphocreatine depletion (ΔPCr) was assessed using 31P magnetic resonance spectroscopy. Responders developed four times higher FTI's during WPHF (99 ± 37 ×103 N.s) than non-responders (26 ± 12 ×103 N.s). For both responders and non-responders, CONV was metabolically more demanding than VOL when ΔPCr was expressed relative to the FTI. Only for the responder group, the ∆PCr/FTI ratio of WPHF (0.74 ± 0.19 M/N.s) was significantly lower compared to CONV (1.48 ± 0.46 M/N.s) but similar to VOL (0.65 ± 0.21 M/N.s). Moreover, the fatigue index was not different between WPHF (-16%) and CONV (-25%) for the responders. WPHF could therefore be considered as the less demanding NMES modality-at least in this subgroup of subjects-by possibly exhibiting a muscle activation pattern similar to VOL contractions

Repeatability of alkaline inorganic phosphate quantification in the skeletal muscle using 31P-magnetic resonance spectroscopy at 3 T

The detection of a secondary inorganic phosphate (Pi) resonance, a possible marker of mitochondrial content in vivo, using phosphorus magnetic resonance spectroscopy (31P-MRS), poses technical challenges at 3 Tesla (T). Overcoming these challenges is imperative for the integration of this biomarker into clinical research. To evaluate the repeatability and reliability of measuring resting skeletal muscle alkaline Pi (Pialk) using with 31P-MRS at 3 T. After an initial set of experiments on five subjects to optimize the sequence, resting 31P-MRS of the quadriceps muscles were acquired on two visits (~4 days apart) using an intra-subjects design, from 13 sedentary to moderately active young male and female adults (22 ± 3 years old) within a whole-body 3 T MR system. Measurement variability attributed to changes in coil position, shimming procedure, and spectral analysis were quantified. 31P-MRS data were acquired with a 31P/-proton (1H) dual-tuned surface coil positioned on the quadriceps using a pulse-acquire sequence. Test-retest absolute and relative repeatability was analyzed using the coefficient of variation (CV) and intra-class correlation coefficients (ICC), respectively. After sequence parameter optimization, Pialk demonstrated high intra-subject repeatability (CV: 10.6 ± 5.4%, ICC: 0.80). Proximo-distal change in coil position along the length of the quadriceps introduced Pialk quantitation variability (CV: 28 ± 5%), due to magnetic field inhomogeneity with more distal coil locations. In contrast, Pialk measurement variability due to repeated shims from the same muscle volume (0.40 ± 0.09mM; CV: 6.6%), and automated spectral processing (0.37 ± 0.01mM; CV: 2.3%), was minor. The quantification of Pialk in skeletal muscle via surface coil 31P-MRS at 3 T demonstrated excellent reproducibility. However, caution is advised against placing the coil at the distal part of the quadriceps to mitigate shimming inhomogeneity

Spectrum of Kidney Involvement in Patients with Myelodysplastic Syndromes.

Myelodysplastic syndromes (MDS) are characterized by a high prevalence of associated autoimmune manifestations. Kidney involvement has been rarely reported in MDS patients. We report on the spectrum of kidney pathological findings in MDS patients. We retrospectively identified MDS patients who had undergone a kidney biopsy between 2001 and 2019 in nine Swiss and French nephrology centres. Nineteen patients (median age 74 years [63-83]) were included. At the time of kidney biopsy, eleven (58%) patients had extra-renal auto-immune manifestations and sixteen (84%) presented with acute kidney injury. Median serum creatinine at diagnosis was 2.8 mg/dL [0.6-8.3] and median urinary protein to creatinine ratio was 1.2 g/g [0.2-11]. Acute tubulo-interstitial nephritis (TIN) was present in seven (37%) patients. Immunofluorescence study in one patient with acute TIN disclosed intense IgG deposits along the tubular basement membrane and Bowman's capsule. Other kidney pathological features included ANCA-negative pauci-immune necrotizing and crescentic glomerulonephritis (n = 3), membranous nephropathy (n = 2), IgA nephropathy (n = 1), IgA vasculitis (n = 1), immunoglobulin-associated membrano-proliferative glomerulonephritis type I (n=1), crescentic C3 glomerulopathy (n = 1), fibrillary glomerulonephritis (n = 1) and minimal change disease (n = 1). Eleven (58%) patients received immunosuppressive treatments, among whom one developed a severe infectious complication. After a median follow-up of 7 month [1-96], nine (47%) patients had chronic kidney disease stage 3 (n = 6) or 4 (n = 3) and five (26%) progressed to end-stage kidney disease. Three patients died. MDS are associated to several autoimmune kidney manifestations, predominantly acute TIN. MDS are to be listed among the potential causes of autoimmune TIN

SUBARU prime focus spectrograph: integration, testing and performance for the first spectrograph

The Prime Focus Spectrograph (PFS) of the Subaru Measurement of Images and Redshifts (SuMIRe) project for Subaru telescope consists in four identical spectrographs fed by 600 fibers each. Each spectrograph is composed by an optical entrance unit that creates a collimated beam and distributes the light to three channels, two visibles and one near infrared. This paper presents the on-going effort for the tests & integration process for the first spectrograph channel: we have developed a detailed Assembly Integration and Test (AIT) plan, as well as the methods, detailed processes and I&T tools. We describe the tools we designed to assemble the parts and to test the performance of the spectrograph. We also report on the thermal acceptance tests we performed on the first visible camera unit. We also report on and discuss the technical difficulties that did appear during this integration phase. Finally, we detail the important logistic process that is require to transport the components from other country to Marseille

Metabolic counterparts of sodium accumulation in multiple sclerosis: A whole brain 23Na-MRI and fast 1H-MRSI study

Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet. To determine in vivo the metabolic counterpart of brain sodium accumulation. Whole brain Na-MR imaging and 3D- H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models. MS patients showed significant Na accumulations with lower choline and glutamate-glutamine (Glx) levels in GM; Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher Na, m-Ins levels with lower NAA in WM T lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T lesions. GM Glx levels were associated with clinical scores. Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores

The ambivalent shadow of the pre-Wilsonian rise of international law

The generation of American international lawyers who founded the American Society of International Law in 1906 and nurtured the soil for what has been retrospectively called a “moralistic legalistic approach to international relations” remains little studied. A survey of the rise of international legal literature in the U.S. from the mid-19th century to the eve of the Great War serves as a backdrop to the examination of the boosting effect on international law of the Spanish American War in 1898. An examination of the Insular Cases before the US Supreme Court is then accompanied by the analysis of a number of influential factors behind the pre-war rise of international law in the U.S. The work concludes with an examination of the rise of natural law doctrines in international law during the interwar period and the critiques addressed.by the realist founders of the field of “international relations” to the “moralistic legalistic approach to international relation

The 18 kDa Translocator Protein (Peripheral Benzodiazepine Receptor) Expression in the Bone of Normal, Osteoprotegerin or Low Calcium Diet Treated Mice

The presence of the translocator protein (TSPO), previously named as the mitochondrial or peripheral benzodiazepine receptor, in bone cells was studied in vitro and in situ using RT-qPCR, and receptor autoradiography using the selective TSPO ligand PK11195