Premature recruitment of oocyte pool and increased mTOR activity in Fmr1 knockout mice and reversal of phenotype with rapamycin.

While mutations in the fragile X mental retardation-1 (FMR1) gene are associated with varying reproductive outcomes in females, the effects of a complete lack of FMR1 expression are not known. Here, we studied the ovarian and reproductive phenotypes in an Fmr1 knockout (KO) mouse model and the role of mammalian target of rapamycin (mTOR) signaling. Breeding, histologic and mTOR signaling data were obtained at multiple time points in KO and wild type (WT) mice fed a control or rapamycin (mTOR inhibitor) diet. KO mice showed an earlier decline in ovarian reserve than WT mice with an increased proportion of activated follicles. mTOR and phosphorylated S6 kinase (p-S6K) levels, a measure of downstream mTOR signaling, were elevated in the KO ovaries. Rapamycin blocked these effects in KO mice, and increased the primordial follicle pool and age of last litter in WT mice. Our data demonstrates an early decline in reproductive capacity in Fmr1 KO mice and proposes that premature recruitment of the primordial pool via altered mTOR signaling may be the mechanism. Reversal of phenotypes and protein levels in rapamycin-treated KO mice, as well as increased reproductive lifespan of rapamycin-fed WT mice, suggest the mTOR pathway as a potential therapeutic target

Gravitational wave astrophysics, data analysis and multimessenger astronomy

This paper reviews gravitational wave sources and their detection. One of the most exciting potential sources of gravitational waves are coalescing binary black hole systems. They can occur on all mass scales and be formed in numerous ways, many of which are not understood. They are generally invisible in electromagnetic waves, and they provide opportunities for deep investigation of Einstein's general theory of relativity. Sect. 1 of this paper considers ways that binary black holes can be created in the universe, and includes the prediction that binary black hole coalescence events are likely to be the first gravitational wave sources to be detected. The next parts of this paper address the detection of chirp waveforms from coalescence events in noisy data. Such analysis is computationally intensive. Sect. 2 reviews a new and powerful method of signal detection based on the GPU-implemented summed parallel infinite impulse response filters. Such filters are intrinsically real time alorithms, that can be used to rapidly detect and localise signals. Sect. 3 of the paper reviews the use of GPU processors for rapid searching for gravitational wave bursts that can arise from black hole births and coalescences. In sect. 4 the use of GPU processors to enable fast efficient statistical significance testing of gravitational wave event candidates is reviewed. Sect. 5 of this paper addresses the method of multimessenger astronomy where the discovery of electromagnetic counterparts of gravitational wave events can be used to identify sources, understand their nature and obtain much greater science outcomes from each identified event

Design and performance of a compact and stationary microSPECT system

Purpose: Over the last ten years, there has been an extensive growth in the development of microSPECT imagers. Most of the systems are based on the combination of conventional, relatively large gamma cameras with poor intrinsic spatial resolution and multipinhole collimators working in large magnification mode. Spatial resolutions range from 0.58 to 0.76 mm while peak sensitivities vary from 0.06% to 0.4%. While pushing the limits of performance is of major importance, the authors believe that there is a need for smaller and less complex systems that bring along a reduced cost. While low footprint and low-cost systems can make microSPECT available to more researchers, the ease of operation and calibration and low maintenance cost are additional factors that can facilitate the use of microSPECT in molecular imaging. In this paper, the authors simulate the performance of a microSPECT imager that combines high space-bandwidth detectors and pinholes with truncated projection, resulting in a small and stationary system. Methods: A system optimization algorithm is used to determine the optimal SPECT systems, given our high resolutions detectors and a fixed field-of-view. These optimal system geometries are then used to simulate a Defrise disk phantom and a hot rod phantom. Finally, a MOBY mouse phantom, with realistic concentrations of Tc99m-tetrofosmin is simulated. Results: Results show that the authors can successfully reconstruct a Defrise disk phantom of 24 mm in diameter without any rotating system components or translation of the object. Reconstructed spatial resolution is approximately 800 mu m while the peak sensitivity is 0.23%. Finally, the simulation of the MOBY mouse phantom shows that the authors can accurately reconstruct mouse images. Conclusions: These results show that pinholes with truncated projections can be used in small magnification or minification mode to obtain a compact and stationary microSPECT system. The authors showed that they can reach state-of-the-art system performance and can successfully reconstruct images with realistic noise levels in a preclinical context. Such a system can be useful for dynamic SPECT imaging. 2013 American Association of Physicists in Medicine

Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages

Genetic depletion of macrophages in Polyoma Middle T oncoprotein (PyMT)‐induced mammary tumors in mice delayed the angiogenic switch and the progression to malignancy. To determine whether vascular endothelial growth factor A (VEGF‐A) produced by tumor‐associated macrophages regulated the onset of the angiogenic switch, a genetic approach was used to restore expression of VEGF‐A into tumors at the benign stages. This stimulated formation of a high‐density vessel network and in macrophage‐depleted mice, was followed by accelerated tumor progression. The expression of VEGF‐A led to a massive infiltration into the tumor of leukocytes that were mostly macrophages. This study suggests that macrophage‐produced VEGF regulates malignant progression through stimulating tumor angiogenesis, leukocytic infiltration and tumor cell invasion

A targeted gene panel that covers coding, non-coding and short tandem repeat regions improves the diagnosis of patients with neurodegenerative diseases

Genetic testing for neurodegenerative diseases (NDs) is highly challenging because of genetic heterogeneity and overlapping manifestations. Targeted-gene panels (TGPs), coupled with next-generation sequencing (NGS), can facilitate the profiling of a large repertoire of ND-related genes. Due to the technical limitations inherent in NGS and TGPs, short tandem repeat (STR) variations are often ignored. However, STR expansions are known to cause such NDs as Huntington\u27s disease and spinocerebellar ataxias type 3 (SCA3). Here, we studied the clinical utility of a custom-made TGP that targets 199 NDs and 311 ND-associated genes on 118 undiagnosed patients. At least one known or likely pathogenic variation was found in 54 patients; 27 patients demonstrated clinical profiles that matched the variants; and 16 patients whose original diagnosis were refined. A high concordance of variant calling were observed when comparing the results from TGP and whole-exome sequencing of four patients. Our in-house STR detection algorithm has reached a specificity of 0.88 and a sensitivity of 0.82 in our SCA3 cohort. This study also uncovered a trove of novel and recurrent variants that may enrich the repertoire of ND-related genetic markers. We propose that a combined comprehensive TGPs-bioinformatics pipeline can improve the clinical diagnosis of NDs

A Method for Data-Driven Simulations of Evolving Solar Active Regions

We present a method for performing data-driven simulations of solar active region formation and evolution. The approach is based on magnetofriction, which evolves the induction equation assuming the plasma velocity is proportional to the Lorentz force. The simulations of active region coronal field are driven by temporal sequences of photospheric magnetograms from the Helioseismic Magnetic Imager (HMI) instrument onboard the Solar Dynamics Observatory (SDO). Under certain conditions, the data-driven simulations produce flux ropes that are ejected from the modeled active region due to loss of equilibrium. Following the ejection of flux ropes, we find an enhancement of the photospheric horizontal field near the polarity inversion line. We also present a method for the synthesis of mock coronal images based on a proxy emissivity calculated from the current density distribution in the model. This method yields mock coronal images that are somewhat reminiscent of images of active regions taken by instruments such as SDO's Atmospheric Imaging Assembly (AIA) at extreme ultraviolet wavelengths.Comment: Accepted to ApJ; comments/questions related to this article are welcome via e-mail, even after publicatio

Mozart K.448 listening decreased seizure recurrence and epileptiform discharges in children with first unprovoked seizures: a randomized controlled study

BACKGROUND: Increasing numbers of reports show the beneficial effects of listening to Mozart music in decreasing epileptiform discharges as well as seizure frequency in epileptic children. There has been no effective method to reduce seizure recurrence after the first unprovoked seizure until now. In this study, we investigated the effect of listening to Mozart K.448 in reducing the seizure recurrence rate in children with first unprovoked seizures. METHODS: Forty-eight children who experienced their first unprovoked seizure with epileptiform discharges were included in the study. They were randomly placed into treatment (n = 24) and control (n = 24) groups. Children in the treatment group listened to Mozart K.448 daily before bedtime for at least six months. Two patients in the treatment group were excluded from analysis due to discontinuation intervention. Finally, forty-six patients were analyzed. Most of these patients (89.1%) were idiopathic in etiology. Seizure recurrence rates and reduction of epileptiform discharges were compared. RESULTS: The average follow-up durations in the treatment and control groups were 18.6 ± 6.6 and 20.1 ± 5.1 months, respectively. The seizure recurrence rate was estimated to be significantly lower in the treatment group than the control group over 24 months (37.2% vs. 76.8%, p = 0.0109). Significant decreases in epileptiform discharges were also observed after 1, 2, and 6 months of listening to Mozart K.448 when compared with EEGs before listening to music. There were no significant differences in gender, mentality, seizure type, and etiology between the recurrence and non-recurrence groups. CONCLUSIONS: Although the case number was limited and control music was not performed in this study, the study revealed that listening to Mozart K.448 reduced the seizure recurrence rate and epileptiform discharges in children with first unprovoked seizures, especially of idiopathic etiology. We believe that Mozart K.448 could be a promising alternative treatment in patients with first unprovoked seizures and abnormal EEGs. Further large-scaled study should be conducted to confirm the effect. TRIAL REGISTRATION: NCT01892605, date: June-19-201

Characterization of the Fiber Connectivity Profile of the Cerebral Cortex in Schizotypal Personality Disorder: A Pilot Study

Schizotypal personality disorder (SPD) is considered one of the classic disconnection syndromes. However, the specific cortical disconnectivity pattern has not been fully investigated. In this study, we aimed to explore significant alterations in whole-cortex structural connectivity in SPD individuals (SPDs) by combining the techniques of brain surface morphometry and white matter (WM) tractography. Diffusion and structural MR data were collected from twenty subjects with SPD (all males; age, 19.7 ± 0.9 yrs) and eighteen healthy controls (all males; age, 20.3 ± 1.0 yrs). To measure the structural connectivity for a given unit area of the cortex, the fiber connectivity density (FiCD) value was proposed and calculated as the sum of the fractional anisotropy of all the fibers connecting to that unit area in tractography. Then, the resultant whole-cortex FiCD maps were compared in a vertex-wise manner between SPDs and controls. Compared with normal controls, SPDs showed significantly decreased FiCD in the rostral middle frontal gyrus (crossing BA9 and BA10) and significantly increased FiCD in the anterior part of the fusiform/inferior temporal cortex (P < 0.05, Monte Carlo simulation corrected). Moreover, the gray matter volume extracted from the left rostral middle frontal cluster was observed to be significantly greater in the SPD group (P = 0.02). Overall, this study identifies a decrease in connectivity in the left middle frontal cortex as a key neural deficit at the whole-cortex level in SPD, thus providing insight into its neuropathological basis