Clinicopathologic Implications of Complement Genetic Variants in Kidney Transplantation

Genetic testing has uncovered rare variants in complement proteins associated with thrombotic microangiopathy (TMA) and C3 glomerulopathy (C3G). Approximately 50% are classified as variants of uncertain significance (VUS). Clinical risk assessment of patients carrying a VUS remains challenging primarily due to a lack of functional information, especially in the context of multiple confounding factors in the setting of kidney transplantation. Our objective was to evaluate the clinicopathologic significance of genetic variants in TMA and C3G in a kidney transplant cohort. We used whole exome next-generation sequencing to analyze complement genes in 76 patients, comprising 60 patients with a TMA and 16 with C3G. Ten variants in complement factor H (CFH) were identified; of these, four were known to be pathogenic, one was likely benign and five were classified as a VUS (I372V, I453L, G918E, T956M, L1207I). Each VUS was subjected to a structural analysis and was recombinantly produced; if expressed, its function was then characterized relative to the wild-type (WT) protein. Our data indicate that I372V, I453L, and G918E were deleterious while T956M and L1207I demonstrated normal functional activity. Four common polymorphisms in CFH (E936D, N1050Y, I1059T, Q1143E) were also characterized. We also assessed a family with a pathogenic variant in membrane cofactor protein (MCP) in addition to CFH with a unique clinical presentation featuring valvular dysfunction. Our analyses helped to determine disease etiology and defined the recurrence risk after kidney transplant, thereby facilitating clinical decision making for our patients. This work further illustrates the limitations of the prediction models and highlights the importance of conducting functional analysis of genetic variants particularly in a complex clinicopathologic scenario such as kidney transplantation

Identification of wheat-Dasypyrum breviaristatum addition lines with stripe rust resistance using C-banding and genomic in situ hybridization

Older adults show more bilateral prefrontal activation during cognitive performance than younger adults, who typically show unilateral activation. This over-recruitment has been interpreted as compensation for declining structure and function of the brain. Here we examined how the relationship between behavioral performance and prefrontal activation is modulated by different levels of working-memory load. Eighteen healthy older adults (70.8 +/- 5.0 years; MMSE 29.3 +/- 0.9) performed a spatial working-memory task (n-back). Oxygenated ([O2Hb]) and deoxygenated ([HHb]) hemoglobin concentration changes were registered by two functional Near-Infrared Spectroscopy (fNIRS) channels located over the left and right prefrontal cortex. Increased working-memory load resulted in worse performance compared to the control condition. [O2Hb] increased with rising working-memory load in both fNIRS channels. Based on the performance in the high working-memory load condition, the group was divided into low and high performers. A significant interaction effect of performance level and hemisphere on [O2Hb] increase was found, indicating that high performers were better able to keep the right prefrontal cortex engaged under high cognitive demand. Furthermore, in the low performers group, individuals with a larger decline in task performance from the control to the high working-memory load condition had a larger bilateral increase of [O2Hb]. The high performers did not show a correlation between performance decline and working-memory load related prefrontal activation changes. Thus, additional bilateral prefrontal activation in low performers did not necessarily result in better cognitive performance. Our study showed that bilateral prefrontal activation may not always be successfully compensatory. Individual behavioral performance should be taken into account to be able to distinguish successful and unsuccessful compensation or declined neural efficiency

Chirped pulse Raman amplification in warm plasma: towards controlling saturation

Stimulated Raman backscattering in plasma is potentially an efficient method of amplifying laser pulses to reach exawatt powers because plasma is fully broken down and withstands extremely high electric fields. Plasma also has unique nonlinear optical properties that allow simultaneous compression of optical pulses to ultra-short durations. However, current measured efficiencies are limited to several percent. Here we investigate Raman amplification of short duration seed pulses with different chirp rates using a chirped pump pulse in a preformed plasma waveguide. We identify electron trapping and wavebreaking as the main saturation mechanisms, which lead to spectral broadening and gain saturation when the seed reaches several millijoules for durations of 10's - 100's fs for 250 ps, 800 nm chirped pump pulses. We show that this prevents access to the nonlinear regime and limits the efficiency, and interpret the experimental results using slowly-varying-amplitude, current-averaged particle-in-cell simulations. We also propose methods for achieving higher efficiencies.close0

The disposition and pharmacokinetics of Dioscorea nipponica Makino extract in rats

This study was aimed to investigate the disposition and pharmacokinetics of the total saponins of dioscorea (TSD) in rats. Male Sprague-Dawley rats were orally administrated with 3H labeled TSD at a single dose ratio of 80 mg TSD per 1 kg rat. Blood samples and feces were collected at different time points to measure the level of TSD activity. At the final time point, determination of the disposition of TSD in lung, kidney, heart, liver, adrenal, and small intestine were performed. From the blood samples' emission of radioactivity, pharmacokinetic parameters were derived as T1/2 = 33.33 ± 4.48 h, T max = 6.5 ± 0.71 h, AUC = 119400 ± 421097.67, and C max = 2643.33 ± 192.26 dpm/ml. There was 51.609% of 3H labeled substance excreted in 24 h. These results suggested that blood concentration of 3H-TSD was extremely low and the majority of TSD was excreted in the feces. The TSD was extensively distributed to multitissues. The radioactivity level was measured to be the highest in the liver, adrenal gland, and wall of the gastrointestinal tract. The radioactivity of TSD was still being detected in blood after 96 h. This showed TSD was excreted in vivo very slowly. © 2008 Academic Journals.published_or_final_versio

Remote control of a robotic hand using a leap sensor

This paper presents a low-cost gesture-based remote control of a ro-botic hand. The proposed control architecture is based on a commercial leap motion sensor and an Arduino board, which have been chosen due to their low-cost and user-friendly features. A specific Matlab code has been implemented to collect data from the leap motion sensor and to generate proper instructions to control a robotic hand, which has been 3D print at Sheffield Hallam Univer-sity. Experimental tests have been carried out validate the effectiveness of the proposed remote control for performing various grasping tasks

An alternative approach to measuring treatment persistence with antipsychotic agents among patients with schizophrenia in the Veterans Health Administration

Prior studies have demonstrated the importance of treatment persistence with anti-psychotic agents in sustaining control of schizophrenic symptoms. However, the conventional approach in measuring treatment persistence tended to use only the first prescription episode even though some patients received multiple prescriptions (or multiple treatment episodes) of the same medication within one year following the initiation of the index drug. In this study, we used data from the Veterans Health Administration in the United States to assess the extent to which patients received multiple prescriptions. The study found that about a quarter of the patients had two or more treatment episodes and that levels of treatment persistence tended to vary across treatment episodes. Based on these results, we offered an alternative approach in which we calculated treatment persistence with typical and atypical antipsychotic agents separately for patients with one, two, or three treatment episodes. Considering that patients with different number of treatment episodes might differ in disease profiles, this treatment episode-specific approach offered a fair comparison of the levels of treatment persistence across patients with different number of treatment episodes. Future research needs to extend the analyses beyond two antipsychotic classes to individual antipsychotic agents. A more comprehensive assessment using appropriate analytic methods should help physicians make prescription choices that will ultimately improve the care of patients with schizophrenia

Electronic correlations in the iron pnictides

In correlated metals derived from Mott insulators, the motion of an electron is impeded by Coulomb repulsion due to other electrons. This phenomenon causes a substantial reduction in the electron's kinetic energy leading to remarkable experimental manifestations in optical spectroscopy. The high-Tc superconducting cuprates are perhaps the most studied examples of such correlated metals. The occurrence of high-Tc superconductivity in the iron pnictides puts a spotlight on the relevance of correlation effects in these materials. Here we present an infrared and optical study on single crystals of the iron pnictide superconductor LaFePO. We find clear evidence of electronic correlations in metallic LaFePO with the kinetic energy of the electrons reduced to half of that predicted by band theory of nearly free electrons. Hallmarks of strong electronic many-body effects reported here are important because the iron pnictides expose a new pathway towards a correlated electron state that does not explicitly involve the Mott transition.Comment: 10 page

Neuroimaging Evidence of Major Morpho-Anatomical and Functional Abnormalities in the BTBR T+TF/J Mouse Model of Autism

BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations