Alternate Metabolic Programs Define Regional Variation of Relevant Biological Features in Renal Cell Carcinoma Progression

ccRCC has recently been redefined as a highly heterogeneous disease. In addition to genetic heterogeneity, the tumor displays risk variability for developing metastatic disease, therefore underscoring the urgent need for tissue-based prognostic strategies applicable to the clinical setting. We’ve recently employed the novel positron emission tomography/magnetic resonance (PET/MR) image modality to enrich our understanding of how tumor heterogeneity can relate to gene expression and tumor biology to assist in defining individualized treatment plans

Design of a pulse power supply unit for micro-ECM

Electrochemical micro-machining (μECM) requires a particular pulse power supply unit (PSU) to be developed in order to achieve desired machining performance. This paper summarises the development of a pulse PSU meeting the requirements of μECM. The pulse power supply provides tens of nanosecond pulse duration, positive and negative bias voltages and a polarity switching functionality. It fulfils the needs for tool preparation with reversed pulsed ECM on the machine. Moreover, the PSU is equipped with an ultrafast overcurrent protection which prevents the tool electrode from being damaged in case of short circuits. The developed pulse PSU was used to fabricate micro-tools out of 170 μm WC-Co alloy shafts via micro-electrochemical turning and drill deep holes via μECM in a disk made of 18NiCr6. The electrolyte used for both processes was a mixture of sulphuric acid and NaNO3 aqueous solutions.The research reported in this paper is supported by the European Commission within the project “Minimizing Defects in Micro-Manufacturing Applications (MIDEMMA)” (FP7-2011-NMP-ICT-FoF-285614

Quantum-statistical transport phenomena in memristive computing architectures

The advent of reliable, nanoscale memristive components is promising for next generation compute-in-memory paradigms, however, the intrinsic variability in these devices has prevented widespread adoption. Here we show coherent electron wave functions play a pivotal role in the nanoscale transport properties of these emerging, non-volatile memories. By characterizing both filamentary and non-filamentary memristive devices as disordered Anderson systems, the switching characteristics and intrinsic variability arise directly from the universality of electron transport in disordered media. Our framework suggests localization phenomena in nanoscale, solid-state memristive systems are directly linked to circuit level performance. We discuss how quantum conductance fluctuations in the active layer set a lower bound on device variability. This finding implies there is a fundamental quantum limit on the reliability of memristive devices, and electron coherence will play a decisive role in surpassing or maintaining Moore's Law with these systems.Comment: 13 pages, 6 figure

Single-Molecule Imaging of Individual Amyloid Protein Aggregates in Human Biofluids.

The misfolding and aggregation of proteins into amyloid fibrils characterizes many neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. We report here a method, termed SAVE (single aggregate visualization by enhancement) imaging, for the ultrasensitive detection of individual amyloid fibrils and oligomers using single-molecule fluorescence microscopy. We demonstrate that this method is able to detect the presence of amyloid aggregates of α-synuclein, tau, and amyloid-β. In addition, we show that aggregates can also be identified in human cerebrospinal fluid (CSF). Significantly, we see a twofold increase in the average aggregate concentration in CSF from Parkinson's disease patients compared to age-matched controls. Taken together, we conclude that this method provides an opportunity to characterize the structural nature of amyloid aggregates in a key biofluid, and therefore has the potential to study disease progression in both animal models and humans to enhance our understanding of neurodegenerative disorders.This research study was funded in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC) and the NIHR rare disease translational research collaboration and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. We are also grateful to the Augustus Newman and Wolfson Foundations for their support. We thank the Royal Society for the University Research Fellowship of Dr. Steven F. Lee (UF120277).This is the final version of the article. It first appeared from ACS via http://dx.doi.org/10.1021/acschemneuro.5b00324

Apraxia and motor dysfunction in corticobasal syndrome

Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.   Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.   Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/2 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.   Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy

Do animal models of brain tumors replicate human peritumoral edema? a systematic literature search

Introduction Brain tumors cause morbidity and mortality in part through peritumoral brain edema. The current main treatment for peritumoral brain edema are corticosteroids. Due to the increased recognition of their side-effect profile, there is growing interest in finding alternatives to steroids but there is little formal study of animal models of peritumoral brain edema. This study aims to summarize the available literature. Methods A systematic search was undertaken of 5 literature databases (Medline, Embase, CINAHL, PubMed and the Cochrane Library). The generic strategy was to search for various terms associated with “brain tumors”, “brain edema” and “animal models”. Results We identified 603 reports, of which 112 were identified as relevant for full text analysis that studied 114 peritumoral brain edema animal models. We found significant heterogeneity in the species and strain of tumor-bearing animals, tumor implantation method and edema assessment. Most models did not produce appreciable brain edema and did not test for observable manifestations thereof. Conclusion No animal model currently exists that enable the investigation of novel candidates for the treatment of peritumoral brain edema. With current interest in alternative treatments for peritumoral brain edema, there is an unmet need for clinically relevant animal models