Registered report: IDH mutation impairs histone demethylation and results in a block to cell differentiation

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from “IDH mutation impairs histone demethylation and results in a block to cell differentiation” by Lu and colleagues, published in Nature in 2012 (Lu et al., 2012). The experiments that will be replicated are those reported in Figures 1B, 2A, 2B, 2D and 4D. Lu and colleagues demonstrated that expression of mutant forms of IDH1 or IDH2 caused global increases in histone methylation and increased levels of 2 hydroxyglutarate (Figure 1B). This was correlated with a block in differentiation (Figures 2A, B and D). This effect appeared to be mediated by the histone demethylase KDM4C (Figure 4D). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Scienceand Science Exchange, and the results of the replications will be published by eLife. DOI: http://dx.doi.org/10.7554/eLife.10860.00

Role for the Peripheral Benzodiazepine Receptor in Neuroinflammation of Neurodegenerative disorders

Neuroinflammation is a major component of several neurodegenerative disorders such as Alzheimer's disease, HIV-associated dementia, Multiple sclerosis and Parkinson's disease. Although the primary pathology underlying each of these diseases is vastly different, neuroinflammation, consisting of chronic activation of brain macrophages, is a significant factor that contributes to neuronal damage in all these conditions. Were it possible to image chronic activation of brain macrophages, it would be possible to monitor developing neuroinflammation and assess the efficacy of therapies that are targeted at modulating CNS inflammation. The goal of this thesis is to determine if activated brain macrophages can be imaged in vivo using positron emission tomography. We propose to take advantage of increased expression of the peripheral benzodiazepine receptor in activated brain macrophages and hypothesize that ligands that bind specifically to this receptor will label activated brain macrophages in vivo using positron emission tomography. The peripheral benzodiazepine receptor is normally expressed at low levels in the central nervous system in astrocytes and brain macrophages and is hypothesized to increase specifically on brain macrophages in neuroinflammation. We show that PK11195, a specific ligand to the peripheral benzodiazepine receptor, shows increased binding to brain macrophages in HIV encephalitis and that PK11195 can be used to image brain macrophages in vivo using positron emission tomography in a macaque model of HIV encephalitis. PK11195 binding is also increased in activated brain macrophages in Alzheimer's disease and shows age dependent increases in transgenic mice models of Alzheimer's disease. Finally we compare binding characteristics of DAA1106, a novel peripheral benzodiazepine receptor ligand, with PK11195 to show that DAA1106 binds with greater affinity in rat models of neuroinflammation both in brain tissues as well as in vivo. These data suggest that ligands of the peripheral benzodiazepine receptor specifically label activated brain macrophages and may be used to image neuroinflammation in vivo using positron emission tomography

Evaluation of a novel antibody to define histone 3.3 G34R mutant brain tumours

Missense somatic mutations affecting histone H3.1 and H3.3 proteins are now accepted as the hallmark of paediatric diffuse intrinsic pontine gliomas (DIPG), non-brain stem paediatric high grade gliomas (pHGG) as well as a subset of adult glioblastoma multiforme (GBM). Different mutations give rise to one of three amino acid substitutions at two critical positions within the histone tails, K27M, G34R/V. Several studies have highlighted gene expression and epigenetic changes associated with histone H3 mutations; however their precise roles in tumourigenesis remain incompletely understood. Determining how such amino acid substitutions in a protein affect its properties can be challenging because of difficulties in detecting and tracking mutant proteins within cells and tissues. Here we describe a strategy for the generation of antibodies to discriminate G34R and G34V mutant histone H3 proteins from their wild-type counterparts. Antibodies were validated by western blotting and immunocytochemistry, using recombinant H3.3 proteins and paediatric GBM cell lines. The H3-G34R antibody demonstrated a high degree of selectivity towards its target sequence. Accordingly, immunostaining on a cohort of 22 formalin-fixed paraffin embedded tumours with a previously known H3.3 G34R mutation status, detected successfully the corresponding mutant protein in 11/11 G34R cases. Since there was a high concordance between genotype and immunohistochemical analysis of G34R mutant tumour samples, we analysed a series of tissue microarrays (TMAs) to assess the specificity of the antibody in a range of paediatric brain tumours, and noted immunoreactivity in 2/634 cases. Importantly, we describe the generation and validation of highly specific antibodies for G34 mutations. Overall our work adds to an extremely valuable portfolio of antibodies, not only for histopathologic detection of tumour-associated mutant histone sequences, but also facilitating the study of spatial/anatomical aspects of tumour formation and the identification of downstream targets and pathways in malignant glioma progression

Estimation of the slope of nuclear symmetry energy via charge radii of mirror nuclei

Charge radii of mirror nuclei are calculated by implementing pairing effects with the Hartree-Fock Bogoliubov approximation. Correlations between the difference of charge radii ($\Delta R_{ch}$) and slope of nuclear symmetry energy (L) are examined for different mirror nuclei pairs of varying masses using 40 different Skyrme energy density functionals. $\Delta R_{ch}-L$ correlations are found to be robust for the binding constraints imposed on density functionals. We observe that $\Delta R_{ch}$ and $L$ show better correlations in relatively heavier pairs than those obtained in the lighter pairs. Our calculations impose a constraint on the slope of nuclear symmetry energy as -20 MeV $\leq L \leq$ 55 MeV with 68\% confidence band using available measurements on charge radii. This is a moderately soft symmetry energy, in contrast to stiff and soft symmetry energy indicated by PREX-II and CREX measurements of neutron skin thickness in $^{208}Pb$ and $^{48}Ca$, respectively. Our result is also in agreement with celestial constraints obtained from observational data for neutron stars.Comment: 13 pages, 4 Figures, 2 Table

Aberrant histone modifications in pediatric brain tumors

Epigenetic modifications, particularly histone post-translational modifications (PTMs), are central to pediatric brain tumor pathogenesis, impacting chromatin structure, gene expression, and genomic stability. Disruptions in histone PTMs, especially lysine methylation and acetylation, arising due to histone mutations or aberrant enzyme modulation are critical drivers of oncogenesis. Lysine methylation, catalyzed by histone methyltransferases (KMTs), modulates chromatin interactions and gene expression through activation or repression, depending on the methylation state and the specific histone residue. Key enzymes, including histone methyltransferases and demethylases, and associated proteins exemplify the functions of writers, readers, and erasers in maintaining histone modification balance. Similarly, histone acetylation, a dynamic process regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), plays a crucial role in pediatric brain tumors. Alterations in these components lead to aberrant gene expression and tumorigenesis. Understanding these disrupted processes offers potential for targeted therapies to rewire oncogenic chromatin states and potentially improve patient outcomes

Web based online Home Automation and security system based on wireless Video Streaming using Internet of Things

The present research work proposes an efficient implementation for IoT (Internet of Things) used for monitoring and controlling the home appliances via World Wide Web. IoT can be viewed as an evolution rather than a revolution. IoT involves leveraging connectivity to efficiently collect and analyze the data from various sensors and relay the data to the mobile or personal computer through Wireless connectivity. The idea behind our research work is managing all the functions of a home with a centralized control system. Introducing the Raspberry Pi to the world of home automation provides numerous customizations to turn a regular home into a smart home. Raspberry Pi provides a low cost platform for interconnecting electrical/electronic devices and various sensors in a home via the internet network. The main objective of the present work is to design a smart home using various sensors which can be controlled and monitored by the Raspberry Pi via the Internet of Things (IoT). This will help the house owners to provide a simple, fast and reliable way to automate their environment. This paper focuses on two aspects of smart home i.e. home automation and home security

Highlighting the versatility of the Tracerlab synthesis modules. Part 2: fully automated production of [ 11 C]‐labeled radiopharmaceuticals using a Tracerlab FX C‐Pro

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/89445/1/jlcr1937.pd

In vivo PET imaging of the neuroinflammatory response in rat spinal cord injury using the TSPO tracer [F-18]GE-180 and effect of docosahexaenoic acid

Centre for Trauma Sciences, funded by the Barts & The London Charity, GE Healthcare Ltd, the Experimental Medicine Awards from the Blizard Institute and the Imaging Centre at the Barts Cancer Institute

Design of an Optical Blood Pressure Sensor for Noninvasive monitoring of blood pressure

In modern society, patients often have access to a wealth of electronic data concerning their social networks and surroundings, but have little personalized insight into their own health. Our plan is to distribute a small handheld device with an array of biometric sensors to collect data about a user’s body. With the patient’s current and past data, we can give the patients a pre-diagnosis (outlining symptoms and possible sickness) using machine learning techniques to create a general summary of the patient’s symptoms and potential treatment while collaborating with physicians to reach a final consensus of the patient’s health status before the patient is aware of his/her illness. We want to empower users with basic knowledge of their vital signs and help them be more proactive in disease prevention while relying less on frequent primary care physician office visits