Traumatic brain injury neuroelectrochemical monitoring: behind-the-ear micro-instrument and cloud application

BACKGROUND: Traumatic Brain Injury (TBI) is a leading cause of fatality and disability worldwide, partly due to the occurrence of secondary injury and late interventions. Correct diagnosis and timely monitoring ensure effective medical intervention aimed at improving clinical outcome. However, due to the limitations in size and cost of current ambulatory bioinstruments, they cannot be used to monitor patients who may still be at risk of secondary injury outside the ICU. METHODS: We propose a complete system consisting of a wearable wireless bioinstrument and a cloud-based application for real-time TBI monitoring. The bioinstrument can simultaneously record up to ten channels including both ECoG biopotential and neurochemicals (e.g. potassium, glucose and lactate), and supports various electrochemical methods including potentiometry, amperometry and cyclic voltammetry. All channels support variable gain programming to automatically tune the input dynamic range and address biosensors' falling sensitivity. The instrument is flexible and can be folded to occupy a small space behind the ear. A Bluetooth Low-Energy (BLE) receiver is used to wirelessly connect the instrument to a cloud application where the recorded data is stored, processed and visualised in real-time. Bench testing has been used to validate device performance. RESULTS: The instrument successfully monitored spreading depolarisations (SDs) - reproduced using a signal generator - with an SNR of 29.07 dB and NF of 0.26 dB. The potentiostat generates a wide voltage range from -1.65V to +1.65V with a resolution of 0.8mV and the sensitivity of the amperometric AFE was verified by recording 5 pA currents. Different potassium, glucose and lactate concentrations prepared in lab were accurately measured and their respective working curves were constructed. Finally,the instrument achieved a maximum sampling rate of 1.25 ksps/channel with a throughput of 105 kbps. All measurements were successfully received at the cloud. CONCLUSION: The proposed instrument uniquely positions itself by presenting an aggressive optimisation of size and cost while maintaining high measurement accuracy. The system can effectively extend neuroelectrochemical monitoring to all TBI patients including those who are mobile and those who are outside the ICU. Finally, data recorded in the cloud application could be used to help diagnosis and guide rehabilitation

Prediction of Promiscuous P-Glycoprotein Inhibition Using a Novel Machine Learning Scheme

BACKGROUND: P-glycoprotein (P-gp) is an ATP-dependent membrane transporter that plays a pivotal role in eliminating xenobiotics by active extrusion of xenobiotics from the cell. Multidrug resistance (MDR) is highly associated with the over-expression of P-gp by cells, resulting in increased efflux of chemotherapeutical agents and reduction of intracellular drug accumulation. It is of clinical importance to develop a P-gp inhibition predictive model in the process of drug discovery and development. METHODOLOGY/PRINCIPAL FINDINGS: An in silico model was derived to predict the inhibition of P-gp using the newly invented pharmacophore ensemble/support vector machine (PhE/SVM) scheme based on the data compiled from the literature. The predictions by the PhE/SVM model were found to be in good agreement with the observed values for those structurally diverse molecules in the training set (n = 31, r(2) = 0.89, q(2) = 0.86, RMSE = 0.40, s = 0.28), the test set (n = 88, r(2) = 0.87, RMSE = 0.39, s = 0.25) and the outlier set (n = 11, r(2) = 0.96, RMSE = 0.10, s = 0.05). The generated PhE/SVM model also showed high accuracy when subjected to those validation criteria generally adopted to gauge the predictivity of a theoretical model. CONCLUSIONS/SIGNIFICANCE: This accurate, fast and robust PhE/SVM model that can take into account the promiscuous nature of P-gp can be applied to predict the P-gp inhibition of structurally diverse compounds that otherwise cannot be done by any other methods in a high-throughput fashion to facilitate drug discovery and development by designing drug candidates with better metabolism profile

Contribution of discourse and morphosyntax skills to reading comprehension in Chinese dyslexic and typically developing children

This study aimed at identifying important skills for reading comprehension in Chinese dyslexic children and their typically developing counterparts matched on age (CA controls) or reading level (RL controls). The children were assessed on Chinese reading comprehension, cognitive, and reading-related skills. Results showed that the dyslexic children performed significantly less well than the CA controls but similarly to RL controls in most measures. Results of multiple regression analyses showed that word-level reading-related skills like oral vocabulary and word semantics were found to be strong predictors of reading comprehension among typically developing junior graders and dyslexic readers of senior grades, whereas morphosyntax, a text-level skill, was most predictive for typically developing senior graders. It was concluded that discourse and morphosyntax skills are particularly important for reading comprehension in the non-inflectional and topic-prominent Chinese system

Down-Regulation of Serum/Glucocorticoid Regulated Kinase 1 in Colorectal Tumours Is Largely Independent of Promoter Hypermethylation

Background: We have previously shown that serum/glucocorticoid regulated kinase 1 (SGK1) is down-regulated in colorectal cancers (CRC) with respect to normal tissue. As hyper-methylation of promoter regions is a well-known mechanism of gene silencing in cancer, we tested whether the SGK1 promoter region was methylated in colonic tumour samples. Methodology/Principal Findings: We investigated the methylation profile of the two CpG islands present in the promoter region of SGK1 in a panel of 5 colorectal cancer cell lines by sequencing clones of bisulphite-treated DNA samples. We further confirmed our findings in a panel of 10 normal and 10 tumour colonic tissue samples of human origin. We observed CpG methylation only in the smaller and more distal CpG island in the promoter region of SGK1 in both normal and tumour samples of colonic origin. We further identified a single nucleotide polymorphism (SNP, rs1743963) which affects methylation of the corresponding CpG. Conclusions/Significance: Our results show that even though partial methylation of the promoter region of SGK1 is present

GAPscreener: An automatic tool for screening human genetic association literature in PubMed using the support vector machine technique

<p>Abstract</p> <p>Background</p> <p>Synthesis of data from published human genetic association studies is a critical step in the translation of human genome discoveries into health applications. Although genetic association studies account for a substantial proportion of the abstracts in PubMed, identifying them with standard queries is not always accurate or efficient. Further automating the literature-screening process can reduce the burden of a labor-intensive and time-consuming traditional literature search. The Support Vector Machine (SVM), a well-established machine learning technique, has been successful in classifying text, including biomedical literature. The GAPscreener, a free SVM-based software tool, can be used to assist in screening PubMed abstracts for human genetic association studies.</p> <p>Results</p> <p>The data source for this research was the HuGE Navigator, formerly known as the HuGE Pub Lit database. Weighted SVM feature selection based on a keyword list obtained by the two-way z score method demonstrated the best screening performance, achieving 97.5% recall, 98.3% specificity and 31.9% precision in performance testing. Compared with the traditional screening process based on a complex PubMed query, the SVM tool reduced by about 90% the number of abstracts requiring individual review by the database curator. The tool also ascertained 47 articles that were missed by the traditional literature screening process during the 4-week test period. We examined the literature on genetic associations with preterm birth as an example. Compared with the traditional, manual process, the GAPscreener both reduced effort and improved accuracy.</p> <p>Conclusion</p> <p>GAPscreener is the first free SVM-based application available for screening the human genetic association literature in PubMed with high recall and specificity. The user-friendly graphical user interface makes this a practical, stand-alone application. The software can be downloaded at no charge.</p

The Effects of Apolipoprotein F Deficiency on High Density Lipoprotein Cholesterol Metabolism in Mice

Apolipoprotein F (apoF) is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP) based on its ability to inhibit cholesteryl ester transfer protein (CETP)-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20–25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/−0.9 mg/dl vs. WT: 1.2+/−0.3 mg/dl, p<0.05). No differences were observed in ABCG1-mediated cholesterol efflux capacity in either sex. Interestingly, ApoB-depleted serum from male KO mice was less effective at promoting ABCA1-mediated cholesterol efflux from J774 macrophages relative to WT controls

The N-Terminal residues 43 to 60 form the interface for dopamine mediated α-synuclein dimerisation

α-synuclein (α-syn) is a major component of the intracellular inclusions called Lewy bodies, which are a key pathological feature in the brains of Parkinson's disease patients. The neurotransmitter dopamine (DA) inhibits the fibrillisation of α-syn into amyloid, and promotes α-syn aggregation into SDS-stable soluble oligomers. While this inhibition of amyloid formation requires the oxidation of both DA and the methionines in α-syn, the molecular basis for these processes is still unclear. This study sought to define the protein sequences required for the generation of oligomers. We tested N- (α-syn residues 43-140) and C-terminally (1-95) truncated α-syn, and found that similar to full-length protein both truncated species formed soluble DA: α-syn oligomers, albeit 1-95 had a different profile. Using nuclear magnetic resonance (NMR), and the N-terminally truncated α-syn 43-140 protein, we analysed the structural characteristics of the DA:α-syn 43-140 dimer and α-syn 43-140 monomer and found the dimerisation interface encompassed residues 43 to 60. Narrowing the interface to this small region will help define the mechanism by which DA mediates the formation of SDS-stable soluble DA:α-syn oligomers

Bacteria clustering by polymers induces the expression of quorum sense controlled phenotypes

Bacteria deploy a range of chemistries to regulate their behaviour and respond to their environment. Quorum sensing is one mean by which bacteria use chemical reactions to modulate pre-infection behaviour such as surface attachment. Polymers that can interfere with bacterial adhesion or the chemical reactions used for quorum sensing are thus a potential means to control bacterial population responses. Here we report how polymeric "bacteria sequestrants", designed to bind to bacteria through electrostatic interactions and thus inhibit bacterial adhesion to surfaces, induce the expression of quorum sensing controlled phenotypes as a consequence of cell clustering. A combination of polymer and analytical chemistry, biological assays and computational modelling has been used to characterise the feedback between bacteria clustering and quorum sensing signaling. We have also derived design principles and chemical strategies for controlling bacterial behaviour at the population leve

A Prokaryotic S1P Lyase Degrades Extracellular S1P In Vitro and In Vivo: Implication for Treating Hyperproliferative Disorders

Sphingosine-1-phosphate (S1P) regulates a broad spectrum of fundamental cellular processes like proliferation, death, migration and cytokine production. Therefore, elevated levels of S1P may be causal to various pathologic conditions including cancer, fibrosis, inflammation, autoimmune diseases and aberrant angiogenesis. Here we report that S1P lyase from the prokaryote Symbiobacterium thermophilum (StSPL) degrades extracellular S1P in vitro and in blood. Moreover, we investigated its effect on cellular responses typical of fibrosis, cancer and aberrant angiogenesis using renal mesangial cells, endothelial cells, breast (MCF-7) and colon (HCT 116) carcinoma cells as disease models. In all cell types, wild-type StSPL, but not an inactive mutant, disrupted MAPK phosphorylation stimulated by exogenous S1P. Functionally, disruption of S1P receptor signaling by S1P depletion inhibited proliferation and expression of connective tissue growth factor in mesangial cells, proliferation, migration and VEGF expression in carcinoma cells, and proliferation and migration of endothelial cells. Upon intravenous injection of StSPL in mice, plasma S1P levels rapidly declined by 70% within 1 h and then recovered to normal 6 h after injection. Using the chicken chorioallantoic membrane model we further demonstrate that also under in vivo conditions StSPL, but not the inactive mutant, inhibited tumor cell-induced angiogenesis as an S1P-dependent process. Our data demonstrate that recombinant StSPL is active under extracellular conditions and holds promise as a new enzyme therapeutic for diseases associated with increased levels of S1P and S1P receptor signaling

Epidemiological Features of Infantile Hypertrophic Pyloric Stenosis in Taiwanese Children: A Nation-Wide Analysis of Cases during 1997–2007

OBJECTIVE: To describe the epidemiological characteristics of infantile hypertrophic pyloric stenosis (IHPS) in ethnic Chinese children. MATERIALS AND METHODS: We reviewed the National Health Insurance claims database and analyzed data from children less than one year of age who had been diagnosed with IHPS (ICD-9-CM 750.5) and had undergone pyloromyotomy (ICD-9-CM 43.3). We analyzed the incidence, gender, age at diagnosis, length of hospital stay, seasonal variation and cost of IHPS from data collected between January 1997 and December 2007. RESULTS: A total of 1,077 infants met inclusion criteria, including 889 boys and 188 girls. The annual incidence of IHPS ranged from 0.30 to 0.47 per 1,000 live births with a mean incidence of 0.39 per 1,000 live births. Between 2002 and 2007, the incidence showed a declining trend (P = 0.025) with coincidentally increasing trends for both exclusive breastfeeding (P = 0.014) and breastfeeding plus bottle feeding (P = 0.004). The male-to-female rate ratio was dynamic and increased from 3.03 during the first two weeks of life to 8.94 during the 8(th) through 10th weeks of life. The overall male-to-female rate ratio was 4.30. The mean age at diagnosis was 43.1 ± 2.4 days. After analyzing the months of birth and hospital admission, no seasonal variation associated with IHPS was detected. The mean length of hospital stay was 8.28 ± 7.10 days. CONCLUSIONS: The incidence of IHPS in Taiwan, a country with a majority ethnic Chinese population, was lower than observed incidences in Caucasian populations living in Western countries. Breastfeeding campaigns and low maternal smoking rates may contribute to the lower incidence of IHPS in Taiwan. However, additional studies with longer follow-up periods are needed