Polymer micro-grippers with an integrated force sensor for biological manipulation

The development of a novel micro-system integrating SU-8 polymer micro-grippers with a tensile force sensor for handling and characterizing the mechanical properties of delicate biological materials, such as fibrils, is presented. The micro-grippers are actuated by the electro-thermal effect and have gripping forces comparable to the common \u27hot-and-cold-arm\u27 grippers. A robust finite element model was developed to investigate system performance and validated experimentally. A new micro-mechanical calibration method using a piezoelectric manipulator with a micro-force measurement system was successfully applied to test the structure. Both FEA simulation and micro-mechanical testing results indicated that the system could fulfil the requirements for micro-object manipulation within a biological environment

Upper respiratory symptoms worsen over time and relate to clinical phenotype in COPD.

Copyright © 2015 by the American Thoracic Society.Rationale: How nasal symptoms in patients with chronic obstructive pulmonary disease (COPD) change over time and resolve during naturally occurring exacerbations has not been described previously. Objectives: To evaluate the evolution and impact of upper airway symptoms in a well-defined COPD cohort when stable and at exacerbation. Methods: Patients in the LondonCOPDcohortwere asked about the presence of nasal symptoms (nasal discharge, sneezing, postnasal drip, blocked nose, and anosmia) over an 8-year period (2005-2013) every 3 months at routine clinic visits while in a stable state and daily during exacerbations with the use of diary cards. Data were prospectively collected, and, in a subgroup of patients,COPDAssessment Test scores and human rhinovirus identification by polymerase chain reaction were available. Patients were also defined as having infrequent or frequent exacerbations (<2 or ≥2 exacerbations/yr, respectively). Measurements and Main Results: At an aggregate of 4,368 visits, 209 patients with COPD were asked about their nasal symptoms. At 2,033 visits when the patients were stable, the odds ratio (OR) for nasal discharge increased by 1.32% per year (95% confidence interval [CI], 1.19-1.45; P<0.001); the OR for sneezing increased by 1.16%(95%CI, 1.05-1.29;P = 0.005); theORfor postnasal drip increased by 1.18% (95% CI, 1.03-1.36; P=0.016); and theOR for anosmia increased by 1.19% (95% CI, 1.03-1.37; P = 0.015). At visits when the patients were having exacerbations, nasal discharge was present for 7 days and blocked nose, sneezing, and postnasal drip increased for just 3 days. Anosmia did not change. Nasal dischargewasmore likely inpatientswith frequent exacerbations (OR, 1.96; 95% CI, 1.17-3.28; P= 0.011), and COPD Assessment Test scores were higher by 1.06 units (95% CI, 0.32-1.80; P=0.005) when patients were stable and higher by 1.30 units (95% CI, 0.05-2.57; P= 0.042) during exacerbations. Conclusions: Upper airway symptoms increase over time in patients with COPD and are related to the frequent exacerbation phenotype. These longitudinal changes may be due to increasing airway inflammation or to progression of COPD

The origin of defects induced in ultra-pure germanium by Electron Beam Deposition

The creation of point defects in the crystal lattices of various semiconductors by subthreshold events has been reported on by a number of groups. These observations have been made in great detail using sensitive electrical techniques but there is still much that needs to be clarified. Experiments using Ge and Si were performed that demonstrate that energetic particles, the products of collisions in the electron beam, were responsible for the majority of electron-beam deposition (EBD) induced defects in a two-step energy transfer process. Lowering the number of collisions of these energetic particles with the semiconductor during metal deposition was accomplished using a combination of static shields and superior vacuum resulting in devices with defect concentrations lower than $10^{11}\,$cm$^{-3}$, the measurement limit of our deep level transient spectroscopy (DLTS) system. High energy electrons and photons that samples are typically exposed to were not influenced by the shields as most of these particles originate at the metal target thus eliminating these particles as possible damage causing agents. It remains unclear how packets of energy that can sometimes be as small of 2eV travel up to a $\mu$m into the material while still retaining enough energy, that is, in the order of 1eV, to cause changes in the crystal. The manipulation of this defect causing phenomenon may hold the key to developing defect free material for future applications.Comment: 18 pages, 9 figure

Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations.

PublishedJournal ArticleResearch Support, Non-U.S. Gov'tThis is an open access article available at http://www.eje-online.org/content/172/6/697.BACKGROUND: Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes and usually presents in the first 6 months of life. We aimed to describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM patients from a single centre and estimate an annual incidence rate of NDM in South-Eastern Anatolian region of Turkey. DESIGN AND METHODS: NDM patients presenting to Diyarbakir Children State Hospital between 2010 and 2013, and patients under follow-up with presumed type 1 diabetes mellitus, with onset before 6 months of age were recruited. Molecular genetic analysis was performed. RESULTS: Twenty-two patients (59% males) were diagnosed with NDM (TNDM-5; PNDM-17). Molecular genetic analysis identified a mutation in 20 (95%) patients who had undergone a mutation analysis. In transient neonatal diabetes (TNDM) patients, the genetic cause included chromosome 6q24 abnormalities (n=3), ABCC8 (n=1) and homozygous INS (n=1). In permanent neonatal diabetes (PNDM) patients, homozygous GCK (n=6), EIF2AK3 (n=3), PTF1A (n=3), and INS (n=1) and heterozygous KCNJ11 (n=2) mutations were identified. Pancreatic exocrine dysfunction was observed in patients with mutations in the distal PTF1A enhancer. Both patients with a KCNJ11 mutation responded to oral sulphonylurea. A variable phenotype was associated with the homozygous c.-331C>A INS mutation, which was identified in both a PNDM and TNDM patient. The annual incidence of PNDM in South-East Anatolian region of Turkey was one in 48 000 live births. CONCLUSIONS: Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The high rate of detection of a mutation likely reflects the contribution of new genetic techniques (targeted next-generation sequencing) and increased consanguinity within our cohort.The genetic testing was funded by the Wellcome Trust (Senior Investigator Award to Profs S Ellard and A T Hattersley), and by Diabetes UK (Project funding to Dr D J Mackay). H Demirbilek was funded by European Society for Paediatric Endocrinology (ESPE) and The Scientific and Technological Research Council of Turkey (TUBITAK) for his 1 year clinical fellowship at University College London (UCL), Institute of Child Health, Great Ormond Street Hospital for Children, NHS Trust, Department of Paediatric Endocrinology

Complex sequencing rules of birdsong can be explained by simple hidden Markov processes

Complex sequencing rules observed in birdsongs provide an opportunity to investigate the neural mechanism for generating complex sequential behaviors. To relate the findings from studying birdsongs to other sequential behaviors, it is crucial to characterize the statistical properties of the sequencing rules in birdsongs. However, the properties of the sequencing rules in birdsongs have not yet been fully addressed. In this study, we investigate the statistical propertiesof the complex birdsong of the Bengalese finch (Lonchura striata var. domestica). Based on manual-annotated syllable sequences, we first show that there are significant higher-order context dependencies in Bengalese finch songs, that is, which syllable appears next depends on more than one previous syllable. This property is shared with other complex sequential behaviors. We then analyze acoustic features of the song and show that higher-order context dependencies can be explained using first-order hidden state transition dynamics with redundant hidden states. This model corresponds to hidden Markov models (HMMs), well known statistical models with a large range of application for time series modeling. The song annotation with these models with first-order hidden state dynamics agreed well with manual annotation, the score was comparable to that of a second-order HMM, and surpassed the zeroth-order model (the Gaussian mixture model (GMM)), which does not use context information. Our results imply that the hierarchical representation with hidden state dynamics may underlie the neural implementation for generating complex sequences with higher-order dependencies

Yangian in the Twistor String

We study symmetries of the quantized open twistor string. In addition to global PSL(4|4) symmetry, we find non-local conserved currents. The associated non-local charges lead to Ward identities which show that these charges annihilate the string gluon tree amplitudes, and have the same form as symmetries of amplitudes in N=4 super conformal Yang Mills theory. We describe how states of the open twistor string form a realization of the PSL(4|4) Yangian superalgebra.Comment: 37 pages, 4 figure

Consequences of converting graded to action potentials upon neural information coding and energy efficiency

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ~50% in generator potentials, to ~3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation

Mouse models for preeclampsia: disruption of redox-regulated signaling

The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined animal models. Homozygous deletion of catechol-Omethyl transferase (Comt-/-) in pregnant mice leads to human preeclampsia-like symptoms (high blood pressure, albuminurea and preterm birth) resulting from extensive vasculo-endothelial pathology, primarily at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol to 2-methoxyestradiol 2 (2ME2) which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha) at late pregnancy. We propose that in wild type (Comt++) pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial superoxide dismutase (MnSOD). Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis in wild type (WT) animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions in mutant animals (Comt-/-) stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD). We predict that a lack of inhibition of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD

Canine respiratory coronavirus employs caveolin-1-mediated pathway for internalization to HRT-18G cells

Canine respiratory coronavirus (CRCoV), identified in 2003, is a member of the Coronaviridae family. The virus is a betacoronavirus and a close relative of human coronavirus OC43 and bovine coronavirus. Here, we examined entry of CRCoV into human rectal tumor cells (HRT-18G cell line) by analyzing co-localization of single virus particles with cellular markers in the presence or absence of chemical inhibitors of pathways potentially involved in virus entry. We also targeted these pathways using siRNA. The results show that the virus hijacks caveolin-dependent endocytosis to enter cells via endocytic internalization