Network-Level Structural Abnormalities of Cerebral Cortex in Type 1 Diabetes Mellitus

Type 1 diabetes mellitus (T1DM) usually begins in childhood and adolescence and causes lifelong damage to several major organs including the brain. Despite increasing evidence of T1DM-induced structural deficits in cortical regions implicated in higher cognitive and emotional functions, little is known whether and how the structural connectivity between these regions is altered in the T1DM brain. Using inter-regional covariance of cortical thickness measurements from high-resolution T1-weighted magnetic resonance data, we examined the topological organizations of cortical structural networks in 81 T1DM patients and 38 healthy subjects. We found a relative absence of hierarchically high-level hubs in the prefrontal lobe of T1DM patients, which suggests ineffective top-down control of the prefrontal cortex in T1DM. Furthermore, inter-network connections between the strategic/executive control system and systems subserving other cortical functions including language and mnemonic/emotional processing were also less integrated in T1DM patients than in healthy individuals. The current results provide structural evidence for T1DM-related dysfunctional cortical organization, which specifically underlie the top-down cognitive control of language, memory, and emotion. © 2013 Lyoo et al

Monoclonal antibody A7-superparamagnetic iron oxide as contrast agent of MR imaging of rectal carcinoma

Superparamagnetic iron oxide (SPIO)-based colloid has been used clinically as a tissue-specific magnetic resonance contrast agent. We coupled monoclonal antibody A7 (Mab A7), which reacts specifically with human colorectal carcinoma, to Ferumoxides (SPIO) and examined the accumulation of this conjugate in xenografted tumours in nude mice. We examined in vitro immunoreactivity of Mab A7 coupled to Ferumoxides and its in vivo distribution in nude mice with human colorectal carcinoma. Magnetic resonance imaging of tumour-bearing nude mice was performed 72 h after injection of A7-Ferumoxides. A7-Ferumoxides retained binding activities that were nearly identical to intact Mab A7. More of the radiolabelled A7-Ferumoxides accumulated in the tumour than normal mouse IgG-Ferumoxides from 12 h onwards after injection (P<0.05). Both A7-Ferumoxides and normal mouse IgG-Ferumoxides disappeared from blood linearly over time. The accumulation levels in normal tissue decreased linearly over time but were lower than levels in tumours from 6 h. In magnetic resonance T2-weighted imaging of the tumour-bearing nude mice, signal intensity was reduced at the margin of the tumour by injection of A7-Ferumoxides. Mab A7 coupled to Ferumoxides is potentially suitable as a magnetic resonance contrast agent for detecting local recurrence of rectal carcinoma

Targeted Disruption of the Low-Affinity Leukemia Inhibitory Factor-Receptor Gene Causes Placental, Skeletal, Neural and Metabolic Defects and Results in Perinatal Death

The low-affinity receptor for leukemia inhibitory factor (LIFR)* interacts with gp130 to induce an intracellular signal cascade, The LIFR-gp130 heterodimer is implicated in the function of diverse systems, Normal placentation is disrupted in LIFR mutant animals, which leads to poor intrauterine nutrition but allows fetuses to continue to term. Fetal bone volume is reduced greater than three-fold and the number of osteoclasts is increased six-fold, resulting in severe osteopenia of perinatal bone. Astrocyte numbers are reduced in the spinal cord and brain stem. Late gestation fetal livers contain relatively high stores of glycogen, indicating a metabolic disorder. Hematologic and primordial germ cell compartments appear normal. Pleiotropic defects in the mutant animals preclude survival beyond the day of birth

Diffusion of an e-learning programme among Danish General Practitioners: A nation-wide prospective survey

<p>Abstract</p> <p>Background</p> <p>We were unable to identify studies that have considered the diffusion of an e-learning programme among a large population of general practitioners. The aim of this study was to investigate the uptake of an e-learning programme introduced to General Practitioners as part of a nation-wide disseminated dementia guideline.</p> <p>Methods</p> <p>A prospective study among all 3632 Danish GPs. The GPs were followed from the launching of the e-learning programme in November 2006 and 6 months forward. Main outcome measures: Use of the e-learning programme. A logistic regression model (GEE) was used to identify predictors for use of the e-learning programme.</p> <p>Results</p> <p>In the study period, a total of 192 different GPs (5.3%) were identified as users, and 17% (32) had at least one re-logon. Among responders at first login most have learnt about the e-learning programme from written material (41%) or from the internet (44%). A total of 94% of the users described their ability of conducting a diagnostic evaluation as good or excellent. Most of the respondents used the e-learning programme due to general interest (90%). Predictors for using the e-learning programme were Males (OR = 1.4, 95% CI 1.1; 2.0) and members of Danish College of General Practice (OR = 2.2, 95% CI 1.5; 3.1), whereas age, experience and working place did not seem to be influential.</p> <p>Conclusion</p> <p>Only few Danish GPs used the e-learning programme in the first 6 months after the launching. Those using it were more often males and members of Danish College of General Practice. Based on this study we conclude, that an active implementation is needed, also when considering electronic formats of CME like e-learning.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT00392483.</p

Using eDNA to detect the distribution and density of invasive crayfish in the Honghe-Hani rice terrace World Heritage site

The Honghe-Hani landscape in China is a UNESCO World Natural Heritage site due to the beauty of its thousands of rice terraces, but these structures are in danger from the invasive crayfish Procambarus clarkii. Crayfish dig nest holes, which collapse terrace walls and destroy rice production. Under the current control strategy, farmers self-report crayfish and are issued pesticide, but this strategy is not expected to eradicate the crayfish nor to prevent their spread since farmers are not able to detect small numbers of crayfish. Thus, we tested whether environmental DNA (eDNA) from paddy-water samples could provide a sensitive detection method. In an aquarium experiment, Real-time Quantitative polymerase chain reaction (qPCR) successfully detected crayfish, even at a simulated density of one crayfish per average-sized paddy (with one false negative). In a field test, we tested eDNA and bottle traps against direct counts of crayfish. eDNA successfully detected crayfish in all 25 paddies where crayfish were observed and in none of the 7 paddies where crayfish were absent. Bottle-trapping was successful in only 68% of the crayfish-present paddies. eDNA concentrations also correlated positively with crayfish counts. In sum, these results suggest that single samples of eDNA are able to detect small crayfish populations, but not perfectly. Thus, we conclude that a program of repeated eDNA sampling is now feasible and likely reliable for measuring crayfish geographic range and for detecting new invasion fronts in the Honghe Hani landscape, which would inform regional control efforts and help to prevent the further spread of this invasive crayfish

Human Herpesvirus 8 Interferon Regulatory Factor-Mediated BH3-Only Protein Inhibition via Bid BH3-B Mimicry

Viral replication efficiency is in large part governed by the ability of viruses to counteract pro-apoptotic signals induced by infection of host cells. For HHV-8, viral interferon regulatory factor-1 (vIRF-1) contributes to this process in part via inhibitory interactions with BH3-only protein (BOP) Bim, recently identified as an interaction partner of vIRF-1. Here we recognize that the Bim-binding domain (BBD) of vIRF-1 resembles a region (BH3-B) of Bid, another BOP, which interacts intramolecularly with the functional BH3 domain of Bid to inhibit it pro-apoptotic activity. Indeed, vIRF-1 was found to target Bid in addition to Bim and to interact, via its BBD region, with the BH3 domain of each. In functional assays, BBD could substitute for BH3-B in the context of Bid, to suppress Bid-induced apoptosis in a BH3-binding-dependent manner, and vIRF-1 was able to protect transfected cells from apoptosis induced by Bid. While vIRF-1 can mediate nuclear sequestration of Bim, this was not the case for Bid, and inhibition of Bid and Bim by vIRF-1 could occur independently of nuclear localization of the viral protein. Consistent with this finding, direct BBD-dependent inactivation by vIRF-1 of Bid-induced mitochondrial permeabilization was demonstrable in vitro and isolated BBD sequences were also active in this assay. In addition to Bim and Bid BH3 domains, BH3s of BOPs Bik, Bmf, Hrk, and Noxa also were found to bind BBD, while those of both pro- and anti-apoptotic multi-BH domain Bcl-2 proteins were not. Finally, the significance of Bid to virus replication was demonstrated via Bid-depletion in HHV-8 infected cells, which enhanced virus production. Together, our data demonstrate and characterize BH3 targeting and associated inhibition of BOP pro-apoptotic activity by vIRF-1 via Bid BH3-B mimicry, identifying a novel mechanism of viral evasion from host cell defenses

Parameterization of a coarse-grained model of cholesterol with point-dipole electrostatics

© 2018, Springer Nature Switzerland AG. We present a new coarse-grained (CG) model of cholesterol (CHOL) for the electrostatic-based ELBA force field. A distinguishing feature of our CHOL model is that the electrostatics is modeled by an explicit point dipole which interacts through an ideal vacuum permittivity. The CHOL model parameters were optimized in a systematic fashion, reproducing the electrostatic and nonpolar partitioning free energies of CHOL in lipid/water mixtures predicted by full-detailed atomistic molecular dynamics simulations. The CHOL model has been validated by comparison to structural, dynamic and thermodynamic properties with experimental and atomistic simulation reference data. The simulation of binary DPPC/cholesterol mixtures covering the relevant biological content of CHOL in mammalian membranes is shown to correctly predict the main lipid behavior as observed experimentally

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference