A homing receptor-IgG chimera as a probe for adhesive ligands of lymph node high endothelial venules.

The binding of lymphocytes to high endothelial venules (HEV) within peripheral lymph nodes (pln) is thought to be mediated by a lectinlike adhesion molecule termed the pln homing receptor (pln HR). The cloning and sequencing of cDNAs encoding both murine and human pln HR revealed that these adhesion molecules contain protein motifs that are homologous to C-type or calcium dependent lectin domains as well as to epidermal growth factor (egf) and complement-regulatory protein domains. We have produced a novel, antibody-like form of the murine HR by joining the extracellular region of the receptor to a human IgG heavy chain. This antibody-like molecule is capable of recognizing carbohydrates, blocking the binding of lymphocytes to pln HEV, and serving as a histochemical reagent for the staining of pln HEV. This murine HR-IgG chimera should prove useful in analyzing the distribution of the HR ligand(s) in normal as well as in inflammatory states

The complement binding-like domains of the murine homing receptor facilitate lectin activity.

The leukocyte homing receptor (HR), the endothelial leukocyte adhesion molecule, and gmp140/platelet activation-dependent granule membrane protein are members of a family of adhesion molecules, termed the lectin cell adhesion molecules (LEC-CAMS) which are unified by a multi-domain structure containing a lectin motif, an epidermal growth factor-like (egf) motif, and variable numbers of a complement binding-like (CB) motif. Previous data have indicated a predominant role for the lectin motif in cell adhesion directed by the LEC-CAMS, although the egf-like domain of the HR may also play a potential role in cell binding. While the role(s) of the CB domains in the LEC-CAMS is currently not understood, they have been hypothesized to act as rigid spacers or stalks for lectin and perhaps, egf domain presentation. In this paper, we analyze the functional characteristics of murine HR-IgG chimeras containing the lectin, lectin plus egf, and lectin plus egf plus CB domains. The Mel 14 mAb, an adhesion blocking antibody which recognizes a conformational determinant in the N-terminus of the HR lectin domain, shows a significantly decreased affinity for a HR construct which lacks the CB motifs, consistent with the possibility that the CB domains are involved with lectin domain structure. In agreement with this conjecture, HR mutants lacking the CB domains show a profound decrease in lectin-specific interaction with the carbohydrate polyphosphomannan ester, suggesting that the changes in Mel 14 affinity for the lectin domain are reflected in lectin functionality. Various assays investigating the interactions between the HR deletion mutants and the peripheral lymph node high endothelium, including cell blocking, immunohistochemical staining, and radioactively labeled ligand binding, all showed that removal of the CB domains results in a lack of HR adhesive function. These results imply that the CB domains of the HR, and, by analogy, the other members of the LEC-CAM family, may play important structural roles involving induction of lectin domain conformation and resultant functionality

Simultaneous X-ray and optical observations of S5 0716+714 after the outburst of March 2004

At the end of March 2004, the blazar S5 0716+714 underwent an optical outburst that prompted for quasi-simultaneous target-of-opportunity observations with the INTEGRAL and XMM-Newton satellites. In this paper, we report the results of the XMM-Newton and INTEGRAL OMC data analysis. The X-ray spectrum is well-represented by a concave broken power-law model, with the break at about 2 keV. In the framework of the synchrotron self-Compton model, the softer part of the spectrum, which is described by a power law of index $\alpha \simeq 1.8$ ($f_\nu \propto \nu^{-\alpha}$), is probably due to synchrotron emission, while the harder part of the spectrum, which has $\alpha \simeq 1$, is due to inverse Compton emission. The blazar shows the long and short-term variability typical of low-frequency peaked BL Lac (LBL): the former is manifested by a gradual decrease in the optical flux from the peak as observed by ground telescopes at the end of March 2004, while the latter is characterized by soft X-ray and optical flares on time scales from a few thousand seconds to few hours. We can follow spectral variations on sub-hour time scales and study their correlation with the flux variability. We find evidence that the peak energy of the time-resolved spectra is increasing with flux. The modeling of the spectral energy distribution compared with archival observations suggests that the long-term variability (from outburst to quiescence or viceversa) could be due to a change in the injected power, while the short-term variability (flares) could be explained with changes in the slope of the distribution of the electrons.Comment: 8 pages, 6 figures. Accepted for publication on A&A Main Journal. Revision of the English gramma

Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches

PMCID: PMC3668194SEP was directly funded by the National Institute for Health Research Cardiovascular Biomedical Research Unit at Barts. SN acknowledges support from the Oxford NIHR Biomedical Research Centre and from the Oxford British Heart Foundation Centre of Research Excellence. SP and PL are funded by a BHF Senior Clinical Research fellowship. RC is supported by a BHF Research Chair and acknowledges the support of the Oxford BHF Centre for Research Excellence and the MRC and Wellcome Trust. PMM gratefully acknowledges training fellowships supporting his laboratory from the Wellcome Trust, GlaxoSmithKline and the Medical Research Council

Understanding Urban Demand for Wild Meat in Vietnam: Implications for Conservation Actions

Vietnam is a significant consumer of wildlife, particularly wild meat, in urban restaurant settings. To meet this demand, poaching of wildlife is widespread, threatening regional and international biodiversity. Previous interventions to tackle illegal and potentially unsustainable consumption of wild meat in Vietnam have generally focused on limiting supply. While critical, they have been impeded by a lack of resources, the presence of increasingly organised criminal networks and corruption. Attention is, therefore, turning to the consumer, but a paucity of research investigating consumer demand for wild meat will impede the creation of effective consumer-centred interventions. Here we used a mixed-methods research approach comprising a hypothetical choice modelling survey and qualitative interviews to explore the drivers of wild meat consumption and consumer preferences among residents of Ho Chi Minh City, Vietnam. Our findings indicate that demand for wild meat is heterogeneous and highly context specific. Wild-sourced, rare, and expensive wild meat-types are eaten by those situated towards the top of the societal hierarchy to convey wealth and status and are commonly consumed in lucrative business contexts. Cheaper, legal and farmed substitutes for wild-sourced meats are also consumed, but typically in more casual consumption or social drinking settings. We explore the implications of our results for current conservation interventions in Vietnam that attempt to tackle illegal and potentially unsustainable trade in and consumption of wild meat and detail how our research informs future consumer-centric conservation actions

Childhood neurodevelopment after prescription of maintenance methadone for opioid dependency in pregnancy:a systematic review and meta-analysis

Aim: To systematically review and meta‐analyse studies of neurodevelopmental outcome of children born to mothers prescribed methadone in pregnancy. Method: MEDLINE, Embase, and PsycINFO were searched for studies published from 1975 to 2017 reporting neurodevelopmental outcomes in children with prenatal methadone exposure. Results: Forty‐one studies were identified (2283 participants). Eight studies were amenable to meta‐analysis: at 2 years the Mental Development Index weighted mean difference of children with prenatal methadone exposure compared with unexposed infants was −4.3 (95% confidence interval [CI] −7.24 to −1.63), and the Psychomotor Development Index weighted mean difference was −5.42 (95% CI −10.55 to −0.28). Seven studies reported behavioural scores and six found scores to be lower among methadone‐exposed children. Twelve studies reported visual outcomes: nystagmus and strabismus were common; five studies reported visual evoked potentials of which four described abnormalities. Factors that limited the quality of some studies, and introduced risk of bias, included absence of blinding, small sample size, high attrition, uncertainty about polydrug exposure, and lack of comparison group validity. Interpretation: Children born to mothers prescribed methadone in pregnancy are at risk of neurodevelopmental problems but risk of bias limits inference about harm. Research into management of opioid use disorder in pregnancy should include evaluation of childhood neurodevelopmental outcome

Notch1 deficiency decreases hepatic lipid accumulation by induction of fatty acid oxidation

Notch signaling pathways modulate various cellular processes, including cell proliferation, differentiation, adhesion, and communication. Recent studies have demonstrated that Notch1 signaling also regulates hepatic glucose production and lipid synthesis. However, the effect of Notch1 signaling on hepatic lipid oxidation has not yet been directly investigated. To define the function of Notch1 signaling in hepatic lipid metabolism, wild type mice and Notch1 deficient antisense transgenic (NAS) mice were fed a high-fat diet. High-fat diet-fed NAS mice exhibited a marked reduction in hepatic triacylglycerol accumulation compared with wild type obese mice. The improved fatty liver was associated with an increased expression of hepatic genes involved in fatty acid oxidation. However, lipogenic genes were not differentially expressed in the NAS liver, suggesting lipolytic-specific regulatory effects by Notch1 signaling. Expression of fatty acid oxidative genes and the rate of fatty acid oxidation were also increased by inhibition of Notch1 signaling in HepG2 cells. In addition, similar regulatory effects on lipid accumulation were observed in adipocytes. Taken together, these data show that inhibition of Notch1 signaling can regulate the expression of fatty acid oxidation genes and may provide therapeutic strategies in obesity-induced hepatic steatosisopen0

A portable near infrared spectroscopy system for bedside monitoring of newborn brain

BACKGROUND: Newborns with critical health conditions are monitored in neonatal intensive care units (NICU). In NICU, one of the most important problems that they face is the risk of brain injury. There is a need for continuous monitoring of newborn's brain function to prevent any potential brain injury. This type of monitoring should not interfere with intensive care of the newborn. Therefore, it should be non-invasive and portable. METHODS: In this paper, a low-cost, battery operated, dual wavelength, continuous wave near infrared spectroscopy system for continuous bedside hemodynamic monitoring of neonatal brain is presented. The system has been designed to optimize SNR by optimizing the wavelength-multiplexing parameters with special emphasis on safety issues concerning burn injuries. SNR improvement by utilizing the entire dynamic range has been satisfied with modifications in analog circuitry. RESULTS AND CONCLUSION: As a result, a shot-limited SNR of 67 dB has been achieved for 10 Hz temporal resolution. The system can operate more than 30 hours without recharging when an off-the-shelf 1850 mAh-7.2 V battery is used. Laboratory tests with optical phantoms and preliminary data recorded in NICU demonstrate the potential of the system as a reliable clinical tool to be employed in the bedside regional monitoring of newborn brain metabolism under intensive care

The pathology of familial breast cancer: Morphological aspects

A small proportion of breast cancers are due to a heritable predisposition. Recently, two predisposition genes, BRCA1 and BRCA2, have been identified and cloned. The morphological features of tumours from patients harbouring mutations in the BRCA1 and BRCA2 genes differ from each other and from sporadic breast cancers. Both are of higher grade than are sporadic cases. An excess of medullary/atypical medullary carcinoma has been reported in patients with BRCA1 mutations. Multifactorial analysis, however, shows that the only features independently associated with BRCA1 mutations are a high mitotic count, pushing tumour margins and a lymphocytic infiltrate. For BRCA2 mutation, an association with tubular/lobular carcinoma has been suggested, but not substantiated in a larger Breast Cancer Linkage Consortium study. In multifactorial analysis, the independent features were a lack of tubule formation and pushing tumour margins only. The morphological analysis has implications for clinical management of patients

PPARgamma activity in subcutaneous abdominal fat tissue and fat mass gain during short-term overfeeding

Objective: As the peroxisome proliferator-activated receptor (PPAR) plays a central role in fat mass regulation, we investigated whether initial subcutaneous PPAR activity is related to fat mass generation during overfeeding. Subjects: Fourteen healthy female subjects (age 254 years, BMI 22.12.3 kg/m2). Design and measurements: Subjects were overfed with a diet supplying 50% more energy than baseline energy requirements for 14 days. Fasting blood samples were analyzed for leptin, insulin and glucose. Fasting subcutaneous abdominal fat biopsies were obtained for analysis of PPAR1, PPAR2, aP2 and UCP2 mRNAs. Results: Initial PPAR1 and 2, aP2 and UCP2 mRNAs were not related to fat gain (P>0.12). However, PPAR1, PPAR2 and aP2 mRNA changes were positively related to changes in plasma leptin (