Using Publicly Available Data to Quantify Plant-Pollinator Interactions and Evaluate Conservation Seeding Mixes in the Northern Great Plains.

Concern over declining pollinators has led to multiple conservation initiatives for improving forage for bees in agroecosystems. Using data available through the Pollinator Library (npwrc.usgs.gov/pollinator/), we summarize plant-pollinator interaction data collected from 2012-2015 on lands managed by the U.S. Fish and Wildlife Service and private lands enrolled in U.S. Department of Agriculture conservation programs in eastern North Dakota (ND). Furthermore, we demonstrate how plant-pollinator interaction data from the Pollinator Library and seed cost information can be used to evaluate hypothetical seeding mixes for pollinator habitat enhancements. We summarize records of 314 wild bee and 849 honey bee (Apis mellifera L.) interactions detected on 63 different plant species. The wild bee observations consisted of 46 species, 15 genera, and 5 families. Over 54% of all wild bee observations were represented by three genera-Bombus, Lassioglossum, and Melissodes. The most commonly visited forbs by wild bees were Monarda fistulosa, Sonchus arvensis, and Zizia aurea. The most commonly visited forbs by A. mellifera were Cirsium arvense, Melilotus officinalis, and Medicago sativa. Among all interactions, 13% of A. mellifera and 77% of wild bee observations were made on plants native to ND. Our seed mix evaluation shows that mixes may often need to be tailored to meet the unique needs of wild bees and managed honey bees in agricultural landscapes. Our evaluation also demonstrates the importance of incorporating both biologic and economic information when attempting to design cost-effective seeding mixes for supporting pollinators in a critically important part of the United States.

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia

The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia

Misdiagnosis of asthma in schoolchildren.

BACKGROUND: A correct diagnosis of asthma is the cornerstone of asthma management. Few pediatric studies have examined the accuracy of physician-diagnosed asthma. OBJECTIVES: We determined the accuracy of parent reported physician-diagnosed asthma in children sampled from a community cohort. METHODS: Nested case-control study that recruited 203 children, aged 9-12, from a community-based sample. Three groups were recruited: asthma cases had a parental report of physician-diagnosed asthma, symptomatic controls had respiratory symptoms without a diagnosis of asthma, and asymptomatic controls had no respiratory symptoms. All participants were assessed and assigned a clinical diagnosis by one of three study physicians, and then completed spirometry, methacholine challenge, and allergy skin testing. The reference standard of asthma required a study physician's clinical diagnosis of asthma and either reversible bronchoconstriction or a positive methacholine challenge. Diagnostic accuracy, sensitivity and specificity were calculated for parent-reported asthma diagnosis compared to the reference standard. RESULTS: One hundred two asthma cases, 52 controls with respiratory symptoms but no asthma diagnosis, and 49 asymptomatic controls were assessed. Physician agreement for the diagnosis of asthma was moderate (kappa 0.46-0.81). Compared to the reference standard, 45% of asthma cases were overdiagnosed and 10% of symptomatic controls were underdiagnosed. Parental report of physician-diagnosed asthma had 75% sensitivity and 92% specificity for correctly identifying asthma. CONCLUSIONS: There is significant misclassification of childhood asthma when the diagnosis relies solely on a clinical history. This study highlights the importance of objective testing to confirm the diagnosis of asthma. Pediatr Pulmonol. 2017;52:293-302. © 2016 Wiley Periodicals, Inc.

Bispecific Antibodies Targeting Different Epitopes on the HIV-1 Envelope Exhibit Broad and Potent Neutralization.

UNLABELLED: The potency and breadth of the recently isolated neutralizing human monoclonal antibodies to HIV-1 have stimulated interest in their use to prevent or to treat HIV-1 infection. Due to the antigenically diverse nature of the HIV-1 envelope (Env), no single antibody is highly active against all viral strains. While the physical combination of two broadly neutralizing antibodies (bNAbs) can improve coverage against the majority of viruses, the clinical-grade manufacturing and testing of two independent antibody products are time and resource intensive. In this study, we constructed bispecific immunoglobulins (IgGs) composed of independent antigen-binding fragments with a common Fc region. We developed four different bispecific IgG variants that included antibodies targeting four major sites of HIV-1 neutralization. We show that these bispecific IgGs display features of both antibody specificities and, in some cases, display improved coverage over the individual parental antibodies. All four bispecific IgGs neutralized 94% to 97% of antigenically diverse viruses in a panel of 206 HIV-1 strains. Among the bispecific IgGs tested, VRC07 × PG9-16 displayed the most favorable neutralization profile. It was superior in breadth to either of the individual antibodies, neutralizing 97% of viruses with a median 50% inhibitory concentration (IC50) of 0.055 µg/ml. This bispecific IgG also demonstrated in vivo pharmacokinetic parameters comparable to those of the parental bNAbs when administered to rhesus macaques. These results suggest that IgG-based bispecific antibodies are promising candidates for the prevention and treatment of HIV-1 infection in humans. IMPORTANCE: To prevent or treat HIV-1 infection, antibodies must potently neutralize nearly all strains of HIV-1. Thus, the physical combination of two or more antibodies may be needed to broaden neutralization coverage and diminish the possibility of viral resistance. A bispecific antibody that has two different antibody binding arms could potentially display neutralization characteristics better than those of any single parental antibody. Here we show that bispecific antibodies contain the binding specificities of the two parental antibodies and that a single bispecific antibody can neutralize 97% of viral strains with a high overall potency. These findings support the use of bispecific antibodies for the prevention or treatment of HIV-1 infection.

Safety, pharmacokinetics and neutralization of the broadly neutralizing HIV-1 human monoclonal antibody VRC01 in healthy adults.

VRC-HIVMAB060-00-AB (VRC01) is a broadly neutralizing HIV-1 monoclonal antibody (mAb) isolated from the B cells of an HIV-infected patient. It is directed against the HIV-1 CD4 binding site and is capable of potently neutralizing the majority of diverse HIV-1 strains. This Phase I dose-escalation study in healthy adults was conducted at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA). Primary objectives were the safety, tolerability and pharmacokinetics (PK) of VRC01 intravenous (i.v.) infusion at 5, 20 or 40 mg/kg, given either once (20 mg/kg) or twice 28 days apart (all doses), and of subcutaneous (s.c.) delivery at 5 mg/kg compared to s.c. placebo given twice, 28 days apart. Cumulatively, 28 subjects received 43 VRC01 and nine received placebo administrations. There were no serious adverse events or dose-limiting toxicities. Mean 28-day serum trough concentrations after the first infusion were 35 and 57 µg/ml for groups infused with 20 mg/kg (n = 8) and 40 mg/kg (n = 5) doses, respectively. Mean 28-day trough concentrations after the second infusion were 56 and 89 µg/ml for the same two doses. Over the 5-40 mg/kg i.v. dose range (n = 18), the clearance was 0.016 l/h and terminal half-life was 15 days. After infusion VRC01 retained expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. The human monoclonal antibody (mAb) VRC01 was well tolerated when delivered i.v. or s.c. The mAb demonstrated expected half-life and pharmacokinetics for a human immunoglobulin G. The safety and PK results support and inform VRC01 dosing schedules for planning HIV-1 prevention efficacy studies.

Spatial analysis of exposure to traffic-related air pollution at birth and childhood atopic asthma in Toronto, Ontario.

Findings from the Toronto Child Health Evaluation Questionnaire (TCHEQ) study indicate that early childhood exposure to traffic-related air pollution (TRAP) is related to the onset of atopic childhood asthma. To test this hypothesis further, we investigated whether spatial patterns in the birth neighbourhood of TCHEQ subjects with atopic asthma (136 of 909 schoolchildren in grades 1-2) could be explained by TRAP and other risk factors. If a causal relationship exists between early childhood residential exposure to TRAP and the development of atopic asthma, we hypothesise that (1) clusters of current asthma should exist around the place of residence at birth, and (2) accounting for residential concentrations of TRAP at birth should explain some of the autocorrelation. Several high asthma clusters were observed. Adjusting for TRAP completely explained one cluster; elsewhere, clusters were only partially explained by TRAP. Findings suggest that exposure during early childhood to TRAP in Toronto is an important contributor to the development of the atopic asthma phenotype and reveal the likely importance of other risk factors not measured in the fixed effects of the model.

Targeting chromatin to improve radiation response.

Chromatin, the structure formed by the wrapping of approximately 146 base pairs of DNA around an octamer of histones, has a profound impact on numerous DNA-based processes. Chromatin modifications and chromatin remodellers have recently been implicated in important aspects of the DNA damage response including facilitating the initial sensing of the damage as well as subsequent recruitment of repair factors. Radiation is an effective cancer therapy for a large number of tumours, and there is considerable interest in finding approaches that might further increase the efficacy of radiotherapy. The use of radiation leads to the generation of DNA damage and, therefore, agents that can affect the sensing and repair of DNA damage may have an impact on overall radiation efficacy. The chromatin modifications as well as chromatin modifiers that have been associated with the DNA damage response will be summarized in this review. An emphasis will be placed on those processes that can be pharmacologically manipulated with currently available inhibitors. The rationale for the use of these inhibitors in combination with radiation will also be described.

Conserving large carnivores: dollars and fence.

Conservationists often advocate for landscape approaches to wildlife management while others argue for physical separation between protected species and human communities, but direct empirical comparisons of these alternatives are scarce. We relate African lion population densities and population trends to contrasting management practices across 42 sites in 11 countries. Lion populations in fenced reserves are significantly closer to their estimated carrying capacities than unfenced populations. Whereas fenced reserves can maintain lions at 80% of their potential densities on annual management budgets of $500 km(-2) , unfenced populations require budgets in excess of $2000 km(-2) to attain half their potential densities. Lions in fenced reserves are primarily limited by density dependence, but lions in unfenced reserves are highly sensitive to human population densities in surrounding communities, and unfenced populations are frequently subjected to density-independent factors. Nearly half the unfenced lion populations may decline to near extinction over the next 20-40 years.

Effect of dietary interventions in the maintenance of normoglycaemia in glycogen storage disease type 1a: a systematic review and meta-analysis.

BACKGROUND: Untreated glycogen storage disease (GSD)-1a patients experience hypoglycaemia and growth retardation. The present study examined the effects of dietary interventions on the maintenance of normoglycaemia. METHODS: Clinical trials were identified from EMBASE (January 1980 to November 2011), MEDLINE (January 1948 to November 2011) and the Cochrane Central Register of Controlled Trials (2011, Issue 4). The intermittent administration of uncooked cornstarch was compared with: (i) continuous nocturnal feeding of dextrose; (ii) modified uncooked cornstarch; and (iii) dextrose and an uncooked cornstarch-dextrose mixture. One author extracted the data, and assessed the trial eligibility and risk of bias. Quality assessment and data extraction were conducted and checked independently. RESULTS: Of 41 articles retrieved, five controlled trials (49 participants) were identified with follow-up at 2 days to 14 years. Results from three nonrandomised controlled trials comparing uncooked cornstarch with continuous nocturnal feeding of dextrose were pooled in a meta-analysis based on a fixed-effect model. Twenty-six participants (three trials) receiving uncooked cornstarch showed a significant increase in blood glucose concentration: mean difference (MD) 0.62 mmol L(-1) [95% confidence interval (CI) = 0.23-1.00] (P = 0.002), 21 (two trials) increased serum insulin: MD 62.37 pmol L(-1) (95% CI = 32.19-92.55) (P < 0.0001) and 22 (three trials) increased plasma total cholesterol: MD 0.68 mmol L(-1) (95% CI = 0.17- 1.20) (P = 0.01) compared to continuous nocturnal feeding of dextrose. Twenty-eight subjects (three trials) showed decreased plasma lactate after nocturnal feeding: MD -0.42 mmol L(-1) (95% CI = -0.58 to -0.25) (P < 0.00001). CONCLUSIONS: Short- to long-term overnight intermittent administration of uncooked cornstarch prevents nocturnal hypoglycaemia in GSD-1a children more effectively than continuous nocturnal feeding of dextrose.

Chest health surveillance utility in the early detection of bronchiolitis obliterans syndrome in children after allo-SCT.

To prospectively assess whether periodic chest health surveillance is beneficial for the early detection of bronchiolitis obliterans syndrome (BOS) in children after allo-SCT. Children up to 18 years of age receiving allo-SCT from September 2009 to September 2011 were included. Surveillance consisted of the following: a 7-item respiratory system questionnaire of cough, wheeze and shortness of breath; focused physical examination; and pulmonary function test (PFT) conducted before SCT and at 1, 3, 6, 9, 12, 18 and 24 months after SCT. Thirty-nine patients were enrolled. Five children developed BOS at a median time of 192 days (range 94-282). Positive response comparisons between the BOS group vs the non-BOS group were NS for history questionnaire (P=0.2), heart rate (P=0.3), respiratory rate (P=0.3) and oxygen saturation monitoring (P=0.8). Differences between the two groups for chest auscultation and PFT were statistically significant (P=0.03 and P=0.01, respectively). However, chest auscultation in the BOS group was only positive after BOS diagnosis. PFT reduction was evident in the asymptomatic phase (BOS group 33%; non-BOS group 4.5%, P=0.01). Changes in PFT, but not history/physical examination, allow the early detection of BOS in children after SCT. Our study is limited by the small sample size.

A guide for identification and continuing care of adult congenital heart disease patients in primary care.

BACKGROUND: Surgical and other advances in the treatment and care of congenital heart disease have resulted in a significant increase in the number of adults with congenital heart disease (ACHD), many of whom have no regular cardiology follow-up. Optimised care for ACHD patients requires continuity of specialist and shared care and education of practitioners and patients. The challenges for managing ACHD were identified by a Health Needs Assessment in the North West and are addressed within the UK Department of Health's ACHD Commissioning Guide. MATERIALS AND METHODS: An ACHD model of care was recommended in the North West of England and developed by the three North West Cardiac & Stroke Networks. Within this, a Task Group focused on the role of primary care in the identification and continuing care of ACHD patients. A feasibility study demonstrated that existing diagnostic Read Codes can identify ACHD patients on general practice registers. An ACHD Toolkit was developed to provide algorithms to guide the appropriate management of ACHD patients through primary, secondary and/or specialist ACHD care and to improve education/knowledge amongst primary care staff about ACHD and its wider implications. RESULTS: Early findings during the development of this Toolkit illustrate a wide disparity of provision between current and optimal management strategies. Patients lost to follow-up have already been identified and their management modified. CONCLUSIONS: By focusing on identifying ACHD patients in primary care and organising/delivering ACHD services, the ACHD Toolkit could help to improve quality, timeliness of care, patient experience and wellbeing.

Canadian Thoracic Society Asthma Management Continuum--2010 Consensus Summary for children six years of age and over, and adults.

BACKGROUND/OBJECTIVE: To integrate new evidence into the Canadian Asthma Management Continuum diagram, encompassing both pediatric and adult asthma. METHODS: The Canadian Thoracic Society Asthma Committee members, comprised of experts in pediatric and adult respirology, allergy and immunology, emergency medicine, general pediatrics, family medicine, pharmacoepidemiology and evidence-based medicine, updated the continuum diagram, based primarily on the 2008 Global Initiative for Asthma guidelines, and performed a focused review of literature pertaining to key aspects of asthma diagnosis and management in children six years of age and over, and adults. RESULTS: In patients six years of age and over, management of asthma begins with establishing an accurate diagnosis, typically by supplementing medical history with objective measures of lung function. All patients and caregivers should receive self-management education, including a written action plan. Inhaled corticosteroids (ICS) remain the first-line controller therapy for all ages. When asthma is not controlled with a low dose of ICS, the literature supports the addition of long-acting beta2-agonists in adults, while the preferred approach in children is to increase the dose of ICS. Leukotriene receptor antagonists are acceptable as second-line monotherapy and as an alternative add-on therapy in both age groups. Antiimmunoglobulin E therapy may be of benefit in adults, and in children 12 years of age and over with difficult to control allergic asthma, despite high-dose ICS and at least one other controller. CONCLUSIONS: The foundation of asthma management is establishing an accurate diagnosis based on objective measures (eg, spirometry) in individuals six years of age and over. Emphasis is placed on the similarities and differences between pediatric and adult asthma management approaches to achieve asthma control.

Bivariate genetic modelling of the response to an oral glucose tolerance challenge: a gene x environment interaction approach.

AIMS/HYPOTHESIS: Twin and family studies have shown the importance of genetic factors influencing fasting and 2 h glucose and insulin levels. However, the genetics of the physiological response to a glucose load has not been thoroughly investigated. METHODS: We studied 580 monozygotic and 1,937 dizygotic British female twins from the Twins UK Registry. The effects of genetic and environmental factors on fasting and 2 h glucose and insulin levels were estimated using univariate genetic modelling. Bivariate model fitting was used to investigate the glucose and insulin responses to a glucose load, i.e. an OGTT. RESULTS: The genetic effect on fasting and 2 h glucose and insulin levels ranged between 40% and 56% after adjustment for age and BMI. Exposure to a glucose load resulted in the emergence of novel genetic effects on 2 h glucose independent of the fasting level, accounting for about 55% of its heritability. For 2 h insulin, the effect of the same genes that already influenced fasting insulin was amplified by about 30%. CONCLUSIONS/INTERPRETATION: Exposure to a glucose challenge uncovers new genetic variance for glucose and amplifies the effects of genes that already influence the fasting insulin level. Finding the genes acting on 2 h glucose independently of fasting glucose may offer new aetiological insight into the risk of cardiovascular events and death from all causes.

Health outcomes in low-income children with current asthma in Canada.

Data collected from the Canadian National Longitudinal Survey of Children and Youth (NLSCY) in 1994/95 and 1996/97 were used to measure longitudinal health outcomes among children with asthma. Over 10 000 children aged 1 to 11 years with complete data on asthma status in both years were included. Outcomes included hospitalizations and health services use (HSU). Current asthma was defined as children diagnosed with asthma by a physician and who took prescribed inhalants regularly, had wheezing or an attack in the previous year, or had their activities limited by asthma. Children having asthma significantly increased their odds of hospitalization (OR = 2.52; 95% CI: 1.71, 3.70) and health services use (OR = 3.80; 95% CI: 2.69, 5.37). Low-income adequacy (LIA) in 1994/ 95 significantly predicts hospitalization and HSU in 1996/97 (OR = 2.68; 95% CI: 1.29, 5.59 and OR = 0.67; 95% CI: 0.45, 0.99, respectively). Our results confirmed that both having current asthma and living in low-income families had a significant impact on the health status of children in Canada. Programs seeking to decrease the economic burden of pediatric hospitalizations need to focus on asthma and low-income populations.

The - 11391 G/A polymorphism of the adiponectin gene promoter is associated with metabolic syndrome traits and the outcome of an energy-restricted diet in obese subjects.

Adiponectin is an adipose tissue-specific hormone that is commonly decreased in obese subjects. Furthermore, single-nucleotide polymorphisms (SNPs) of the adiponectin gene have been associated with metabolic phenotypes. The present study investigated whether the adiponectin gene promoter variant -11391 G/A (rs17300539) could predict the risk of developing traits characterizing the metabolic syndrome (MetS) and the impact of weight management. The -11391 G/A SNP was genotyped in 180 Spanish volunteers (BMI: 31.4+/-3.2 kg/m (2); age: 35+/-5 years). Clinical measurements were determined at baseline, following an 8-week low-calorie diet (LCD), and at 32 and 60 weeks. At baseline, the GG genotype was associated with higher HOMA-IR, insulin and triacylglyceride concentrations than other genotypes (p<0.05) and was also related with a higher risk of insulin resistance (OR: 2.437, p=0.025) and MetS clinical manifestations (OR: 3.236, p=0.003). Following the LCD, the increased risk in GG subjects compared with others disappeared (p>0.05). By 32 weeks after dietary therapy (n=84), GG carriers had recovered the risk of metabolic comorbidities (OR: 2.420, p=0.043). This risk was even more evident after 60 weeks (OR: 2.875, p=0.014). These data show an increased risk of insulin resistance and MetS complications in obese subjects of the -11391 GG genotype. The risk was markedly reduced during an energy-restricted diet, but was not sustained. Carriage of the A allele therefore confers protection from weight regain, and the effect is particularly evident 32-60 weeks after the dietary intervention, when improvement in GG subjects had disappeared.

TUB is a candidate gene for late-onset obesity in women.

AIMS/HYPOTHESES: We recently reported significant associations between BMI and three TUB single nucleotide polymorphisms (SNPs) in two Dutch cohorts enriched for type 2 diabetes. Here, we attempted a replication of these associations in a large population-based cohort of female twins comprehensively phenotyped for measures of general and central obesity. METHODS: Two TUB SNPs (rs2272382, rs2272383) and a third (rs1528133), 22 kb distal to RIC3, were genotyped in 2694 Europid women from the St Thomas' UK Adult Twin Registry (Twins UK) (mean age +/- SD: 47.6 +/- 12.7 years; 42.8% postmenopausal). We explored the hypothesis that TUB is a candidate gene for late-onset obesity in humans through testing the interaction of the SNPs by menopausal status. RESULTS: In the whole cohort, none of the three SNPs showed a significant main effect on measures of general or central obesity. However, for central obesity the rs2272382 SNP showed a significant interaction with menopausal status (p = 0.036). Postmenopausal women homozygous for the minor allele of rs2272382 showed significantly more general obesity (p = 0.022) and central obesity (p = 0.009) than carriers of the major allele. Differences (beta [95% CI]) between the two genotype groups were 0.92 kg/m2 (0.03-1.81) for BMI (p = 0.036), 2.73 cm (0.62-4.84) for waist circumference (p = 0.013) and 2.43% (0.27-4.60) for per cent central fat (p = 0.027). These associations were confirmed by a sibling transmission disequilibrium test for central obesity, waist circumference and per cent central fat. CONCLUSIONS/INTERPRETATION: We have replicated associations of TUB SNP rs2272382 with measures of general and central obesity in normal postmenopausal women. These findings confirm TUB as a candidate gene for late-onset obesity in humans.

Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neurons.

Protein phosphorylation serves as a critical biochemical regulator of short-term and long-term synaptic plasticity. Receptor protein tyrosine kinases (RPTKs) including members of the trk, eph and erbB subfamilies have been shown to modulate signaling cascades that influence synaptic function in the central nervous system (CNS). Tyro3 is one of three RPTKs belonging to the "TAM" receptor family, which also includes Axl and Mer. Tyro3 is the most widely expressed of these receptors in the CNS. Despite recent advances suggesting roles for members of this receptor family in the reproductive and immune systems, their functions in the CNS remain largely unexplored. In an effort to elucidate the roles of Tyro3 and its ligand, the protein growth arrest-specific gene6 (Gas6) in the hippocampus and cortex, we performed a detailed study of the localization and signaling of Tyro3 polypeptides in rat hippocampal and cortical neurons. Tyro3 was readily detected in dendrites and in the soma where it was distributed in a punctate pattern. Tyro3 exhibited only a limited level of co-localization with postsynaptic density protein-95 (PSD-95), suggesting that while located within dendrites, it was not confined to the postsynaptic compartment. In addition, Tyro3 was also identified in the axons and growth cones of immature neurons. The prominent expression of Tyro3 in dendrites suggested that it may be capable of modulating signaling pathways triggered by synaptic transmission. We have provided evidence in support of this role by demonstrating that Gas6 induced the phosphorylation of Tyro3 in cortical neurons in vitro, resulting in the recruitment of the mitogen-activated protein kinase (MAPK) and the phosphoinositide-3 kinase (PI(3)K) signaling pathways. As these pathways play critical roles in the induction of hippocampal long-term potentiation (LTP), these findings suggest that Tyro3 signaling may influence synaptic plasticity in the dendritic compartment of hippocampal and cortical neurons.

SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women.

Insulin regulates apoB metabolism via activation of PI3K or regulation of MTP via MAPK/ERK signalling. SHP-2 enhances both pathways through increased IRS-1 phosphorylation. We hypothesized that variants in the SHP-2 gene PTPN11 and PI3K p85alpha subunit gene PIK3R1 may influence fasting levels of plasma apoB and/or LDL cholesterol. We tested association of tagging SNPs (tSNPs) in each gene with serum lipids in a large sample of unselected population-based Caucasian female twins (n=2771, mean age 47.4+/-12.5 years) and then tested interaction between tSNPs in determining apoB and LDL levels. PTPN11 tSNP rs11066322 was associated with apoB (P=0.007) and rs11066320 was associated with LDL cholesterol (P=0.016). PIK3R1 tSNP rs251406 was associated with apoB (P=0.0003) and rs706713 was associated with LDL cholesterol (P=0.009). PTPN11 tSNP rs11066322 interacted with PIK3R1 tSNP rs251406 in determining serum apoB levels (P=0.012) and with PIK3R1 tSNP rs40318 in determining LDL cholesterol levels (P=0.009). Association of single tSNPs with both apoB and LDL cholesterol as well as interactions between the two genes suggest that variants influencing SHP-2 activity may modulate the acute pathway by which insulin regulates these lipids.