Discovery of a Missense Mutation (Q222K) of the APOE Gene from the Australian Imaging, Biomarker and Lifestyle Study.

After age, polymorphisms of the Apolipoprotein E (APOE) gene are the biggest risk factor for the development of Alzheimer's disease (AD). During our investigation to discovery biomarkers in plasma, using 2D gel electrophoresis, we found an individual with and unusual apoE isoelectric point compared to APOE ɛ2, ɛ3, and ɛ4 carriers. Whole exome sequencing of APOE from the donor confirmed a single nucleotide polymorphism (SNP) in exon 4, translating to a rare Q222K missense mutation. The apoE ɛ4 (Q222K) mutation did not form dimers or complexes observed for apoE ɛ2 & ɛ3 proteins.

Bipolar Electric Field Pulses in the Martian Magnetosheath and Solar Wind; Their Implication and Impact Accessed by System Scale Size.

The scale size of the plasma boundary region between the sheath and ionosphere in the Martian system is often similar to the gyro-radii of sheath protons, ∼200 km. As a result, ion energization via kinetic structures may play an important role in modifying the ion trajectories and thus be important when evaluating the large-scale dynamics of the Martian system. In this paper, we report observations made with the MAVEN Langmuir Probe and Waves instrument of solitary bipolar electric field structures, and assess their potential role in ion energization in the Martian system. The observed structures appear as short duration (∼0.5 ms) bipolar electric field pulses of ∼1-25 mV/m, and are frequently observed in the upstream solar wind and inside the sheath. The study presented in this paper suggests that the bipolar electric field structures observed at Mars have an average electrostatic potential drop of ∼0.07 V. The estimated upper rate at which these structures could further energize the protons is estimated, assuming the protons gain the full 0.07 eV, to be ∼0.13 eV per gyration, or a change in proton energy of ∼0.3%, and a corresponding change in the gyroradius of ∼0.3 km. These numbers imply that to first order the bipolar structures are not a significant source of ion energization in the Martian magnetosheath.

Plasma microRNA vary in association with the progression of Alzheimer's disease.

INTRODUCTION: Early intervention in Alzheimer's disease (AD) requires the development of an easily administered test that is able to identify those at risk. Focusing on microRNA robustly detected in plasma and standardizing the analysis strategy, we sought to identify disease-stage specific biomarkers. METHODS: Using TaqMan microfluidics arrays and a statistical consensus approach, we assessed plasma levels of 185 neurodegeneration-related microRNA, in cohorts of cognitively normal amyloid ß-positive (CN-Aß+), mild cognitive impairment (MCI), and Alzheimer's disease (AD) participants, relative to their respective controls. RESULTS: Distinct disease stage microRNA biomarkers were identified, shown to predict membership of the groups (area under the curve [AUC] >0.8) and were altered dynamically with AD progression in a longitudinal study. Bioinformatics demonstrated that these microRNA target known AD-related pathways, such as the Phosphoinositide 3-kinase (PI3K-Akt) signalling pathway. Furthermore, a significant correlation was found between miR-27a-3p, miR-27b-3p, and miR-324-5p and amyloid beta load. DISCUSSION: Our results show that microRNA signatures alter throughout the progression of AD, reflect the underlying disease pathology, and may prove to be useful diagnostic markers.

Analysis of plasma proteins using 2D gels and novel fluorescent probes: in search of blood based biomarkers for Alzheimer's disease.

BACKGROUND: The Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimer's disease. METHODS: The concentration of proteins in plasma covers a vast range of 12 orders of magnitude. Therefore, to search for medium to low abundant biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3400 protein species resolved on the 2D gels were compared using in-gel differential analysis with spectrally resolved fluorescent protein detection dyes (Zdyes™). Here we report on analysis of pooled plasma samples from an initial screen of a sex-matched cohort of 72 probable AD patients and 72 healthy controls from the baseline time point of AIBL. RESULTS: We report significant changes in variants of apolipoprotein E, haptoglobin, α1 anti-trypsin, inter-α trypsin inhibitor, histidine-rich glycoprotein, and a protein of unknown identity. α1 anti-trypsin and α1 anti-chymotrypsin demonstrated plasma concentrations that were dependent on APOE ε4 allele dose. Our analysis also identified an association with the level of Vitamin D binding protein fragments and complement factor I with sex. We then conducted a preliminary validation study, on unique individual samples compared to the discovery cohort, using a targeted LC-MS/MS assay on a subset of discovered biomarkers. We found that targets that displayed a high degree of isoform specific changes in the 2D gels were not changed in the targeted MS assay which reports on the total level of the biomarker. CONCLUSIONS: This demonstrates that further development of mass spectrometry assays is needed to capture the isoform complexity that exists in theses biological samples. However, this study indicates that a peripheral protein signature has potential to aid in the characterization of AD.

A high-resolution picture of kinship practices in an Early Neolithic tomb.

To explore kinship practices at chambered tombs in Early Neolithic Britain, here we combined archaeological and genetic analyses of 35 individuals who lived about 5,700 years ago and were entombed at Hazleton North long cairn1. Twenty-seven individuals are part of the first extended pedigree reconstructed from ancient DNA, a five-generation family whose many interrelationships provide statistical power to document kinship practices that were invisible without direct genetic data. Patrilineal descent was key in determining who was buried in the tomb, as all 15 intergenerational transmissions were through men. The presence of women who had reproduced with lineage men and the absence of adult lineage daughters suggest virilocal burial and female exogamy. We demonstrate that one male progenitor reproduced with four women: the descendants of two of those women were buried in the same half of the tomb over all generations. This suggests that maternal sub-lineages were grouped into branches whose distinctiveness was recognized during the construction of the tomb. Four men descended from non-lineage fathers and mothers who also reproduced with lineage male individuals, suggesting that some men adopted the children of their reproductive partners by other men into their patriline. Eight individuals were not close biological relatives of the main lineage, raising the possibility that kinship also encompassed social bonds independent of biological relatedness.

Proximity to sources of airborne lead is associated with reductions in Children's executive function in the first four years of life.

Although policies to remove lead from gasoline have resulted in a substantial reduction in airborne lead, multiple industries are known to generate lead that is released in the air. The present study examines the extent to which residential proximity to a documented source of airborne lead is associated with intellectual and executive function in children. Data were available for n = 849 children from the Family Life Project. Geolocation for children's residences between birth and 36 months were referenced against the Environmental Protection Agency's Risk Screening Environmental Indicators (RSEI) database, which estimates exposure for each ½ mile grid in the contiguous United States. Instrumental variable models were employed to estimate causal associations between exposure and cognitive outcomes measured at 36, 48, and 60 months, using census-documented density of manufacturing employment as the instrument. Models of continuous lead dosage indicated small negative effects for both child IQ and executive function (EF). These results indicate that RSEI estimates of airborne lead exposure are meaningfully associated with decrements in cognitive development.

Increased glutaminyl cyclase activity in brains of Alzheimer's disease individuals.

Glutaminyl cyclases (QC) catalyze the formation of neurotoxic pGlu-modified amyloid-ß peptides found in the brains of people with Alzheimer's disease (AD). Reports of several-fold increases in soluble QC (sQC) expression in the brain and peripheral circulation of AD individuals has prompted the development of QC inhibitors as potential AD therapeutics. There is, however, a lack of standardized quantitative data on QC expression in human tissues, precluding inter-laboratory comparison and validation. We tested the hypothesis that QC is elevated in AD tissues by quantifying levels of sQC protein and activity in post-mortem brain tissues from AD and age-matched control individuals. We found a modest but statistically significant increase in sQC protein, which paralleled a similar increase in enzyme activity. In plasma samples sourced from the Australian Imaging, Biomarker and Lifestyle study we determined that QC activity was not different between the AD and control group, though a modest increase was observed in female AD individuals compared to controls. Plasma QC activity was further correlated with levels of circulating monocytes in AD individuals. These data provide quantitative evidence that alterations in QC expression are associated with AD pathology.

DSM Borderline Criterion Function Across Age-Groups: A Cross-Sectional Mixed-Method Study.

DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) Section II criteria for borderline personality disorder (BPD) lack developmental operationalization. The aim of the current study was to evaluate whether DSM criteria operate similarly across adolescents and adults to determine if developmental adjustment for DSM criteria was needed. Three age cohorts were recruited: adolescents (ages 12-17 years; n = 484), young adults (ages 18-25 years; n = 442), and adults (ages ≥26 years; n = 953). The Child Interview for DSM-IV BPD and the Structured Clinical Interview for DSM-IV Axis II disorders were administered to adolescents and adults, respectively. Item response theory methods were used to evaluate differential item (or criterion) functioning (DIF) of BPD criteria across adolescents and adults. Qualitative analyses were then used to evaluate the potential sources of DIF. Item response theory results demonstrated DIF across adolescents and adults for all DSM BPD criteria. Qualitative analyses suggested that the source of DIF was most likely due to rater/interviewer bias. Results furthermore suggested that behavioral criteria may represent the heterotypic features of BPD, while intra- and interpersonal criteria represent the homotypic features of the disorder. The article concludes with recommendations for developmentally informed guidelines for the assessment of BPD.

Characterization of the metal status of natively purified alpha-synuclein from human blood, brain tissue, or recombinant sources using size exclusion ICP-MS reveals no significant binding of Cu, Fe or Zn.

Abnormal protein structure and function have been implicated as the toxic species in many diseases including neurodegenerative diseases, such as Parkinson's. One key pathological hallmark in Parkinson's disease is the formation of Lewy bodies, of which alpha-synuclein is the major component. These Lewy bodies are formed by the aggregation and oligomerization of alpha-synuclein. The oligomeric form of the protein is suspected to be the main contributor to the neurotoxicity seen in the disease. The formation of toxic oligomers has been shown to occur through reactions with lipids, dopamine, hydrogen peroxide as well as metals. The interplay between metals and alpha-synuclein has also been proposed to cause oxidative stress, which promotes the formation of protein aggregates. Most studies investigating the relationship of Cu, Fe and Zn with alpha-synuclein have relied on the use of recombinant protein and there is little evidence that the interaction between metals and alpha-synuclein are physiologically relevant. To address this gap in our knowledge we have characterized the metal content and metal binding capacity of alpha-synuclein purified from human erythrocytes and brain tissue. In addition, we examined the ability of dityrosine cross-linked alpha-synuclein oligomers to bind Cu, Fe and Zn. Using size exclusion chromatography-inductively coupled plasma-mass spectrometry we demonstrated that native human alpha-synuclein, recombinant familial mutants and oligomers do not bind to significant amounts of metal even when they are added to the protein in excess.

High performance plasma amyloid-ß biomarkers for Alzheimer's disease.

To facilitate clinical trials of disease-modifying therapies for Alzheimer's disease, which are expected to be most efficacious at the earliest and mildest stages of the disease, supportive biomarker information is necessary. The only validated methods for identifying amyloid-ß deposition in the brain-the earliest pathological signature of Alzheimer's disease-are amyloid-ß positron-emission tomography (PET) imaging or measurement of amyloid-ß in cerebrospinal fluid. Therefore, a minimally invasive, cost-effective blood-based biomarker is desirable. Despite much effort, to our knowledge, no study has validated the clinical utility of blood-based amyloid-ß markers. Here we demonstrate the measurement of high-performance plasma amyloid-ß biomarkers by immunoprecipitation coupled with mass spectrometry. The ability of amyloid-ß precursor protein (APP)669-711/amyloid-ß (Aß)1-42 and Aß1-40/Aß1-42 ratios, and their composites, to predict individual brain amyloid-ß-positive or -negative status was determined by amyloid-ß-PET imaging and tested using two independent data sets: a discovery data set (Japan, n = 121) and a validation data set (Australia, n = 252 including 111 individuals diagnosed using 11C-labelled Pittsburgh compound-B (PIB)-PET and 141 using other ligands). Both data sets included cognitively normal individuals, individuals with mild cognitive impairment and individuals with Alzheimer's disease. All test biomarkers showed high performance when predicting brain amyloid-ß burden. In particular, the composite biomarker showed very high areas under the receiver operating characteristic curves (AUCs) in both data sets (discovery, 96.7%, n = 121 and validation, 94.1%, n = 111) with an accuracy approximately equal to 90% when using PIB-PET as a standard of truth. Furthermore, test biomarkers were correlated with amyloid-ß-PET burden and levels of Aß1-42 in cerebrospinal fluid. These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-ß burden at an individual level. These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.

Trajectories of depressive and anxiety symptoms in older adults: a 6-year prospective cohort study.

OBJECTIVE: Depressive and anxiety symptoms are common in older adults, significantly affect quality of life, and are risk factors for Alzheimer's disease. We sought to identify the determinants of predominant trajectories of depressive and anxiety symptoms in cognitively normal older adults. METHOD: Four hundred twenty-three older adults recruited from the general community underwent Aß positron emission tomography imaging, apolipoprotein and brain-derived neurotrophic factor genotyping, and cognitive testing at baseline and had follow-up assessments. All participants were cognitively normal and free of clinical depression at baseline. Latent growth mixture modeling was used to identify predominant trajectories of subthreshold depressive and anxiety symptoms over 6 years. Binary logistic regression analysis was used to identify baseline predictors of symptomatic depressive and anxiety trajectories. RESULTS: Latent growth mixture modeling revealed two predominant trajectories of depressive and anxiety symptoms: a chronically elevated trajectory and a low, stable symptom trajectory, with almost one in five participants falling into the elevated trajectory groups. Male sex (relative risk ratio (RRR) = 3.23), lower attentional function (RRR = 1.90), and carriage of the brain-derived neurotrophic factor Val66Met allele in women (RRR = 2.70) were associated with increased risk for chronically elevated depressive symptom trajectory. Carriage of the apolipoprotein epsilon 4 allele (RRR = 1.92) and lower executive function in women (RRR = 1.74) were associated with chronically elevated anxiety symptom trajectory. CONCLUSION: Our results indicate distinct and sex-specific risk factors linked to depressive and anxiety trajectories, which may help inform risk stratification and management of these symptoms in older adults at risk for Alzheimer's disease. Copyright © 2017 John Wiley & Sons, Ltd.

Body distortions in Anorexia Nervosa: Evidence for changed processing of multisensory bodily signals.

Body size and shape distortion is a core feature of Anorexia Nervosa (AN) - patients experience their body as fat while objectively being very thin. The cause of this distortion is unclear and disturbances in body perception could be involved. Body perception comprises estimating shape and location of one's body and requires integrating multisensory signals. We investigated if and how body location perception is changed and tested 23 AN patients and 23 healthy controls (HC) in a Rubber Hand Illusion (RHI) reaching paradigm. We presented two types of multisensory conflicts (visual-proprioceptive hand location; visual-tactile touch synchrony) and tested if the impact of visual-proprioceptive and visual-tactile signals on hand location perception differs between AN and HC groups. We found significant group differences in shifts of reaching trajectories, indicating that the influence of proprioceptive signals on hand location estimates is reduced in AN. Hand location estimates were relatively more biased towards external visual information, and shorter illness durations predicted a larger visual bias. Although touch synchrony also significantly influenced hand location estimates, this effect did not differ between groups. Our findings provide compelling evidence that multisensory body location perception - specifically the processing of visual-proprioceptive signals - is changed in AN.

Stigma experienced by people using mental health services in San Diego County.

OBJECTIVE: This paper describes how individuals struggling with severe mental illness experience stigma along multiple dimensions including their experiences of discrimination by others, their unwillingness to disclose information about their mental health, and their internalization or rejection of the negative and positive aspects of having mental health problems. METHODS: This cross-sectional study employs descriptive analyses and linear regression to assess the relationship between demographics, mental health diagnoses and self-reported stigma among people receiving mental health services in a large and ethnically diverse county public mental health system (n = 1,237) in 2009. We used the King Stigma Scale to measure three factors related to stigma: discrimination, disclosure, and positive aspects of mental illness. RESULTS: Most people (89.7 %) reported experiencing some discrimination from having mental health problems. Regression analyses revealed that younger people in treatment experienced more stigma related to mental health problems. Women reported experiencing more stigma than men, but men were less likely to endorse the potentially positive aspects of facing mental health challenges than women. Although people with mood disorders reported more discomfort with disclosing mental illness than people with schizophrenia, they did not report experiencing more discrimination than people with schizophrenia. CONCLUSIONS: Study findings suggest that the multidimensional experiences of stigma differ as a function of age, gender, and diagnosis. Importantly, these findings should inform anti-stigma efforts by describing different potential treatment barriers due to experiences of stigma among people using mental health services, especially among younger people and women who may be more susceptible to stigma.

Lithography-free approach to highly efficient, scalable SERS substrates based on disordered clusters of disc-on-pillar structures.

We present a lithography-free technological strategy that enables fabrication of large area substrates for surface-enhanced Raman spectroscopy (SERS) with excellent performance in the red to NIR spectral range. Our approach takes advantage of metal dewetting as a facile means to create stochastic arrays of circular patterns suitable for subsequent fabrication of plasmonic disc-on-pillar (DOP) structures using a combination of anisotropic reactive ion etching (RIE) and thin film deposition. Consistent with our previous studies of individual DOP structures, pillar height which, in turn, is defined by the RIE processing time, has a dramatic effect on the SERS performance of stochastic arrays of DOP structures. Our computational analysis of model DOP systems confirms the strong effect of the pillar height and also explains the broadband sensitivity of the implemented SERS substrates. Our Raman mapping data combined with SEM structural analysis of the substrates exposed to benzenethiol solutions indicates that clustering of shorter DOP structures and bundling of taller ones is a likely mechanism contributing to higher SERS activity. Nonetheless, bundled DOP structures appeared to be consistently less SERS-active than vertically aligned clusters of DOPs with optimized parameters. The latter are characterized by average SERS enhancement factors above 10(7).

Local Health Department Provision of WIC Services Relative to Local "Need"- Examining 3 States and 5 Years.

Great variation exists in the nature of LHD service delivery and it varies, in part, relative to jurisdiction population size. Larger LHD jurisdictions may achieve an economy of scale in WIC service delivery that is not matched in smaller areas. Overall, we found that WIC service provision appears relatively consistent across study states and in the presence of increasing need, with greater responsiveness to need in urban areas. As demand for some preventive services increases LHDs in rural areas may need greater support than LHDs in large jurisdictions for meeting local demand. Unlike WIC, LHD-provided services that have less consistently maintained service-delivery guidelines may have a harder time responding to increasing need. The relative consistency of a federally-funded program such as WIC may serve as a good baseline for further study of less consistently delivered programs among LHDs. LHD service statistics can serve as useful data sources in measuring volume of service delivery relative to need.

Building academic capacity through statewide partnerships.

In 2008, Texas was challenged by the Center to Champion Nursing in America, an initiative of the Robert Wood Johnson Foundation and AARP, to join a nationwide campaign for action to increase nursing education capacity. This article describes how one state created academic partnerships to achieve capacity building and strengthened relationships and commitments to invest in nursing education. Three year outcomes include a) the creation of a statewide team to address nursing education capacity, b) progress toward doubling the number of nursing graduates from the state's schools of nursing, c) strengthening and emphasizing retention efforts across the state, d) regionalization, including implementation of a $1 million grant and e) transitioning the statewide team to a broader focus and commitment to the Initiative on the Future of Nursing via the formation of a Regional Action Coalition.

Homocysteine, vitamin B12, and folic acid levels in Alzheimer's disease, mild cognitive impairment, and healthy elderly: baseline characteristics in subjects of the Australian Imaging Biomarker Lifestyle study.

There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate.

Innovation in nursing education: a statewide grant initiative.

Meeting the challenges of the nursing shortage appears to be daunting for schools of nursing across the nation as they struggle to meet educational capacity needs with limited resources. A statewide grant program was developed and implemented through legislative initiatives providing opportunities for schools of nursing to respond to the need for innovation in nursing education. This article shares some of the successes and challenges identified through the process of implementing and evaluating this grant program. Insights into the political and regulatory process are provided as a model for other states to consider. Examples of educational strategies that were successful in improving the recruitment and retention of students and faculty are discussed. Nursing and other health care leaders across the nation should look to policy initiatives such as grant programs to infuse innovation into educational programs and to address educational capacity issues compounding the nursing shortage.

Synthesis and biological evaluation of leucine enkephalin turn mimetics.

A cyclic Leu-enkephalin mimetic containing a 7-membered ring, and two linear analogues, has been prepared on solid phase. In the cyclic mimetic the intramolecular (1-4) hydrogen bond found in crystalline Leu-enkephalin has been replaced by an ethylene bridge. In addition, the amide bond between Tyr1 and Gly2 has been replaced by a methylene ether isostere and Gly3 has been deleted. The two linear analogues both contain the methylene ether isostere instead of the Tyr1-Gly2 amide bond and the shorter of the two lacks Gly3. The three compounds, and a beta-turn mimetic analogous to the 7-membered turn mimetic but with Gly3 included, were evaluated for specific binding to micro- and delta-opioid receptors in rat brain membranes. With the exception of the beta-turn mimetic the three other Leu-enkephalin analogues all bound with varying affinity to the micro- and delta-opioid receptors. From the results it could be concluded that Leu-enkephalin binds in a turn conformation to the opiate receptors, but that this conformation is not a (1-4) beta-turn.