Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-beta Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease

Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer’s disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer’s Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer’s Project’s meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-β (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD

The plight of the sense-making ape

This is a selective review of the published literature on object-choice tasks, where participants use directional cues to find hidden objects. This literature comprises the efforts of researchers to make sense of the sense-making capacities of our nearest living relatives. This chapter is written to highlight some nonsensical conclusions that frequently emerge from this research. The data suggest that when apes are given approximately the same sense-making opportunities as we provide our children, then they will easily make sense of our social signals. The ubiquity of nonsensical contemporary scientific claims to the effect that humans are essentially--or inherently--more capable than other great apes in the understanding of simple directional cues is, itself, a testament to the power of preconceived ideas on human perception

Recognition of Handwriting from Electromyography

Handwriting – one of the most important developments in human culture – is also a methodological tool in several scientific disciplines, most importantly handwriting recognition methods, graphology and medical diagnostics. Previous studies have relied largely on the analyses of handwritten traces or kinematic analysis of handwriting; whereas electromyographic (EMG) signals associated with handwriting have received little attention. Here we show for the first time, a method in which EMG signals generated by hand and forearm muscles during handwriting activity are reliably translated into both algorithm-generated handwriting traces and font characters using decoding algorithms. Our results demonstrate the feasibility of recreating handwriting solely from EMG signals – the finding that can be utilized in computer peripherals and myoelectric prosthetic devices. Moreover, this approach may provide a rapid and sensitive method for diagnosing a variety of neurogenerative diseases before other symptoms become clear

Chronic pain and sex differences:Women accept and move, while men feel blue

Purpose The aim of this study is to explore differences between male and female patients entering a rehabilitation program at a pain clinic in order to gain a greater understanding of different approaches to be used in rehabilitation. Method 1371 patients referred to a specialty pain rehabilitation clinic, completed sociodemographic and pain related questionnaires. They rated their pain acceptance (CPAQ-8), their kinesiophobia (TSK), the impact of pain in their life (MPI), anxiety and depression levels (HAD) and quality of life scales: the SF-36, LiSat-11, and the EQ-5D. Because of the large sample size of the study, the significance level was set at the p amp;lt;= .01. Results Analysis by t-test showed that when both sexes experience the same pain severity, women report significantly higher activity level, pain acceptance and social support while men report higher kinesiophobia, mood disturbances and lower activity level. Conclusion Pain acceptance (CPAQ-8) and kinesiophobia (TSK) showed the clearest differences between men and women. Pain acceptance and kinesiophobia are behaviorally defined and have the potential to be changed.Funding Agencies|Swedish Association of Local Authorities and Regions (SALAR); Vardal Foundation; RehSAM; AFA insurance, Sweden; Swedish Association for Survivors of Accident and Injury (RTP); Renee Eanders Foundation</p

Memory-guided force output is associated with self-reported ADHD symptoms in young adults

Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed mental health disorder in childhood and persists into adulthood in up to 65 % of cases. ADHD is associated with adverse outcomes such as the ability to gain and maintain employment and is associated with an increased risk for substance abuse obesity workplace injuries and traffic accidents A majority of diagnosed children have motor deficits; however, few studies have examined motor deficits in young adults. This study provides a novel examination of visuomotor control of grip force in young adults with and without ADHD. Participants were instructed to maintain force production over a 20-second trial with and without real-time visual feedback about their performance. The results demonstrated that when visual feedback was available, adults with ADHD produced slightly higher grip force than controls. However, when visual feedback was removed, adults with ADHD had a faster rate of decay of force, which was associated with ADHD symptom severity and trait impulsivity. These findings suggest that there may be important differences in the way that adults with ADHD integrate visual feedback during continuous motor tasks. These may account for some of the motor impairments reported in children with ADHD. These deficits could result from (1) dysfunctional sensory motor integration and/or (2) deficits in short-term visuomotor memory

Enhanced Fusion Pore Expansion Mediated by the Trans-Acting Endodomain of the Reovirus FAST Proteins

The reovirus fusion-associated small transmembrane (FAST) proteins are virus-encoded membrane fusion proteins that function as dedicated cell–cell fusogens. The topology of these small, single-pass membrane proteins orients the majority of the protein on the distal side of the membrane (i.e., inside the cell). We now show that ectopic expression of the endodomains of the p10, p14, and p15 FAST proteins enhances syncytiogenesis induced by the full-length FAST proteins, both homotypically and heterotypically. Results further indicate that the 68-residue cytoplasmic endodomain of the p14 FAST protein (1) is endogenously generated from full-length p14 protein expressed in virus-infected or transfected cells; (2) enhances syncytiogenesis subsequent to stable pore formation; (3) increases the syncytiogenic activity of heterologous fusion proteins, including the differentiation-dependent fusion of murine myoblasts; (4) exerts its enhancing activity from the cytosol, independent of direct interactions with either the fusogen or the membranes being fused; and (5) contains several regions with protein–protein interaction motifs that influence enhancing activity. We propose that the unique evolution of the FAST proteins as virus-encoded cellular fusogens has allowed them to generate a trans-acting, soluble endodomain peptide to harness a cellular pathway or process involved in the poorly understood process that facilitates the transition from microfusion pores to macrofusion and syncytiogenesis

Nucleolin Inhibits G4 Oligonucleotide Unwinding by Werner Helicase

The Werner protein (WRNp), a member of the RecQ helicase family, is strongly associated with the nucleolus, as is nucleolin (NCL), an important nucleolar constituent protein. Both WRNp and NCL respond to the effects of DNA damaging agents. Therefore, we have investigated if these nuclear proteins interact and if this interaction has a possible functional significance in DNA damage repair.Here we report that WRNp interacts with the RNA-binding protein, NCL, based on immunoprecipitation, immunofluorescent co-localization in live and fixed cells, and direct binding of purified WRNp to nucleolin. We also map the binding region to the C-terminal domains of both proteins. Furthermore, treatment of U2OS cells with 15 µM of the Topoisomerase I inhibitor, camptothecin, causes the dissociation of the nucleolin-Werner complex in the nucleolus, followed by partial re-association in the nucleoplasm. Other DNA damaging agents, such as hydroxyurea, Mitomycin C, and aphidicolin do not have these effects. Nucleolin or its C-terminal fragment affected the helicase, but not the exonuclease activity of WRNp, by inhibiting WRN unwinding of G4 tetraplex DNA structures, as seen in activity assays and electrophoretic mobility shift assays (EMSA).These data suggest that nucleolin may regulate G4 DNA unwinding by WRNp, possibly in response to certain DNA damaging agents. We postulate that the NCL-WRNp complex may contain an inactive form of WRNp, which is released from the nucleolus upon DNA damage. Then, when required, WRNp is released from inhibition and can participate in the DNA repair processes

The mismeasure of ape social cognition

In his classic analysis, The Mismeasure of Man, Gould (1981) demolished the idea that intelligence was an inherent, genetic trait of different human groups by emphasizing, among other things, (a) its sensitivity to environmental input, (b) the incommensurate pre-test preparation of different human groups, and (c) the inadequacy of the testing contexts, in many cases. According to Gould, the root cause of these oversights was confirmation bias by psychometricians, an unwarranted commitment to the idea that intelligence was a fixed, immutable quality of people. By virtue of a similar, systemic interpretive bias, in the last two decades, numerous contemporary researchers in comparative psychology have claimed human superiority over apes in social intelligence, based on two-group comparisons between postindustrial, Western Europeans and captive apes, where the apes have been isolated from European styles of social interaction, and tested with radically different procedures. Moreover, direct comparisons of humans with apes suffer from pervasive lapses in argumentation: Research designs in wide contemporary use are inherently mute about the underlying psychological causes of overt behavior. Here we analyze these problems and offer a more fruitful approach to the comparative study of social intelligence, which focuses on specific individual learning histories in specific ecological circumstances

Reconstructing Galaxy Histories from Globular Clusters

Nearly a century after the true nature of galaxies as distant "island universes" was established, their origin and evolution remain great unsolved problems of modern astrophysics. One of the most promising ways to investigate galaxy formation is to study the ubiquitous globular star clusters that surround most galaxies. Recent advances in our understanding of the globular cluster systems of the Milky Way and other galaxies point to a complex picture of galaxy genesis driven by cannibalism, collisions, bursts of star formation and other tumultuous events.Comment: Review Article published in Nature, 1 January 2004. 18 pages, 4 figures, pdf format onl