Miracle-dz/UniFAR-FTUs huggingface dataset:
The hierarchy of functional loss associated with cognitive decline in older persons.

OBJECTIVES We studied a representative cohort of community-dwelling elderly persons to (i) examine the relationship between the loss of specific functional activities and cognitive status at the time of these losses, (ii) compare the cognitive status of participants who have and have not lost independence in these functional activities, and (iii) determine whether a hierarchical scale of functional loss is associated with declining cognitive status. METHODS A cohort of 5874 community-dwelling persons aged 65 years and older from the Canadian Study of Health and Aging I and II were analyzed. At baseline and 5 years later, cognitive status with the Modified Mini-Mental State Examination (3MS) and functional status with 14 Older American Resources and Services (OARS) items were measured. For each OARS functional item, the mean 3MS scores for persons who lost independence during the 5-year period versus those who did not were compared. RESULTS For each functional item, the 5-year decline in 3MS scores of persons who lost independence were significantly greater than those who remained independent (e.g., ability to do finances), with an 18-point decline for those who lost independence and a 2-point decline for those who retained independence. A hierarchy of functional items existed, with instrumental activities of daily living (ADLs) (e.g., shopping, banking, and cooking) being lost at higher cognitive scores than basic ADL items (e.g., eating, dressing, and walking), although there was some overlap. CONCLUSIONS This is the first prospective study using a large representative cohort of elderly persons to demonstrate that progressive cognitive decline is associated with a specific pattern of loss of functional tasks. Clear cognitive thresholds at which development of dependency in OARS functional items occurred. By providing estimates of the cognitive status of persons at the time at which they developed dependency in specific functional items, a natural hierarchy of functional loss associated with cognitive decline emerged. For caregivers, clinicians, and health policy makers, this information can help anticipate the pattern of functional decline and the subsequent care needs of persons with declining cognition, potentially improving the quality of life of these persons and their caregivers and playing an important part in health care planning.
Ezrin Binds to DEAD-Box RNA Helicase DDX3 and Regulates Its Function and Protein Level

ABSTRACT Ezrin is a key regulator of cancer metastasis that links the extracellular matrix to the actin cytoskeleton and regulates cell morphology and motility. We discovered a small-molecule inhibitor, NSC305787, that directly binds to ezrin and inhibits its function. In this study, we used a nano-liquid chromatography-tandem mass spectrometry (nano-LC–MS-MS)-based proteomic approach to identify ezrin-interacting proteins that are competed away by NSC305787. A large number of the proteins that interact with ezrin were implicated in protein translation and stress granule dynamics. We validated direct interaction between ezrin and the RNA helicase DDX3, and NSC305787 blocked this interaction. Downregulation or long-term pharmacological inhibition of ezrin led to reduced DDX3 protein levels without changes in DDX3 mRNA. Ectopic overexpression of ezrin in low-ezrin-expressing osteosarcoma cells caused a notable increase in DDX3 protein levels. Ezrin inhibited the RNA helicase activity of DDX3 but increased its ATPase activity. Our data suggest that ezrin controls the translation of mRNAs preferentially with a structured 5′ untranslated region, at least in part, by sustaining the protein level of DDX3 and/or regulating its function. Therefore, our findings suggest a novel function for ezrin in regulation of gene translation that is distinct from its canonical role as a cytoskeletal scaffold at the cell membrane.
Dissecting the genetics of the human transcriptome identifies novel trait-related trans-eQTLs and corroborates the regulatory relevance of non-protein coding loci†

Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait-associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters and enrichment of co-localized functional elements. We found eQTLs for about 85% of analysed genes, and 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs; however, our data suggest that most cis-heritability of these transcripts seems explained. Dissection of co-localized functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene expression, pathways and disease-related processes.
Intrinsic activation of PI3K/Akt signaling pathway and its neuroprotective effect against retinal injury

Purpose. The aim of this study was to determine whether the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway can function as a neuroprotective pathway following induced retinal injury. Methods. The activation of Akt was assessed by immunoblot analysis, and the role of PI3K/Akt pathway was evaluated by TUNEL staining and counting the number of retrogradelylabeled retinal ganglion cells (RGCs) in the whole retina at 168 h after injury with or without PI3K specific inhibitor, LY294002. Results. Akt was induced within one hr and reached a maximum 6hrs after optic nerve clamping. The activation was observed in the RGC layer including RGCs, the inner plexiform layer, inner nuclear layer, and in the photoreceptor outer segments. The number of surviving RGCs was decreased significantly 168 hrs after injury. LY294002 partially inhibited the activation of Akt, and significantly decreased the number of surviving RGCs as compared with that of injury alone. Conclusions. These results indicate that the PI3K/Akt signaling pathway is activated intrinsically and has a neuroprotective effect on injured RGCs.
Formula feeding potentiates docosahexaenoic and arachidonic acid biosynthesis in term and preterm baboon neonates Published, JLR Papers in Press, October 1, 2003. DOI 10.1194/jlr.M300106-JLR200

Infant formulas supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now available in the United States; however, little is known about the factors that affect biosynthesis. Baboon neonates were assigned to one of four treatments: term, breast-fed; term, formula-fed; preterm (155 of 182 days gestation), formula-fed; and preterm, formula+DHA/ARA-fed. Standard formula had no DHA/ARA; supplemented formula had 0.61%wt DHA (0.3% of calories) and 1.21%wt ARA (0.6% of calories), and baboon breast milk contained 0.68 ± 0.22%wt DHA and 0.62 ± 0.12%wt ARA. At 14 days adjusted age, neonates received a combined oral dose of [U-13C]α-linolenic acid (LNA*) and [U-13C]linoleic acid (LA*), and tissues were analyzed 14 days after dose. Brain accretion of linolenic acid-derived DHA was ∼3-fold greater for the formula groups than for the breast-fed group, and dietary DHA partially attenuated excess DHA synthesis among preterms. A similar, significant pattern was found in other organs. Brain linoleic acid-derived ARA accretion was significantly greater in the unsupplemented term group but not in the preterm groups compared with the breast-fed group. These data show that formula potentiates the biosynthesis/accretion of DHA/ARA in term and preterm neonates compared with breast-fed neonates and that the inclusion of DHA/ARA in preterm formula partially restores DHA/ARA biosynthesis to lower, breast-fed levels. Current formula DHA concentrations are inadequate to normalize long-chain polyunsaturated fatty acids synthesis to that of breast-fed levels.
Catheter ablation in selected patients with depressed left ventricular ejection fraction and persistent atrial fibrillation unresponsive to current cardioversion.

AIMS In congestive heart failure (CHF) patients with persistent atrial fibrillation (AF), direct current cardioversion (DCC) may reveal participation of tachycardiamediated process to left ventricular (LV) dysfunction by restoring sinus rhythm (SR). However, if DCC fails to restore SR, patients' management remains challenging. The aim of the study was to assess the AF catheter ablation benefit in a selected group of CHF patients with LV ejection fraction (LVEF) <40% and persistent AF unresponsive to DCC, in whom a tachycardia-mediated process is thought to be predominant. METHODS AND RESULTS Between January 2008 and September 2011, among 129 CHF patients with persistent AF referred to our institution, 34 (63.8 ± 9-year old, 24 men) presented AF refractory to DCC with an estimated high likelihood of tachycardia-mediated LV dysfunction according to a specific set of criteria. These 34 patients underwent stepwise AF ablation and were closely followed up. After a mean 1.9 AF ablation procedures per patient and 17.6 ± 7 months after the last procedure, all patients were in SR. The New York Heart Association class improved from 2.8 ± 0.3 to 1 ± 0.2 (P< 0.001) and the LVEF increased from 30.4 ± 6 to 54.6 ± 6% (P< 0.0001) after 3-6 months of SR, with a persistent benefit as long as the SR was maintained. CONCLUSION Atrial fibrillation catheter ablation in selected CHF patients with persistent AF refractory to DCC and without any other evidence for secondary LV dysfunction leads to a substantial LVEF improvement in the majority of them. However, redo procedures are frequent in order to achieve mid-term SR maintenance.
Realization of different driving characteristics for autonomous vehicle by using model predictive control

This paper presents a control system for autonomous driving based on MPC in which driving style can be easily modified by changing control parameters. Each of the motion controls for the longitudinal and the lateral direction are formulated as the model predictive control problem. Finally the experimental verification by using driving simulator and a real electric vehicle is performed by implementing MPC on each platform, and it is confirmed that the proposed system can produce a large variety of driving characteristics. The implemented MPC package will also be beneficial to the developers and researchers in various fields other than control engineering field.
Adhesion Study of Copper Layer Deposited onto Liquid Crystalline Polymer for Electronic Packaging

The adhesion of copper/liquid-crystalline polymer bilayer lamination structures with various thickness fabricated with chemical electroless copper deposition (CECD) and surfaced activated bonding (SAB) were characterized mechanical shear-off tests. The influence on the surface morphology and chemical state during different processes, including sulfuric acid bath, heat treatments, plasma treatments and moisture aging processes are studied with X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SAM). Thus the two fabrication methods are compared and potential methods to intensify the adhesion strength are present. The results are valuable for the future work aimed at achieving a LCP substrate based system-in-a-packaging (SiP) fabrication flow
Developments and current pharmacotherapeutic recommendations for ankylosing spondylitis

The introduction of anti-TNFα therapy into the field of rheumatology has led to dramatic improvements in patient care, perhaps the most remarkable being in the management of ankylosing spondylitis. As experience with these compounds grows, their place in therapeutic strategy is becoming clearer, and it has been possible to develop evidence- and expertise-based recommendations for the management of ankylosing spondylitis to aid the clinician in patient care. This review outlines treatment advances in ankylosing spondylitis, including the use of anti-TNFα agents, and how these have been incorporated into clinical recommendations for daily use.
Simulated Cytoskeletal Collapse via Tau Degradation

We present a coarse-grained two dimensional mechanical model for the microtubule-tau bundles in neuronal axons in which we remove taus, as can happen in various neurodegenerative conditions such as Alzheimers disease, tauopathies, and chronic traumatic encephalopathy. Our simplified model includes (i) taus modeled as entropic springs between microtubules, (ii) removal of taus from the bundles due to phosphorylation, and (iii) a possible depletion force between microtubules due to these dissociated phosphorylated taus. We equilibrate upon tau removal using steepest descent relaxation. In the absence of the depletion force, the transverse rigidity to radial compression of the bundles falls to zero at about 60% tau occupancy, in agreement with standard percolation theory results. However, with the attractive depletion force, spring removal leads to a first order collapse of the bundles over a wide range of tau occupancies for physiologically realizable conditions. While our simplest calculations assume a constant concentration of microtubule intercalants to mediate the depletion force, including a dependence that is linear in the detached taus yields the same collapse. Applying percolation theory to removal of taus at microtubule tips, which are likely to be the protective sites against dynamic instability, we argue that the microtubule instability can only obtain at low tau occupancy, from 0.06–0.30 depending upon the tau coordination at the microtubule tips. Hence, the collapse we discover is likely to be more robust over a wide range of tau occupancies than the dynamic instability. We suggest in vitro tests of our predicted collapse.
Common Variants in a Novel Gene, FONG on Chromosome 2q33.1 Confer Risk of Osteoporosis in Japanese

Osteoporosis is a common disease characterized by low bone mass, decreased bone quality and increased predisposition to fracture. Genetic factors have been implicated in its etiology; however, the specific genes related to susceptibility to osteoporosis are not entirely known. To detect susceptibility genes for osteoporosis, we conducted a genome-wide association study in Japanese using ∼270,000 SNPs in 1,747 subjects (190 cases and 1,557 controls) followed by multiple levels of replication of the association using a total of ∼5,000 subjects (2,092 cases and 3,114 controls). Through these staged association studies followed by resequencing and linkage disequilibrium mapping, we identified a single nucleotide polymorphism (SNP), rs7605378 associated with osteoporosis. (combined P = 1.51×10−8, odds ratio = 1.25). This SNP is in a previously unknown gene on chromosome 2q33.1, FONG. FONG is predicted to encode a 147 amino-acid protein with a formiminotransferase domain in its N-terminal (FTCD_N domain) and is ubiquitously expressed in various tissues including bone. Our findings would give a new insight into osteoporosis etiology and pathogenesis.
CASK Regulates SAP97 Conformation and Its Interactions with AMPA and NMDA Receptors

SAP97 interacts with AMPA receptors (AMPARs) and NMDA receptors (NMDARs) during sorting and trafficking to synapses. Here we addressed how SAP97 distinguishes between AMPARs and NMDARs and what role the adaptor/scaffold protein, CASK, plays in the process. Using intramolecular SAP97 Förster resonance energy transfer sensors, we demonstrated that SAP97 is in “extended” or “compact” conformations in vivo. SAP97 conformation was regulated by a direct interaction between SAP97 and CASK through L27 protein-interaction domains on each protein. Unbound SAP97 was mostly in the compact conformation, while CASK binding stabilized it in an extended conformation. In HEK cells and rat hippocampal neurons, SAP97 in the compact conformation preferentially associated and colocalized with GluA1-containing AMPARs, and in the extended conformation colocalized with GluN2B-containing NMDARs. Altogether, our findings suggest a molecular mechanism by which CASK binding regulates SAP97 conformation and its subsequent sorting and synaptic targeting of AMPARs and NMDARs during trafficking to synapses.
The biology of human mesenchymal stem cells

Mesenchymal stem cells (MSCs) are a population of progenitor cells derived from the bone marrow which are capable of differentiating into mesenchymal tissues. There is growing interest in development of MSCs as a therapeutic agent for the treatment of a wide range of diseases, as well as providing a model system to investigate human mesenchymal development. This review will focus on the historical evidence for the existence of MSC, as well as recent progress in our basic understanding of these cells.
Is dark silicon useful? Harnessing the four horsemen of the coming dark silicon apocalypse

Due to the breakdown of Dennardian scaling, the percentage of a silicon chip that can switch at full frequency is dropping exponentially with each process generation. This utilization wall forces designers to ensure that, at any point in time, large fractions of their chips are effectively dark or dim silicon, i.e., either idle or significantly underclocked. As exponentially larger fractions of a chip's transistors become dark, silicon area becomes an exponentially cheaper resource relative to power and energy consumption. This shift is driving a new class of architectural techniques that “spend” area to “buy” energy efficiency. All of these techniques seek to introduce new forms of heterogeneity into the computational stack. We envision that ultimately we will see widespread use of specialized architectures that leverage these techniques in order to attain orders-of-magnitude improvements in energy efficiency. However, many of these approaches also suffer from massive increases in complexity. As a result, we will need to look towards developing pervasively specialized architectures that insulate the hardware designer and the programmer from the underlying complexity of such systems. In this paper, I discuss four key approaches - the four horsemen - that have emerged as top contenders for thriving in the dark silicon age. Each class carries with its virtues deep-seated restrictions that requires a careful understanding of the underlying tradeoffs and benefits.
Unbiased conjugate direction boosting for conditional random fields

Conditional Random Fields (CRFs) currently receive a lot of attention for labeling sequences. To train CRFs, Dietterich et al. proposed a functional gradient optimization approach: the potential functions are represented as weighted sums of regression trees that are induced using Friedman’s gradient tree boosting method. In this paper, we improve upon this approach in two ways. First, we identify an expectation selection bias implicitly imposed and compensate for it. Second, we employ a more sophisticated boosting algorithm based on conjugate gradients in function space. Initial experiments show performance gains over the basic functional gradient approach.
THE HIGHLY ECCENTRIC PRE-MAIN-SEQUENCE SPECTROSCOPIC BINARY RX J0529.3+1210

The young system RX J0529.3+1210 was initially identified as a single-lined spectroscopic binary. Using high-resolution infrared spectra, acquired with NIRSPEC on Keck II, we measured radial velocities for the secondary. The method of using the infrared regime to convert single-lined spectra into double-lined spectra, and derive the mass ratio for the binary system, has been successfully used for a number of young, low-mass binaries. For RX J0529.3+1210, a long-period (462 days) and highly eccentric (0.88) binary system, we determine the mass ratio to be 0.78 ± 0.05 using the infrared double-lined velocity data alone, and 0.73 ± 0.23 combining visible light and infrared data in a full orbital solution. The large uncertainty in the latter is the result of the sparse sampling in the infrared and the high eccentricity: the stars do not have a large velocity separation during most of their ∼1.3 yr orbit. A mass ratio close to unity, consistent with the high end of the 1σ uncertainty for this mass ratio value, is inconsistent with the lack of a visible light detection of the secondary component. We outline several scenarios for a color difference in the two stars, such as one heavily spotted component, higher-order multiplicity, or a unique evolutionary stage, favoring detection of only the primary star in visible light, even in a mass ratio ∼1 system. However, the evidence points to a lower ratio. Although RX J0529.3+1210 exhibits no excess at near-infrared wavelengths, a small 24 μm excess is detected, consistent with circumbinary dust. The properties of this binary and its membership in λ Ori versus a new nearby stellar moving group at ∼90 pc are discussed. We speculate on the origin of this unusual system and on the impact of such high eccentricity, the largest observed in a pre-main-sequence double-lined system to date, on the potential for planet formation.
Benign versus secondary-progressive multiple sclerosis: the potential role of proton MR spectroscopy in defining the nature of disability.

PURPOSE We determined the clinical utility of proton MR spectroscopy in defining the extent of disability in benign versus secondary-progressive multiple sclerosis (MS). METHODS Thirty patients with clinically definite MS, including 16 patients with benign MS and 14 with secondary-progressive MS, and a group of 13 healthy volunteers were studied with combined stimulated-echo acquisition mode proton MR spectroscopy and MR imaging (all patients received contrast material). RESULTS Acute enhancing lesions of benign and secondary-progressive MS were characterized by a reduction in N-acetylaspartate (NAA)/choline and NAA/creatine and an increase in inositol compounds/creatine as compared with normal white matter. Such variations were also detected in chronic unenhancing lesions in patients with secondary-progressive MS, although they were not found in chronic unenhancing lesions in patients with benign MS. Chronic lesions of the two forms of the disease have significative differences in NAA and inositol signals. CONCLUSION Proton MR spectroscopy is able to show metabolic changes occurring in the white matter of patients with MS. Such changes differ according to the phase (acute versus chronic) and the clinical form (benign versus secondary-progressive) of the disease.