Miracle-dz/UniFAR-FTUs huggingface dataset:
Acupuncture as a complex intervention: a holistic model.

OBJECTIVES Our understanding of acupuncture and Chinese medicine is limited by a lack of inquiry into the dynamics of the process. We used a longitudinal research design to investigate how the experience, and the effects, of a course of acupuncture evolved over time. DESIGN AND OUTCOME MEASURES This was a longitudinal qualitative study, using a constant comparative method, informed by grounded theory. Each person was interviewed three times over 6 months. Semistructured interviews explored people's experiences of illness and treatment. Across-case and within-case analysis resulted in themes and individual vignettes. SUBJECTS AND SETTINGS Eight (8) professional acupuncturists in seven different settings informed their patients about the study. We interviewed a consecutive sample of 23 people with chronic illness, who were having acupuncture for the first time. RESULTS People described their experience of acupuncture in terms of the acupuncturist's diagnostic and needling skills; the therapeutic relationship; and a new understanding of the body and self as a whole being. All three of these components were imbued with holistic ideology. Treatment effects were perceived as changes in symptoms, changes in energy, and changes in personal and social identity. The vignettes showed the complexity and the individuality of the experience of acupuncture treatment. The process and outcome components were distinct but not divisible, because they were linked by complex connections. The paper depicts these results as a diagrammatic model that illustrates the components and their interconnections and the cyclical reinforcement, both positive and negative, that can occur over time. CONCLUSIONS The holistic model of acupuncture treatment, in which "the whole being greater than the sum of the parts," has implications for service provision and for research trial design. Research trials that evaluate the needling technique, isolated from other aspects of process, will interfere with treatment outcomes. The model requires testing in different service and research settings.
Aβ40 Reduces P-Glycoprotein at the Blood–Brain Barrier through the Ubiquitin–Proteasome Pathway

Failure to clear amyloid-β (Aβ) from the brain is in part responsible for Aβ brain accumulation in Alzheimer's disease (AD). A critical protein for clearing Aβ across the blood–brain barrier is the efflux transporter P-glycoprotein (P-gp) in the luminal plasma membrane of the brain capillary endothelium. P-gp is reduced at the blood–brain barrier in AD, which has been shown to be associated with Aβ brain accumulation. However, the mechanism responsible for P-gp reduction in AD is not well understood. Here we focused on identifying critical mechanistic steps involved in reducing P-gp in AD. We exposed isolated rat brain capillaries to 100 nm Aβ40, Aβ40, aggregated Aβ40, and Aβ42. We observed that only Aβ40 triggered reduction of P-gp protein expression and transport activity levels; this occurred in a dose- and time-dependent manner. To identify the steps involved in Aβ-mediated P-gp reduction, we inhibited protein ubiquitination, protein trafficking, and the ubiquitin–proteasome system, and monitored P-gp protein expression, transport activity, and P-gp-ubiquitin levels. Thus, exposing brain capillaries to Aβ40 triggers ubiquitination, internalization, and proteasomal degradation of P-gp. These findings may provide potential therapeutic targets within the blood–brain barrier to limit P-gp degradation in AD and improve Aβ brain clearance. SIGNIFICANCE STATEMENT The mechanism reducing blood–brain barrier P-glycoprotein (P-gp) in Alzheimer's disease is poorly understood. In the present study, we focused on defining this mechanism. We demonstrate that Aβ40 drives P-gp ubiquitination, internalization, and proteasome-dependent degradation, reducing P-gp protein expression and transport activity in isolated brain capillaries. These findings may provide potential therapeutic avenues within the blood–brain barrier to limit P-gp degradation in Alzheimer's disease and improve Aβ brain clearance.
Development and growth of the lung

The lung is designed to provide a large internal surface area in which the inspired air and capillary blood get in intimate contact to each other and thus allow for an efficient exchange of gases. This goal is achieved by a sequence of distinct but overlapping developmental processes (Fig. 5-1; Table 5-1). Organogenesis (embryonic stage) starts with a ventral outpouching of the foregut giving rise to the left and right lung buds. The following development of the airways and gas exchange structures is based on two different mechanisms. Starting from the lung buds, a continuous process of branching and growth into the surrounding mesenchyme preforms the whole conducting airway tree and probably also parts of the respiratory airways (branching morphogenesis). Most of this process takes place during the pseudoglandular stage. The tremendous increase of the gas exchange surface area in late fetal and postnatal lung development is brought about by a process of repetitive airspace septation leading to the formation of alveoli (stage of alveolarization). The canalicular and saccular stages may be considered as intermediate stages between both developmental principles. In the canalicular stage the first air-blood barriers are formed and surfactant production starts. During the saccular stage the switch from branching to septation occurs. Following bulk alveolarization, which in humans occurs mainly after birth, the interalveolar septa and their capillary networks are remodeled to optimize gas exchange during the stage of microvascular maturation. At this point lung development is viewed as finished; it is followed by normal growth of the organ. However, we assume today that some form of late alveolarization at a slow rate may exist. Relative to lung development, the time point of birth varies greatly among mammalian species. In humans, birth occurs early in the alveolar stage. The staging of lung development as described traditionally is highly descriptive. It is based on light microscopical observations of morphologic changes in the developing lung (Figs. 5-1 and 5-2). Large overlaps exist between subsequent stages for two reasons. First, lung development proceeds metachrotically from the proximal to the peripheral portions of the airway tree. Second, some developmental steps and maturation processes defining the stages may run in parallel in neighboring areas. The beginning of pulmonary development is relatively well defined by the first appearance of the future trachea and the lung buds in the region of the foregut. There is no such clear limit, however, as to when it ends during childhood. Thus, lung development slowly blends into lung growth and it boils down to a question of sophisticated definitions when development ends and growth starts.
Neogene paleogeography provides context for understanding the origin and spatial distribution of cryptic diversity in a widespread Balkan freshwater amphipod

Background The Balkans are a major worldwide biodiversity and endemism hotspot. Among the freshwater biota, amphipods are known for their high cryptic diversity. However, little is known about the temporal and paleogeographic aspects of their evolutionary history. We used paleogeography as a framework for understanding the onset of diversification in Gammarus roeselii: (1) we hypothesised that, given the high number of isolated waterbodies in the Balkans, the species is characterised by high level of cryptic diversity, even on a local scale; (2) the long geological history of the region might promote pre-Pleistocene divergence between lineages; (3) given that G. roeselii thrives both in lakes and rivers, its evolutionary history could be linked to the Balkan Neogene paleolake system; (4) we inspected whether the Pleistocene decline of hydrological networks could have any impact on the diversification of G. roeselii. Material and Methods DNA was extracted from 177 individuals collected from 26 sites all over Balkans. All individuals were amplified for ca. 650 bp long fragment of the mtDNA cytochrome oxidase subunit I (COI). After defining molecular operational taxonomic units (MOTU) based on COI, 50 individuals were amplified for ca. 900 bp long fragment of the nuclear 28S rDNA. Molecular diversity, divergence, differentiation and historical demography based on COI sequences were estimated for each MOTU. The relative frequency, geographic distribution and molecular divergence between COI haplotypes were presented as a median-joining network. COI was used also to reconstruct time-calibrated phylogeny with Bayesian inference. Probabilities of ancestors’ occurrence in riverine or lacustrine habitats, as well their possible geographic locations, were estimated with the Bayesian method. A Neighbour Joining tree was constructed to illustrate the phylogenetic relationships between 28S rDNA haplotypes. Results We revealed that G. roeselii includes at least 13 cryptic species or molecular operational taxonomic units (MOTUs), mostly of Miocene origin. A substantial Pleistocene diversification within-MOTUs was observed in several cases. We evidenced secondary contacts between very divergent MOTUs and introgression of nDNA. The Miocene ancestors could live in either lacustrine or riverine habitats yet their presumed geographic localisations overlapped with those of the Neogene lakes. Several extant riverine populations had Pleistocene lacustrine ancestors. Discussion Neogene divergence of lineages resulting in substantial cryptic diversity may be a common phenomenon in extant freshwater benthic crustaceans occupying areas that were not glaciated during the Pleistocene. Evolution of G. roeselii could be associated with gradual deterioration of the paleolakes. The within-MOTU diversification might be driven by fragmentation of river systems during the Pleistocene. Extant ancient lakes could serve as local microrefugia during that time.
Equilibrium Efficiency Improvement in MIMO Interference Systems: A Decentralized Stream Control Approach

We consider a multi-link MIMO interference system in which each link wishes to maximize its own mutual information by choosing its own signal vector, which leads to a multi-player game. We show the existence of a Nash equilibrium and obtain sufficient conditions for the uniqueness of equilibrium. We consider two decentralized link adjustment algorithms called best-response process (a.k.a. iterative water- filling) and gradient-play (an autonomous and non-cooperative version of the well-known gradient ascent algorithm). Under our uniqueness conditions, we establish the convergence of these algorithms to the unique equilibrium provided that the links use some inertia. To improve the efficiency of an equilibrium with respect to the total mutual information by imposing limits on the number of independent data streams, we present a stream control approach using linear transformation of the link covariance matrices. We then show how to decentralize our stream control approach by allowing the links to negotiate the limits on the number of independent data streams that they are willing to impose upon themselves. To achieve this, we introduce a variation of a learning algorithm called "adaptive play" that has desirable convergence properties in potential games with reduced computation.
Developmental Improvement and Age-Related Decline in Unfamiliar Face Matching

Age-related changes have been documented widely in studies of face recognition and eyewitness identification. However, it is not clear whether these changes arise from general developmental differences in memory or occur specifically during the perceptual processing of faces. We report two experiments to track such perceptual changes using a 1-in-10 (experiment 1) and 1-in-1 (experiment 2) matching task for unfamiliar faces. Both experiments showed improvements in face matching during childhood and adult-like accuracy levels by adolescence. In addition, face-matching performance declined in adults of the age of 65 years. These findings indicate that developmental improvements and aging-related differences in face processing arise from changes in the perceptual encoding of faces. A clear face inversion effect was also present in all age groups. This indicates that those age-related changes in face matching reflect a quantitative effect, whereby typical face processes are engaged but do not operate at the best-possible level. These data suggest that part of the problem of eyewitness identification in children and elderly persons might reflect impairments in the perceptual processing of unfamiliar faces.
Family physicians’ self-perceived importance of providing genetic test information to patients: A cross-sectional study from Slovenia

Background Management of patients with genetic problems, including provision of genetic testing, is increasingly becoming a part of primary health care. The aim of this study was to determine the family physicians’ (FPs) self-perceived importance of providing genetic test information to their patients. Material/Methods This was an observational cross-sectional postal study in the whole population of Slovenian family physicians (N=950). Its main outcome measure was the perceived importance of providing genetic test information on each of 10 items on a 5-point Likert scale. Results There were 271 (27.1% response rate) FPs that completed the questionnaire, out of which 205 (75.6%) were women. Mean age of the sample was 45.5±10.6 years. More than 90% of Slovene FPs felt that it was their professional duty to discuss genetic testing issues with their patients. They were particularly prone to discuss clinical implications of positive and negative test results, as well as giving the patients information about the risk of passing a mutation onto children. Conclusions Most Slovene family physicians feel responsible and willing to offer and discuss genetic testing and implications with their patients. Additional education should be provided to empower them for this task.
Lithium response in bipolar disorders and core clock genes expression

Abstract Objectives: We examine whether the lithium response is associated with changes in the expression of core clock genes. Methods: The effect of a therapeutic concentration of lithium (1 mM) on the expression levels of 17 circadian genes was examined in lymphoblastoid cell lines (LCLs) derived from two well-characterized groups of bipolar disorder patients, defined as lithium non-responders (NR, n = 20) or excellent responders (ER, n = 16). Quantitative real-time PCR (qRT-PCR) was conducted at 2, 4 and 8 days (d2, d4 and d8) with and without lithium exposure. Results: At d2, in ER only, BHLHE41, RORA, PER1, ARNTL, CRY2, BHLHE40 and CSNK1D were upregulated, whereas NR1D1 was downregulated. At d4, in ER only, CRY1 was downregulated. At d8, in NR only, GSK3β was upregulated and DBP, TIMELESS and CRY1 were downregulated. Significant Group × Lithium interactions existed for NR1D1 at d2 (P = 0.02), and CRY1 at d4 (P = 0.02). Longitudinal analyses showed differential temporal evolutions between NR and ER (significant Time × Group interaction) for PER3, NR1D1, DBP, RORA, CSNK1D and TIMELESS; and a significant Time × Lithium interaction for NR1D1. Coexpression data analyses suggested distinct groups of circadian genes concurrently modulated by lithium. Conclusions: In LCLs, lithium influences expression of circadian genes with differences in amplitude and kinetics according to the patient’s lithium response status.
Nuclear‐targeted chimeric vector enhancing nonviral gene transfer into skeletal muscle of Fabry mice in vivo

Poor nuclear entry, especially into nondividing cells, is a limiting factor in nonviral gene delivery. We have engineered a novel chimeric vector relying on the controlled assembly of a TAT‐tagged multisubunit DNA binding protein (EcoR124I) with expression plasmids containing the EcoR124I recognition site. Molecular interactions of this molecular assembly were studied by electrophoretic mobility shift assay and atomic force microscopy. Maintenance of nanocomplexes in an appropriate stoichiometric ratio was both necessary and sufficient to produce a signifi cant (> 8‐fold) increase in the activity of the therapeutic a‐galactosidase A enzyme after intramuscular administration in the mouse model of Fabry disease. To our knowledge, this is the first molecular targeting system significantly enhancing plasmid‐based expression in skeletal muscle. Coinjection with pluronic SP1017 produced further enhancement of gene expression, demonstrating cumulative effects of the increased nuclear delivery by TAT chimeras and transcription activation by the pluronic. Cell penetration peptides (CPP), such as TAT, have been shown to improve delivery of macromolecules, when linked directly. However, in our system TAT‐enhanced targeting took place even though it was linked to the plasmid DNA molecule indirectly via two noncovalent bonds. Therefore, this proof‐of principle result indicates that TAT (and potentially other CPP) can be used for targeting modular chimeric vectors and therapeutic nanodevices. — Lavigne M. D. , Yates, L. , Coxhead, P., Górecki D. C. Nuclear‐targeted chimeric vector enhancing nonviral gene transfer into skeletal muscle of Fabry mice in vivo. FASEB J. 22, 2097–2107 (2008)
Working memory deficit as a core neuropsychological dysfunction in schizophrenia.

OBJECTIVE This study tested the hypothesis that impaired working memory is a core deficit underlying multiple neuropsychological deficits in schizophrenia patients. METHOD The subjects were 27 men with stable chronic schizophrenia treated with atypical antipsychotics and 38 normal participants. They were assessed with a battery of neuropsychological tests. Verbal working memory was measured with the WAIS digit span tests, and the Dot Test was used to test spatial working memory. RESULTS In the patients, verbal working memory showed significant correlations with visual retention, visual orientation, simple motor function, visuomotor coordination, and executive function but not with memory for objects, memory for faces, recognition of facial emotions, or attention. Spatial working memory showed significant correlations with visual retention, visual orientation, memory for objects, memory for faces, and simple motor function but not attention, executive function, or visuomotor coordination. In the comparison group, no correlations between working memory and other neuropsychological functions were found. CONCLUSIONS These findings support the hypothesis that working memory is a core deficit in schizophrenia. The authors postulate that the lower capacity for verbal and spatial "on-line storage" is rate limiting in the performance of other cognitive functions. Executive functions rely critically on the phonetic loop, complex visual functions such as object and face memory rely on the spatial on-line storage system (visuospatial scratch pad), while other functions such as visual orientation depend critically on both capacities.
Repeatable evaluation of search services in dynamic environments

In dynamic environments, such as the World Wide Web, a changing document collection, query population, and set of search services demands frequent repetition of search effectiveness (relevance) evaluations. Reconstructing static test collections, such as in TREC, requires considerable human effort, as large collection sizes demand judgments deep into retrieved pools. In practice it is common to perform shallow evaluations over small numbers of live engines (often pairwise, engine A vs. engine B) without system pooling. Although these evaluations are not intended to construct reusable test collections, their utility depends on conclusions generalizing to the query population as a whole. We leverage the bootstrap estimate of the reproducibility probability of hypothesis tests in determining the query sample sizes required to ensure this, finding they are much larger than those required for static collections. We propose a semiautomatic evaluation framework to reduce this effort. We validate this framework against a manual evaluation of the top ten results of ten Web search engines across 896 queries in navigational and informational tasks. Augmenting manual judgments with pseudo-relevance judgments mined from Web taxonomies reduces both the chances of missing a correct pairwise conclusion, and those of finding an errant conclusion, by approximately 50%.
EEG-based workload estimation across affective contexts

Workload estimation from electroencephalographic signals (EEG) offers a highly sensitive tool to adapt the human–computer interaction to the user state. To create systems that reliably work in the complexity of the real world, a robustness against contextual changes (e.g., mood), has to be achieved. To study the resilience of state-of-the-art EEG-based workload classification against stress we devise a novel experimental protocol, in which we manipulated the affective context (stressful/non-stressful) while the participant solved a task with two workload levels. We recorded self-ratings, behavior, and physiology from 24 participants to validate the protocol. We test the capability of different, subject-specific workload classifiers using either frequency-domain, time-domain, or both feature varieties to generalize across contexts. We show that the classifiers are able to transfer between affective contexts, though performance suffers independent of the used feature domain. However, cross-context training is a simple and powerful remedy allowing the extraction of features in all studied feature varieties that are more resilient to task-unrelated variations in signal characteristics. Especially for frequency-domain features, across-context training is leading to a performance comparable to within-context training and testing. We discuss the significance of the result for neurophysiology-based workload detection in particular and for the construction of reliable passive brain–computer interfaces in general.
Efficacy and safety of low-dose clopidogrel after 12-month dual antiplatelet therapy for patients having drug-eluting stent implantation.

BACKGROUND To prevent stent thrombosis (ST) after implantation of drug-eluting stents (DESs) in patients with coronary heart disease, 12-month dual antiplatelet therapy (DAPT) is recommended. However, the optimal long-term antiplatelet regimen is not clear for the patients who have completed the 12-month DAPT. METHODS We reviewed the data of 755 consecutive patients who had undergone percutaneous coronary intervention (PCI) three years ago and completed 12-month DAPT. They were divided into three groups according to the antiplatelet medication they had used for two years after 12-month DAPT [low-dose clopidogrel (Talcom(®), 25mg/d), clopidogrel (Plavix(®), 75mg/d) and aspirin (100 mg/d)]. The efficacy (a composite incidence of cardiac death, myocardial infarction and target vessel revascularization) and safety (incidences of bleeding, gastrointestinal trouble and drug discontinuation) were compared among the three groups. RESULTS The rates of multi-vessel lesions, prior MI, hemoglobin A1C (HbA1c) and low-density lipoprotein cholesterol were significantly higher in the clopidogrel (75 mg/day) group than in the other two groups (P>0.05 for both comparisons). There was no significant difference in the overall composite incidence of cardiac death, myocardial infarction and target vessel revascularization in the three groups at three years after PCI. The rates of bleeding (especially minor bleeding), gastrointestinal trouble, drug discontinuation and any blood transfusion were markedly lower in the low-dose clopidogrel (25 mg/d) group than in the other two treatment groups (P<0.05). CONCLUSIONS The 25-mg maintenance dose of clopidogrel after 12-month DAPT may be more preferable to Chinese patients who have undergone DES implantation, because of its lower cost but no less efficacy and safety.