Miracle-dz/UniFAR-FTUs huggingface dataset:
The cholinergic hypothesis of Alzheimer’s disease: a review of progress

Alzheimer’s disease is one of the most common causes of mental deterioration in elderly people, accounting for around 50%-60% of the overall cases of dementia among persons over 65 years of age. The past two decades have witnessed a considerable research effort directed towards discovering the cause of Alzheimer’s disease with the ultimate hope of developing safe and effective pharmacological treatments. This article examines the existing scientific applicability of the original cholinergic hypothesis of Alzheimer’s disease by describing the biochemical and histopathological changes of neurotransmitter markers that occur in the brains of patients with Alzheimer’s disease both at postmortem and neurosurgical cerebral biopsy and the behavioural consequences of cholinomimetic drugs and cholinergic lesions. Such studies have resulted in the discovery of an association between a decline in learning and memory, and a deficit in excitatory amino acid (EAA) neurotransmission, together with important roles for the cholinergic system in attentional processing and as a modulator of EAA neurotransmission. Accordingly, although there is presently no “cure” for Alzheimer’s disease, a large number of potential therapeutic interventions have emerged that are designed to correct loss of presynaptic cholinergic function. A few of these compounds have confirmed efficacy in delaying the deterioration of symptoms of Alzheimer’s disease, a valuable treatment target considering the progressive nature of the disease. Indeed, three compounds have received European approval for the treatment of the cognitive symptoms of Alzheimer’s disease, first tacrine and more recently, donepezil and rivastigmine, all of which are cholinesterase inhibitors.
On the use of filter-bank energies driven from the autocorrelation sequence for noisy speech recognition

The OSA-LP (One-Sided Autocorrelation LP) representation of speech signal has shown to be attractive for noisy speech recognition because of both its high recognition performance with respect to the conventional LP in severe conditions of additive broad-band noise and its computational simplicity. However, the mel-cepstrum representation, which comes from a filter bank (FB) analysis, has become increasingly popular. Furthermore, hybrid techniques that combine filter-bank and LP analysis, have also been proposed. The aim of this paper is to gain some perspective of the merit of the autocorrelation, LP and FB based techniques in a real environment.
Educational Video Game Design: A Review of the Literature

Much attention has been directed to the use of video games for learning in recent years, in part due to the staggering amounts of capital spent on games in the entertainment industry, but also because of their ability to captivate player attention and hold it for lengthy periods of time as players learn to master game complexities and accomplish objectives. This review of the literature on video game research focuses on publications analyzing educational game design, namely those that present design elements conducive to learning, the theoretical underpinnings of game design, and learning outcomes from video game play.
Swelling-induced and controlled curving in layered gel beams

We describe swelling-driven curving in originally straight and non-homogeneous beams. We present and verify a structural model of swollen beams, based on a new point of view adopted to describe swelling-induced deformation processes in bilayered gel beams, that is based on the split of the swelling-induced deformation of the beam at equilibrium into two components, both depending on the elastic properties of the gel. The method allows us to: (i) determine beam stretching and curving, once assigned the characteristics of the solvent bath and of the non-homogeneous beam, and (ii) estimate the characteristics of non-homogeneous flat gel beams in such a way as to obtain, under free-swelling conditions, three-dimensional shapes. The study was pursued by means of analytical, semi-analytical and numerical tools; excellent agreement of the outcomes of the different techniques was found, thus confirming the strength of the method.
Food allergy Response to treatment with sodium cromoglycate

decline in chloramphenicol blood levels despite sustained IV treatment in high dosage. This decrease is probably explained by the induction of hepatic microsomal enzymes by phenobarbitone. Increased glucuronidation of chloramphenicol and a consequent decrease in therapeutic activity have been demonstrated in rats pretreated with phenobarbitone (Bella et al., 1968). The conventional chloramphenicol dose for meningitis and septicaemia is 50-100 mg/kg per 24 h in infants and children. A lower dose is usually recommended for neonates whose renal and liver immaturity delays chloramphenicol excretion, but Black et al. (1978) showed that doses of up to 95 mg/kg per 24 h may be needed to maintain therapeutic blood levels in this age group also. Our two patients show that during treatment with phenobarbitone even the maximum recommended dose of chloramphenicol, 100 mg/kg per 24 h, may be insufficient to maintain peak blood levels within the therapeutic range 15-25 mg/l. We therefore recommend that in all patients who receive enzymeinducing anticonvulsants (Conney, 1967), chloramphenicol blood levels should be measured every one or 2 days to avoid the hazards of excessive or inadequate dosage. It is possible that newer anticonvulsants with less enzyme-inducing activity, such as sodium valproate, will prove to have less effect on chloramphenicol metabolism than phenobarbitone.
The Caenorhabditis elegans paxillin orthologue, PXL-1, is required for pharyngeal muscle contraction and for viability

Caenorhabditis elegans pxl-1 is the orthologue of vertebrate paxillin and is expressed in body wall and pharyngeal muscle. In body wall muscle PXL-1 localizes to dense bodies, M-lines, and adhesion plaques, and in pharyngeal muscle PXL-1 localizes to podosome-like actin attachment complexes. PXL-1 is required in the pharynx for muscle contraction and viability.
Liquidity of the Hong Kong Stock Market since the Asian Financial Crisis Prepared

This paper looks into how the liquidity of Hong Kong stock market has evolved since the Asian financial crisis, and examines the determinants of changes in liquidity. Various conventional liquidity indicators are constructed for the study period from 1997 to June 2001, and they show that, having deteriorated during the Asian financial crisis and the Russia crisis, market liquidity has mostly recovered to the pre-crisis level in the more recent period. However, these conventional liquidity indicators have the drawbacks of being not able to capture fully the dynamics of liquidity. Thus, a GARCH model is developed for five selected stocks to relate the sensitivity of their price movements to net order flows, using a unique set of 30-second tick-by-tick data of the Hong Kong Stock Exchange. Empirical results from our model illustrate clearly a sharp deterioration of market liquidity during the crises, followed by an apparent recovery in the post-crisis period. Based on a simple OLS regression estimation, we also analyse the determinants of the time-variation of market liquidity. It is found that financial crises exert their influence on local liquidity mainly through their effect on domestic interest rates and price volatility, while global liquidity and risk conditions also play a significant role. ∗ The views expressed in this paper are solely our own and not necessarily those of the Hong Kong Monetary Authority (HKMA). We are grateful to Stefan Gerlach, Grace Lau, and internal seminar participants for useful comments and Polly Lai for excellent secretarial assistance. All remaining errors are ours.
Preclinical metabolism and the disposition of vornorexant/TS‐142, a novel dual orexin 1/2 receptor antagonist for the treatment of insomnia

Abstract We investigated the metabolism and disposition of vornorexant, a novel dual orexin receptor antagonist, in rats and dogs, and clarified in vitro metabolite profiles in humans. Furthermore, we investigated the pharmacokinetics of active metabolites in rats and dogs and their CNS distribution in rats to elucidate its contribution to drug efficacy. [14C]vornorexant was rapidly and mostly absorbed after the oral administration in rats and dogs. The drug‐derived radioactivity, including metabolites, was distributed to major organs such as the liver, kidneys in rats, and was almost eliminated within 24 h post‐dose in both species. Metabolite profiling revealed that main clearance mechanism of vornorexant was metabolism via multiple pathways by oxidation. The major circulating components were the cleaved metabolites (M10, M12) in rats, and the unchanged form in dogs, followed by M1, and then M3. Incubation with human hepatocytes resulted in formation of metabolites, including M1, M3, M10, and M12. The metabolic pathways were similar in all tested species. Resulting from the PK and CNS distribution of active metabolites (M1 and M3) with weaker pharmacological activity, the concentration of the unchanged form was higher than that of active metabolites in rat CSF and dog plasma, suggesting that the unchanged form mainly contributed to the drug efficacy. These findings demonstrate that vornorexant is absorbed immediately after administration, and vornorexant and its metabolites are rapidly and completely eliminated in rats and dogs. Thus, vornorexant may have favorable pharmacokinetic profiles as a hypnotic drug to provide rapid onset of action and minimal next‐day residual effects in humans.
Trends in hospitalization for heart failure in Scotland, 1990-1996. An epidemic that has reached its peak?

AIMS Studies in the 1980s and early 1990s showed striking increases in hospitalization rates for heart failure. This report describes contemporary trends in hospitalization for heart failure. METHODS Scotland (population of 5.1 million) has a well described system for recording details of all hospitalizations. All hospital discharges (and deaths) can be linked to each patient. We examined the period 1990-1996 (158 989 hospitalizations with a principal or secondary diagnosis of heart failure). RESULTS Compared to 1990, the number of hospitalizations with a principal diagnosis of heart failure increased in men (by 16%) and women (by 12%), although the highest numbers were recorded in 1993 in women (21%) and in 1994 in men (24%). Similar trends were seen for the number of patients hospitalized overall and those having a 'first ever' hospitalization. Hospitalizations with a secondary diagnosis of heart failure increased much more strikingly (by 110% and 60% in men and women, respectively). Re-hospitalization became more common, increasing by 53% and representing 23% of all hospitalizations in 1996. Median length of stay fell (from 9 to 8 days in men and 13 to 10 days in women with a principal diagnosis of heart failure), resulting in 100 877 fewer inpatient days. Heart failure (principal diagnosis) still, however, accounted for 4.2% of all inpatient medicine/geriatric bed-days in 1996. Although inpatient case fatality fell slightly, the total number of deaths due to heart failure (principal diagnosis) increased slightly. CONCLUSIONS Heart failure continues to be a common cause of hospitalization. The previously reported 'epidemic' of increasing rates of hospitalization for heart failure in Scotland and elsewhere between 1980 and 1990, however, seems to have peaked (in about 1993/4).
MicroRNAs Regulate Osteogenesis and Chondrogenesis of Mouse Bone Marrow Stromal Cells

MicroRNAs (miRNAs) are non-coding RNAs that bind to target mRNA leading to translational arrest or mRNA degradation. To study miRNA-mediated regulation of osteogenesis and chondrogenesis, we compared the expression of 35 miRNAs in osteoblasts and chondroblasts derived from mouse marrow stromal cells (MSCs). Differentiation of MSCs resulted in up- or downregulation of several miRNAs, with miR-199a expression being over 10-fold higher in chondroblasts than in undifferentiated MSCs. In addition, miR-124a was strongly upregulated during chondrogenesis while the expression of miR-96 was substantially suppressed. A systems biological analysis of the potential miRNA target genes and their interaction networks was combined with promoter analysis. These studies link the differentially expressed miRNAs to collagen synthesis and hypoxia, key pathways related to bone and cartilage physiology. The global regulatory networks described here suggest for the first time how miRNAs and transcription factors are capable of fine-tuning the osteogenic and chondrogenic differentiation of mouse MSCs.
Prevalence and imaging characteristics of cerebral small vessel disease in a Colombian population aged 40 years and older

Abstract Cerebral small vessel disease is a major contributor to both brain aging and cognitive decline. This study aimed to determine the prevalence of cerebral small vessel disease in a Colombian population over 40 years of age who attended a Radiology and Diagnostic Imaging service for brain MRI between October 2018 and March 2019. This was an observational, cross-sectional and analytical study of 710 adult patients over 40 years of age who attended the Radiology and Diagnostic Imaging service for a brain MRI. The analysed data were obtained from an anonymized database of the service. We studied 710 MRI scans of patients aged between 40 and 104 years. The most frequent risk factor was hypertension (36.2%). Brain abnormalities associated with cerebral small vessel disease, such as white matter hyperintensities, were seen in 56.20% of the population, and brain atrophy was observed in 12.96%. Brain disease prevalence increased with age (23.18% for those aged 55 years, 54.49% for those aged 55–64 years, 69.8% for those aged 65–74 years and 90.53% for those older than 75 years). The prevalence of cerebral small vessel disease in our population was similar to that reported in the world literature, as were the prevalence of the evaluated cardiovascular risk factors. Additionally, we identified an association between hypertension and advanced age with cerebral small vessel disease, with white matter hyperintensities being the most characteristic finding.
Impact of Acceptance and Commitment Therapy on Perceived Stress and Special Health Self-Efficacy in Seven to Fifteen-Year-Old Children With Diabetes Mellitus

Background: Diabetes Mellitus (DM) imposes restrictions on physical, emotional and social functioning of children and adolescents. Objectives: The aim of this study was to determine the impact of acceptance and commitment therapy (ACT) on perceived stress and special health self-efficacy in seven to fifteen-year-old children with DM. Patients and Methods: The present study was a clinical trial with a pretest-posttest control group design. The study population included all seven to fifteen-year-old patients who had referred to the Diabetes Mellitus Association of Tabriz, Iran, of whom 40 participants were selected using convenient sampling. They were randomly allocated to two matched groups (experimental and control). The experimental group participated in therapy sessions, while the control group did not receive any interventions. The research instruments were perceived stress and special health self-efficacy scales. Results: The multiple analysis of covariance (MANCOVA) results showed that the treatment was effective on variables of perceived stress and special health self-efficacy (P < 0.001). Conclusions: The ACT is effective for reducing perceived stress and increasing special health self-efficacy in children with DM.
The radiation of cynodonts and the ground plan of mammalian morphological diversity

Cynodont therapsids diversified extensively after the Permo-Triassic mass extinction event, and gave rise to mammals in the Jurassic. We use an enlarged and revised dataset of discrete skeletal characters to build a new phylogeny for all main cynodont clades from the Late Permian to the Early Jurassic, and we analyse models of morphological diversification in the group. Basal taxa and epicynodonts are paraphyletic relative to eucynodonts, and the latter are divided into cynognathians and probainognathians, with tritylodonts and mammals forming sister groups. Disparity analyses reveal a heterogeneous distribution of cynodonts in a morphospace derived from cladistic characters. Pairwise morphological distances are weakly correlated with phylogenetic distances. Comparisons of disparity by groups and through time are non-significant, especially after the data are rarefied. A disparity peak occurs in the Early/Middle Triassic, after which period the mean disparity fluctuates little. Cynognathians were characterized by high evolutionary rates and high diversity early in their history, whereas probainognathian rates were low. Community structure may have been instrumental in imposing different rates on the two clades.
Frequency of Regulatory T Cells is Not Affected by Transient B Cell Depletion Using Anti-CD20 Antibodies in Rheumatoid Arthritis

Objectives Transient B cell depletion with the monoclonal anti-CD20 antibody rituximab has shown favourable clinical responses in patients with rheumatoid arthritis (RA). Recently a characteristic regeneration pattern of B cell subpopulations has been reported. However, little is known about the impact of B-cell depletion on peripheral T cells in particular regulatory T cells. Materials and Methodology 17 patients with RA having failed anti-TNF were treated with rituximab. Four colour staining was performed using CD19, CD3, CD4, CD8, CD16, CD56, CD25, HLA-DR, HLA-G and intracellular Foxp3 at five time points spanning up to 12 months after rituximab. In addition, quantification of the soluble form of the HLA class I molecule HLA-G by ELISA has been performed. Results Peripheral B cell depletion lasted 6 to 9 months. The absolute number of CD3+, CD4+ and CD8+ lymphocytes showed no significant changes up to 1 year after B-cell depletion compared to before therapy. Only the relative frequency for CD3 and CD4 showed a significant increase (p < 0.05). In particular, CD4+CD25++ and Foxp3 positive regulatory T cells remained constant. The percentage of HLA-G positive cells in the CD4+ or CD8+ population did not change significantly either. The amount of sHLA-G remained without significant changes. Conclusion Absolute T cell counts showed no significant changes after rituximab compared to the time point before therapy.In particular, the frequency of regulatory T cells with a CD4+CD25++ phenotype as well as positive Foxp3 expression were numerically stable. Additionally, HLA-G positive regulatory T cells and soluble levels of HLA-G showed no significant changes.
The epidemiology of premature aging and associated comorbidities

: Hutchinson–Gilford Progeria Syndrome and Werner syndrome, also known as childhood- and adulthood-progeria, respectively, represent two of the best characterized human progeroid diseases with clinical features mimicking physiological aging at an early age. The discovery of their genetic basis has led to the identification of several gene mutations leading to a spectrum of progeroid phenotypes ranging from moderate and mild–severe to very aggressive forms. In parallel, the creation of disease registers and databases provided available data for the design of relatively large-scale epidemiological studies, thereby allowing a better understanding of the nature and frequency of the premature aging-associated signs and symptoms. The aim of this article is to review the most recent findings concerning the epidemiology of premature aging disorders, their genetic basis, and the most recent reports residues Underlined LMNA mutations in atypical wS cases. Recessive ZMPSTE24 mutations also disrupt prelamin A processing and are associated with three distinct, but related, human diseases that share features of premature aging, with a gradation of severity: mandibuloacral dysplasia, atypical HGPS, and restrictive dermopathy. Concerning ZMPSTE24 mutations, the term (ch) indicates a compound heterozygous mutation (in ink), otherwise the mutation was found in homozygosis in the patient
The climate of the European region during the 20th and 21st centuries according to Feddema

The climate of the European region during 20th and 21st centuries in terms of Feddema's (2005) annual and seasonal climate characteristics is analysed. Observed data for the 20th century are taken from the CRU TS 1.2 data set. The projected data for the 21st century are obtained using simulation results of nine regional climate models run in the scope of the ENSEMBLES project. In the analysis, the European region is arbitrarily divided into three sub‐regions: the northern (72°–55°N), middle (55°–42°N) and southern (42°–35°N) zones. We focused on the analysis of the relationships between Feddema's climatic characteristics and the main geographical constraints (latitude, longitude, relief and land‐locked waterbodies). It is shown that Feddema's climatic maps agree well with the expected effects of the main geographical controls. Climate type/geographical control dependence is very strong in the upland coastal regions of the Atlantic Ocean, that is, in the Norwegian Alps, the Scottish Highlands and the Galician Massif Mountains. A characteristic seasonal‐type change can be observed in these regions: The seasonality of P changes through the seasonality of both P and T into the seasonality of T. This behaviour is registered by all model simulations in both the 20th and 21st centuries. The Atlantic Ocean–relief–longitude interplay effect on Feddema's climate types can be observed in all three zones. The uplands in Europe determine climate on the local scale. This upland effect is stronger when it is combined with the effect of extensive land‐locked water bodies. This relationship is obtained by all model simulations in both the 20th and 21st centuries. Lastly, the area heterogeneity of the European region's climate is well reproduced. The observations and the modelling tools show that the climate became and will become warmer and dryer during the course of the 20th and 21st centuries.
Event Calculus Planning Through Satisfiability

Previous work on event calculus planning has viewed it as an abductive task, whose implementation through abductive logic programming reduces to partial order planning. By contrast, this paper presents a formal framework for tackling event calculus planning through satisfiability, in the style of Kautz and Selman. A provably correct conjunctive normal form encoding for event calculus planning problems is supplied, rendering them soluble by an off-the-shelf SAT solver.
Supplementary Online Content

Role of the medial prefrontal cortex in impaired decision making in juvenile attention-deficit/hyperactivity disorder. eMethods. Supplementary methods eResults. Supplementary results eFigure 1. Analysis of the FRN eFigure 2. Neural correlates of RPEs and decision function eFigure 3. Analysis of sgACC/VS-ROI and functional connectivity eTable 1. Behavioral comparison between groups eTable 2. Results of the Bayesian model comparison eTable 3. Results of additional fMRI analyses: main task effect of RPE (cue + outcome) and decision steepness (model parameter β) This supplementary material has been provided by the authors to give readers additional information about their work.