Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluating bempedoic acid for the treatment of hyperlipidaemia

ABSTRACT Introduction: Despite the effectiveness of statins in the treatment of lipid disorders, residual risk still exists, and hitherto studies where additional drugs were added to statin therapy have been mainly negative or the outcomes were very modest. Therefore there is still a need for new and effective oral agents in the combination therapy of lipid disorders. Areas covered: The review covers the current state of knowledge on the mechanism of action of bempedoic acid (ETC-1002) and results from recent clinical studies. Expert opinion: ETC-1002 is a novel oral lipid-lowering therapy. The reduction of both low-density lipoprotein cholesterol (LDL-C) and high sensitivity C-reactive protein (hsCRP) demonstrated by ETC-1002 in clinical trials suggests that agent may have the potential for CV risk reduction. Adverse effects of current lipid-lowering agents can be dose-limiting, and combination approaches to lipid-lowering may often be utilized for optimal CV risk reduction. Because of this, new lipid-modulating drugs are urgently required. ETC-1002 has a unique mechanism of action (adenosine triphosphate-citrate lyase inhibition). It has been shown to be safe in combination with statins as well as ezetimibe, and appears to effectively lower LDL-C and has the potential to reduce the risk of muscle-related adverse events, which can limit the utilization and effectiveness of statin therapy.
Early‐onset depression and the emotional and behavioral characteristics of offspring

We compared the emotional and behavioral characteristics of offspring of parents with early‐onset depression and the offspring of parents with late‐onset depression. Forty‐three parents who met criteria for major depressive disorder (MDD) completed the Achenbach Child Behavior Checklist‐Parent Report Version (CBCL) for a birth child (n=43, age range 6–17 years). Parents were classified as having either early SD onset (<19 years) or late‐onset (≥19 years) MDD based on responses gathered during the SCID‐P interview. Unpaired t‐tests were used to compare the two offspring groups on CBCL clinical and competency scales. Chi‐square analyses and unpaired t‐tests were used to compare the two parent groups on demographic and clinical features. Offspring of parents with early‐onset depression scored significantly higher on the majority of the CBCL clinical scale scores when compared with offspring of parents with late‐onset depression, rated as exhibiting higher levels of the characteristics measured: withdrawn, anxious/depressed, social problems, thought problems, attention problems, delinquent behavior, and aggressive behavior. Additionally, this group had a significantly higher total T score (a global measure of psychopathology) and significantly lower social functioning. Children of parents with early‐onset depression may be at higher risk for behavioral and emotional problems than offspring of parents with late‐onset depression. This finding may be significant in uncovering sources of vulnerability and formulating intervention strategies for offspring of depressed parents. Depression and Anxiety 18:104–108, 2003. © 2003 Wiley‐Liss, Inc.
Study of mitochondrial respiratory defects on reprogramming to human induced pluripotent stem cells

Reprogramming of somatic cells into a pluripotent state is known to be accompanied by extensive restructuring of mitochondria and switch in metabolic requirements. Here we utilized Leber's hereditary optic neuropathy (LHON) as a mitochondrial disease model to study the effects of homoplasmic mtDNA mutations and subsequent oxidative phosphorylation (OXPHOS) defects in reprogramming. We obtained fibroblasts from a total of 6 LHON patients and control subjects, and showed a significant defect in complex I respiration in LHON fibroblasts by high-resolution respiratory analysis. Using episomal vector reprogramming, our results indicated that human induced pluripotent stem cell (hiPSC) generation is feasible in LHON fibroblasts. In particular, LHON-specific OXPHOS defects in fibroblasts only caused a mild reduction and did not significantly affect reprogramming efficiency, suggesting that hiPSC reprogramming can tolerate a certain degree of OXPHOS defects. Our results highlighted the induction of genes involved in mitochondrial biogenesis (TFAM, NRF1), mitochondrial fusion (MFN1, MFN2) and glycine production (GCAT) during reprogramming. However, LHON-associated OXPHOS defects did not alter the kinetics or expression levels of these genes during reprogramming. Together, our study provides new insights into the effects of mtDNA mutation and OXPHOS defects in reprogramming and genes associated with various aspects of mitochondrial biology.
Adaptations to short-term muscle unloading in young and aged men.

INTRODUCTION The purpose of this investigation was to determine whether young (21.7 yr) and aged (68.5 yr) men experienced similar responses to 7 d of muscle unloading (N = 10 per group). METHODS Unilateral lower limb suspension (ULLS) was used to impose muscle unloading of the knee extensors. To compare the effects of unloading on aged and young men, a repeated-measures factorial ANOVA was used to assess those effects on isometric strength, as well as strength, total work, and average power during isokinetic contractions conducted at 0.53, 1.05, and 2.09 rad.s(-1). RESULTS Data showed that at slower speeds of movement, only a main effect of unloading was identified with young and aged men displaying similar and significant (P < 0.05) ULLS-induced decrements in strength, work, and power. The decrease in isometric strength correlated well with loss of electromyographic activity of contracting muscles (r = 0.79, P = 0.0002). At higher speeds of isokinetic contractions, not only was a main effect of age detected (young > aged), but it was also revealed that aged men, but not young men, experienced significant unloading-induced declines in muscle performance. Moreover, unloading resulted in a significant increase in plasma cortisol, a potent catabolic hormone, only among aged men. In contrast to other variables assessed, muscle endurance, quantified during 30 repetitions completed at 3.14 rad.s(-1), did not differ between age groups, nor was it altered by unloading. CONCLUSION These findings suggest that young and aged men respond differently to muscle unloading, but in assessing muscle performance, these differences are manifested only during faster contractile velocities.
Numerical modeling of 1D arterial networks coupled with a lumped parameters description of the heart

The investigations on the pressure wave propagation along the arterial network and its relationships with vascular physiopathologies can be supported nowadays by numerical simulations. One dimensional (1D) mathematical models, based on systems of two partial differential equations for each arterial segment suitably matched at bifurcations, can be simulated with low computational costs and provide useful insights into the role of wave reflections. Some recent works have indeed moved in this direction. The specific contribution of the present paper is to illustrate a 1D numerical model numerically coupled with a model for the heart action. Typically, the action of the heart on the arterial system is modelled as a boundary condition at the entrance of the aorta. However, the left ventricle (LV) and the vascular network are a strongly coupled single mechanical system. This coupling can be relevant in the numerical description of pressure waves propagation, particularly when dealing with pathological situations. In this work, we propose a simple lumped parameter model for the heart and show how it can be coupled numerically with a 1D model for the arteries. Numerical results actually confirm the relevant impact of the heart-arteries coupling in realistic simulations.
Poincaré Embeddings for Learning Hierarchical Representations

Representation learning has become an invaluable approach for learning from symbolic data such as text and graphs. However, while complex symbolic datasets often exhibit a latent hierarchical structure, state-of-the-art methods typically learn embeddings in Euclidean vector spaces, which do not account for this property. For this purpose, we introduce a new approach for learning hierarchical representations of symbolic data by embedding them into hyperbolic space -- or more precisely into an n-dimensional Poincare ball. Due to the underlying hyperbolic geometry, this allows us to learn parsimonious representations of symbolic data by simultaneously capturing hierarchy and similarity. We introduce an efficient algorithm to learn the embeddings based on Riemannian optimization and show experimentally that Poincare embeddings outperform Euclidean embeddings significantly on data with latent hierarchies, both in terms of representation capacity and in terms of generalization ability.
Tuberculosis knowledge among patients in out-patient settings in Split, Croatia.

SETTING Patients of five randomly selected general practitioners in Split, Croatia. OBJECTIVE To investigate knowledge about tuberculosis (TB) and to identify target groups for information, education and communication activities. DESIGN Cross-sectional survey based on a structured questionnaire using a convenience sampling among subjects aged > or =18 years. Data were stratified by sex, age group, educational background, personal monthly income and contact with TB patients. TB knowledge scores were determined from the number of correct answers to 12 selected questions. RESULTS The questionnaires were completed by 386 subjects. No statistically significant differences were observed between females and males with respect to age, educational background or contact with TB patients, except for personal income, which was higher in males (P < 0.001). The mean TB knowledge score was 9.4 +/- 1.98 (range 1-12, median 10). A low score was associated with the youngest age group, 18-29 years (P = 0.018), and with <12 years of education (P = 0.002). CONCLUSION Educational background and age groups of respondents were important determinants of TB knowledge. Although the study sample showed a satisfactory level of knowledge, the results demonstrated several misconceptions that need to be clarified. Uncertainties in core TB knowledge need to be addressed choosing less educated and young people as specific target groups.
Ergonomics and cytotechnologists: Reported musculoskeletal discomfort

Analysis of this survey of 244 responding cytotechnologists shows that a high percentage still suffer from musculoskeletal disorders commonly associated with poor ergonomic design in the workplace, despite the variety of ergonomically designed microscopes that have been introduced into the market. Although Kalavar and Hunting surveyed a small group of cytotechnologists in the Washington, DC, area in 1996, no broad‐based study has focused specifically on these professionals. The landmark study of microscope ergonomics, published by Soderberg in 1980, documented widespread musculoskeletal complaints in the electronics industry. This article identifies and discusses the types of musculoskeletal discomforts experienced by cytotechnologists. We propose that both practicing and student cytotechnologists receive training in ergonomic principles and appropriate interventions, such as improved work practices, proper ergonomic aids, well‐designed workstations, and ergonomically designed equipment. More than 85% of respondents reported some musculoskeletal discomfort. Among the symptoms presented are headache, neck pain and stiffness, pain of the lower and upper back, and upper‐extremity discomfort. Neurological symptoms, such as numbness, tingling, and/or pain in the hand and fingers, are often associated with repetitive motion. More than one‐third reported numbness, tingling, and/or pain in the left‐hand fingers, usually used for the fine‐focus control knob. Almost one‐half of respondents reported such symptoms for the right hand and fingers, normally used to manipulate the mechanical stage controls. Only 9% of the respondents were left‐handed. Most (91%) were right handed. Although just over one‐third (34.4%) of respondents worked for an employer with an ergonomics program, ergonomic assessments had been performed for only about one‐half (17.6%) of these. In addition, approximately 10% of respondents indicated that ergonomics assessments had been performed on their workstations, even though the employer did not have an ergonomics program. Because of the high prevalence of reported symptoms, we recommend that all cytologists be trained in basic ergonomic principles and the proper use of ergonomic aids. These interventions should reduce the prevalence of musculoskeletal discomfort in medical microscopists. Diagn. Cytopathol. 2003;29:364–367. © 2003 Wiley‐Liss, Inc.
Immunosuppressive Therapy Improves Both Short- and Long-Term Prognosis in Patients With Virus-Negative Nonfulminant Inflammatory Cardiomyopathy

Background: Inflammatory cardiomyopathy (infl-CMP) is characterized by increased cardiac inflammation in the absence of viruses, ischemia, valvular disease, or other apparent causes. Studies addressing the efficacy of immunosuppressive therapy in patients with infl-CMP are sparse. This study retrospectively investigates whether immunosuppressive agents on top of heart failure therapy according to current guidelines improves cardiac function and long-term outcome in patients with infl-CMP. Methods and Results: Within the Innsbruck and Maastricht Cardiomyopathy Registry, a total of 209 patients fulfilled the criteria for infl-CMP using endomyocardial biopsy (≥14 infiltrating inflammatory cells/mm2). A total of 110 (53%) patients received immunosuppressive therapy and 99 (47%) did not. To correct for potential selection bias, 1:1 propensity score matching was used on all significant baseline parameters, resulting in a total of 90 patients per group. Baseline characteristics did not significantly differ between both patient groups, reflecting optimal propensity score matching. After a median follow-up of 31 (15–47) months, immunosuppressive therapy resulted in an improved long-term outcome (eg, heart transplantation–free survival) as compared with standard heart failure therapy alone (Log-rank P=0.043; hazard ratio, 0.34 [95% CI, 0.17–0.92]) and in a significant larger increase of left ventricular ejection fraction after a mean of 12 months follow-up, as compared with patients receiving standard heart failure treatment only (12.2% versus 7.3%, respectively; P=0.036). Conclusions: To conclude, this study suggests that immunosuppressive therapy in infl-CMP patients results in an improved heart transplantation–free survival as compared with standard heart failure therapy alone, underscoring the urgent need for a large prospective multicenter trial.
AP-2-complex-mediated endocytosis of Drosophila Crumbs regulates polarity by antagonizing Stardust

ABSTRACT Maintenance of epithelial polarity depends on the correct localization and levels of polarity determinants. The evolutionarily conserved transmembrane protein Crumbs is crucial for the size and identity of the apical membrane, yet little is known about the molecular mechanisms controlling the amount of Crumbs at the surface. Here, we show that Crumbs levels on the apical membrane depend on a well-balanced state of endocytosis and stabilization. The adaptor protein 2 (AP-2) complex binds to a motif in the cytoplasmic tail of Crumbs that overlaps with the binding site of Stardust, a protein known to stabilize Crumbs on the surface. Preventing endocytosis by mutation of AP-2 causes expansion of the Crumbs-positive plasma membrane domain and polarity defects, which can be partially rescued by removing one copy of crumbs. Strikingly, knocking down both AP-2 and Stardust leads to the retention of Crumbs on the membrane. This study provides evidence for a molecular mechanism, based on stabilization and endocytosis, to adjust surface levels of Crumbs, which are essential for maintaining epithelial polarity. Summary: The proper amount of the polarity determinant Crumbs is crucial for apico-basal epithelial cell polarity. Here, we show that its level is controlled by Stardust-dependent stabilization and AP-2-mediated endocytosis.
Young children's understanding of desire formation.

Two studies examined preschoolers' appreciation of how mental states arise. In Study 1, children aged 3 to 5 (24 at each age) better understood perception-generated beliefs (e.g., that looking in a certain location generates a belief about the location's content) and attitude-generated desires (e.g., that positive experiences with an activity generate a desire to partake of the activity again) than physiology-generated desires (e.g., that not eating for a long time generates a desire for food). In Study 2, 4- and 5-year-olds (48 at each age) better understood the effects of quantity of experience (e.g., eating a lot vs. a little) than of time of experience (eating just now vs. a long time ago) on physiological states and desires. The findings suggest that whether children reason in more advanced fashion about desires or beliefs depends on which aspects of these mental states are considered.
Acute liver failure: mechanisms of immune‐mediated liver injury

Acute liver failure (ALF) is a syndrome of diverse aetiology, including hepatic encephalopathy, renal, cardiac and pulmonary failures, which result in a rapid loss of hepatic function. The mechanisms of liver injury contributing to ALF can be summarized into two categories: direct damage and immune‐mediated liver injury. This review summarizes current concepts of immune‐mediated liver injury from both clinical studies and animal models. We highlight immune responses of ALF from the liver injury perspective, which combines a variety of molecular and cellular mechanisms, particularly, the contribution of cytokines and the innate immune system. Hepatic and circulating inflammatory cytokines play a significant role in the pathophysiology of ALF including hepatocyte necrosis, extrahepatic complications and hepatocyte regeneration. Overproduction of cytokines, if unchecked, is hazardous to the host and may cause severe outcomes. Measuring pro‐inflammatory cytokines in ALF may be of value for predictors of outcome. Innate and adaptive immune systems both involved in ALF contribute to immune‐mediated liver injury. The innate immune response is activated much more rapidly compared with adaptive immunity, particularly in acute liver injury where the host has little time to trigger an effective adaptive immune response. From this point of view, the innate immune system may make a more profound contribution than the adaptive immune system. Furthermore, immune responses crosstalk with other physiological or pathophysiological factors, for example, coagulation factors which in turn determine the outcome of ALF and these are discussed.
Depressive distress among homosexually active African American men and women.

OBJECTIVE Although early surveys of psychological adjustment among gay men and lesbians suggest only minor and not clinically relevant differences from heterosexual populations, concerns about psychiatric morbidity associated with HIV infection have renewed interest in the prevalence of psychological distress in this population, particularly among gay men. These later studies have focused primarily on white men. However, research indicates higher crude prevalence rates of psychological distress in community-drawn samples of African American subjects than in white subjects and also higher rates in women than in men. The authors examined rates of depressive distress and suicidal thoughts among homosexually active African American men and women who might be especially at risk for psychiatric morbidity due to multiple stigmatized social statuses. METHOD Two nationally recruited groups of homosexually active African Americans (829 men and 603 women) completed self-administered questionnaires, including the Center for Epidemiologic Studies Depression Scale. RESULTS Homosexually active black women were as distressed as HIV-infected gay black men. Men with symptomatic HIV disease were significantly more distressed than men who were HIV infected but asymptomatic, HIV-antibody negative, or whose HIV status was unknown. Both men and women reported distress levels in excess of those previously reported in studies of blacks or primarily white gay men. CONCLUSIONS Further research is needed to identify specific predictors of life stressors and lack of social support among homosexually active African Americans who appear to be at higher risk for depressive distress.
Modeling of wind turbine power curve

Energy is available in two different alternatives, non-renewable (coal, fuel and natural gas) and renewable (solar, wind, hydro and wave) sources. Especially, after the industrial revolution in the nineteenth century, first coal and then fuel oil are used as primary energy sources for the needs of modern communities. As it is known, fossil fuels have limited potential, and at the current rate of exploitation they are expected to be depleted within the next centuries. This is one of the reasons why clean, sustainable and environmentally friendly alternative energy resources like wind, solar, etc are currently sought. This paper aims to characterize the power curve of the wind energy production and to estimate the power when a WTG operates between the cut-in wind speed and the rated wind speed. These are done by different methods and their performance is measured using the root mean square error(RMSE). Through the results, it is proved that cluster center estimation method is the best method among all of the other proposed methods.
Replication origin–flanking roadblocks reveal origin-licensing dynamics and altered sequence dependence

In eukaryotes, DNA replication initiates from multiple origins of replication for timely genome duplication. These sites are selected by origin licensing, during which the core enzyme of the eukaryotic DNA replicative helicase, the Mcm2-7 (minichromosome maintenance) complex, is loaded at each origin. This origin licensing requires loading two Mcm2-7 helicases around origin DNA in a head-to-head orientation. Current models suggest that the origin–recognition complex (ORC) and cell-division cycle 6 (Cdc6) proteins recognize and encircle origin DNA and assemble an Mcm2-7 double-hexamer around adjacent double-stranded DNA. To test this model and assess the location of Mcm2-7 initial loading, we placed DNA–protein roadblocks at defined positions adjacent to the essential ORC-binding site within Saccharomyces cerevisiae origin DNA. Roadblocks were made either by covalent cross-linking of the HpaII methyltransferase to DNA or through binding of a transcription activator-like effector (TALE) protein. Contrary to the sites of Mcm2-7 recruitment being precisely defined, only single roadblocks that inhibited ORC–DNA binding showed helicase loading defects. We observed inhibition of helicase loading without inhibition of ORC–DNA binding only when roadblocks were placed on both sides of the origin to restrict sliding of a helicase-loading intermediate. Consistent with a sliding helicase-loading intermediate, when either one of the flanking roadblocks was eliminated, the remaining roadblock had no effect on helicase loading. Interestingly, either origin-flanking nucleosomes or roadblocks resulted in helicase loading being dependent on an additional origin sequence known to be a weaker ORC–DNA-binding site. Together, our findings support a model in which sliding helicase-loading intermediates increase the flexibility of the DNA sequence requirements for origin licensing.