Miracle-dz/UniFAR-FTUs huggingface dataset:
Alzheimer’s Disease as a Membrane Disorder: Spatial Cross-Talk Among Beta-Amyloid Peptides, Nicotinic Acetylcholine Receptors and Lipid Rafts

Biological membranes show lateral and transverse asymmetric lipid distribution. Cholesterol (Chol) localizes in both hemilayers, but in the external one it is mostly condensed in lipid-ordered microdomains (raft domains), together with saturated phosphatidyl lipids and sphingolipids (including sphingomyelin and glycosphingolipids). Membrane asymmetries induce special membrane biophysical properties and behave as signals for several physiological and/or pathological processes. Alzheimer’s disease (AD) is associated with a perturbation in different membrane properties. Amyloid-β (Aβ) plaques and neurofibrillary tangles of tau protein together with neuroinflammation and neurodegeneration are the most characteristic cellular changes observed in this disease. The extracellular presence of Aβ peptides forming senile plaques, together with soluble oligomeric species of Aβ, are considered the major cause of the synaptic dysfunction of AD. The association between Aβ peptide and membrane lipids has been extensively studied. It has been postulated that Chol content and Chol distribution condition Aβ production and posterior accumulation in membranes and, hence, cell dysfunction. Several lines of evidence suggest that Aβ partitions in the cell membrane accumulate mostly in raft domains, the site where the cleavage of the precursor AβPP by β- and γ- secretase is also thought to occur. The main consequence of the pathogenesis of AD is the disruption of the cholinergic pathways in the cerebral cortex and in the basal forebrain. In parallel, the nicotinic acetylcholine receptor has been extensively linked to membrane properties. Since its transmembrane domain exhibits extensive contacts with the surrounding lipids, the acetylcholine receptor function is conditioned by its lipid microenvironment. The nicotinic acetylcholine receptor is present in high-density clusters in the cell membrane where it localizes mainly in lipid-ordered domains. Perturbations of sphingomyelin or cholesterol composition alter acetylcholine receptor location. Therefore, Aβ processing, Aβ partitioning, and acetylcholine receptor location and function can be manipulated by changes in membrane lipid biophysics. Understanding these mechanisms should provide insights into new therapeutic strategies for prevention and/or treatment of AD. Here, we discuss the implications of lipid-protein interactions at the cell membrane level in AD.
Having a Calling on Board: Effects of Calling on Job Satisfaction and Job Performance Among South Korean Newcomers

Despite increasing research on calling, how calling functions for those experiencing transition from school to work and how their calling prior to working relates to later well-being and job outcomes has been understudied. The current study explored effects of perceiving a calling on job satisfaction and job performance, as measured at organizational entry and 2 years after organizational entry. Using a time-lagged collection of a sample of South Korean newcomers, the results based on structural equation modeling revealed that perceiving a calling was positively related to supervisor-rated job performance. Job involvement, which was measured 1 year later, fully mediated the relation between perceiving a calling and job satisfaction, but the hypothesized mediating role of job involvement on the link between perceiving a calling and job performance was not supported. We also examined moderating roles of perceived organizational support and perceived person-job fit on the relation between perceiving a calling on job involvement and found that perceived organizational support facilitated the effects of perceiving a calling on job involvement. Implications of these findings are discussed.
Venom Atypical Extracellular Vesicles as Interspecies Vehicles of Virulence Factors Involved in Host Specificity: The Case of a Drosophila Parasitoid Wasp

Endoparasitoid wasps, which lay eggs inside the bodies of other insects, use various strategies to protect their offspring from the host immune response. The hymenopteran species of the genus Leptopilina, parasites of Drosophila, rely on the injection of a venom which contains proteins and peculiar vesicles (hereafter venosomes). We show here that the injection of purified L. boulardi venosomes is sufficient to impair the function of the Drosophila melanogaster lamellocytes, a hemocyte type specialized in the defense against wasp eggs, and thus the parasitic success of the wasp. These venosomes seem to have a unique extracellular biogenesis in the wasp venom apparatus where they acquire specific secreted proteins/virulence factors and act as a transport system to deliver these compounds into host lamellocytes. The level of venosomes entry into lamellocytes of different Drosophila species was correlated with the rate of parasitism success of the wasp, suggesting that this venosome-cell interaction may represent a new evolutionary level of host-parasitoid specificity.
Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves' Disease Patients via Two Distinct Mechanisms

Graves' disease (GD) involves the presence of agonistic auto-antibodies against the thyrotropin receptor (TSHR), which are responsible for the clinical symptoms. While failure of TSHR tolerance is central to GD pathogenesis, the process leading to this failure remains poorly understood. Two mechanisms intimately linked to tolerance have been proposed to explain the association of SNPs located in TSHR intron 1 to GD: (1) differential alternative splicing in the thyroid; and (2) modulation of expression in the thymus. To elucidate the relative contribution to these two mechanisms to GD pathogenesis, we analyzed the level of full-length and ST4 and ST5 isoform expression in the thyroid (n = 49) and thymus (n = 39) glands, and the influence of intron 1-associated SNPs on such expression. The results show that: (1) the level of flTSHR and ST4 expression in the thymus was unexpectedly high (20% that of the thyroid); (2) while flTSHR is the predominant isoform, the levels are similar to ST4 (ratio flTSHR/ST4 = 1.34 in the thyroid and ratio flTSHR/ST4 in the thymus = 1.93); (3) next-generation sequencing confirmed the effect of the TSHR intron 1 polymorphism on TSHR expression in the thymus with a bias of 1.5 ± 0.2 overexpression of the protective allele in the thymus compared to the thyroid; (4) GD-associated intron 1 SNPs did not influence TSHR alternative splicing of ST4 and ST5 in the thyroid and thymus; and (5) three-color confocal imaging showed that TSHR is associated with both thymocytes, macrophages, and dendritic cells in the thymus. Our findings confirm the effect of intron 1 polymorphisms on thymic TSHR expression and we present evidence against an effect on the relative expression of isoforms. The high level of ST4 expression in the thymus and its distribution within the tissue suggest that this would most likely be the isoform that induces central tolerance to TSHR thus omitting most of the hinge and transmembrane portion. The lack of central tolerance to a large portion of TSHR may explain the relatively high frequency of autoimmunity related to TSHR and its clinical consequence, GD.
Effects of Metformin on TSH Levels and Benign Nodular Goiter Volume in Patients Without Insulin Resistance or Iodine Insufficiency

Objectives: To evaluate the impact of metformin (MTF) use on TSH levels, thyroid volume and volume of benign thyroid nodules (TNs). Additionally, to study if iodine status influences the outcomes. Methods: A total of 23 euthyroid patients (42 TNs) with benign thyroid nodules, diagnosed by fine needle aspiration biopsy, were randomly assigned to MTF or placebo (P) use for 6 months. Serum TSH, homeostatic model assessment for insulin resistance (HOMA-IR), and urinary iodine concentrations (UIC) were assessed. Ultrasound was used to evaluate TNs and thyroid volumes (TV) and their variations throughout the study. Diabetic patients, those undergoing levothyroxine replacement, and/or using thyroid- or insulin level-influencing drugs were excluded. Results: The sample consisted predominantly of patients without IR. Both intervention groups were similar regarding several confounding variables and showed a comparable median UIC. Serum TSH decreased significantly after MTF (−0.21 vs. 0.09 mUI/L in the P group; p = 0.015). At 6 months, no significant variations were found between groups with respect to TN volumes, TV, HOMA-IR, or body mass index (BMI). However, a tendency toward enlargement of TV with placebo (16.0%; p = 0.09) and a protective effect of MTF on growing TN (OR: 0.25; CI 0.05–1.20) was detected after excluding patients with IR (a lower UIC subgroup). The reduction on TSH levels with MTF maintained in the population without iodine insufficiency (−0.24 vs. +0.07 in the P group; p = 0.046) and was accentuated in those with excessive or more than adequate UIC (−0.69; p = 0.043). A protective effect of MTF on growing TN was suggested (OR: 0.11; IC: 0.02–0.84) in those with higher UIC. Conclusions: This study demonstrated that MTF caused a reduction in TSH levels in benign nodular goiter. This effect was more accentuated in patients with higher levels of UIC and was accompanied by a suggested protective effect on TN enlargement.
Thromboembolic Risk of 4-Factor Prothrombin Complex Concentrate versus Fresh Frozen Plasma for Urgent Warfarin Reversal in the Emergency Department

Introduction Warfarin is a potent anticoagulant used for the prevention and treatment of venous and arterial thrombosis. Occasionally, patients require emergent warfarin reversal due to active bleeding, supratherapeutic international normalized ratio, or emergent diagnostic or therapeutic interventions. Various agents can be used for emergent warfarin reversal, including fresh frozen plasma (FFP) and 4-factor prothrombin complex concentrate (4F-PCC). Both FFP and 4F-PCC are generally considered safe; however, both agents contain coagulation factors and have the potential to provoke a thromboembolic event. Although clinical trials have compared the efficacy and safety of FFP and 4F-PCC, data are limited comparing the risk of thromboembolism between the two agents. Methods A retrospective chart review was performed at a single, urban, academic medical center comparing the incidence of thromboembolism with FFP or 4F-PCC for warfarin reversal during a three-year period in the emergency department (ED) at Massachusetts General Hospital. Patients were included in the study if they were at least 18 years of age and were on warfarin per electronic health records. Patients were excluded if they had received both FFP and 4F-PCC during the same visit. The primary outcome was the frequency of thromboembolism within 30 days of 4F-PCC or FFP. Secondary outcomes included time to thromboembolic event and in-hospital mortality. Results Three hundred and thirty-six patients met the inclusion criteria. Thromboembolic events within 30 days of therapy occurred in seven patients (2.7%) in the FFP group and 14 patients (17.7%) in the 4F-PCC group (p=<0.001). Death occurred in 39 patients (15.2%) who received FFP and 18 patients (22.8%) who received 4F-PCC (p=0.115). Since the 4F-PCC group was treated disproportionately for central nervous system (CNS) bleeding, a subgroup analysis was performed including patients requiring reversal due to CNS bleeds that received vitamin K. The primary outcome remained statistically significant, occurring in four patients (4.1%) in the FFP group and nine patients (14.1%) in the 4F-PCC group (p=0.02). Conclusion Our study found a significantly higher risk of thromboembolic events in patients receiving 4F-PCC compared to FFP for urgent warfarin reversal. This difference remained statistically significant when controlled for CNS bleeds and administration of vitamin K.
Evidence-Informed Practice: Diagnostic Questions in Urinary Tract Infections in the Elderly

Introduction Routine interventions in the practice of medicine often lack definitive evidence or are based on evidence that is either not high quality or of only modest-to-marginal effect sizes. An abnormal urinalysis in an elderly patient presenting to the emergency department (ED) with non-specific symptoms represents one condition that requires an evidence-informed approach to diagnosis and management of either asymptomatic bacteriuria or urinary tract infection (UTI). The emergency provider often will not have access to urine cultures, and the risks associated with antibiotic use in the elderly are not without potentially significant side effects. Methods We performed a historical and clinical review of the growing body of literature suggesting measurable differences in the systemic immune response manifest among patients with asymptomatic pyuria and UTI, including increases in the pro-inflammatory cytokine interleukin-6 and the acute phase reactant procalcitonin. Results Serum procalcitonin, a peptide that undergoes proteolysis into calcitonin, has been demonstrated to quickly and reliably rise in patients with severe bacterial infections, and may serve as a potentially sensitive and specific marker for identification of bacterial illness. Conclusion In the absence of validated risk scores for diagnosing UTI in elderly patients presenting to the ED, there may be a role for the use of procalcitonin in this patient population.
Hypertension in Thyroid Disorders

Arterial hypertension represents a major global health concern; more than one fourth of the population is affected by high blood pressure. Albeit the underlying cause of the disease remains unclear in the vast majority of the cases, ~10% are of secondary origin. Endocrine disorders are common illnesses and some of them may lead to elevated blood pressure, among which thyroid diseases are of high prevalence and often overlooked, especially in mild cases. Overt and subclinical hyper- and hypothyroidism can both lead to (mostly mild) hypertension; however, the underlying mechanisms are only partially understood. The results of clinical studies are often controversial. During the past decades, some genetic mutations in the hypothalamus-pituitary-thyroid axis with cardiovascular consequences were revealed. Atherosclerotic changes resulting from lipid abnormalities due to thyroid dysfunction also affect the vasculature and can cause elevated blood pressure. The review gives a synopsis of our knowledge how thyroid hormone metabolism and functional thyroid diseases affect the cardiovascular system, their negative impact and causative role in the development of hypertension.
Bayesian modelling of a hepatitis A outbreak in men who have sex with men in Sydney, Australia, 1991/1992

Abstract To control hepatitis A spread by vaccination, accurate estimation of transmissibility is vital. Regan et al. (2016) proposed a model of hepatitis A virus (HAV) transmission and used least squares to calibrate model to the 1991/1992 HAV outbreak in men who have sex with men (MSM) in Sydney, Australia. Based on the estimate of R0, they obtained the critical immunity of 70% and showed that when the proportion immune <70%, there is a definite chance for outbreaks to take place. The immunity level from previous surveys ranges from 32% to 64% after 1996 while no outbreaks in Australian MSMs have been reported since 1996. Further noticing the ill-distributed parameters, we argue that their estimate of R0 is not accurate. In this study, we revisited their model by Bayesian inference, which has privilege over least squares. We obtained the appropriate posterior distributions of parameters and the estimate of R0 ranges from 1.38 to 2.89, indicating a critical immunity of 65%. The reduction in critical immunity and outbreak probabilities predicts the absence of outbreaks in Australian MSMs since 1996. Our study shows the importance of using appropriate methods to provide reliable and accurate estimates of the model parameters especially the transmissibility.
A Prospective, Randomized, Open-Label, Multicenter, Phase III Noninferiority Trial to Compare the Clinical Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroid Technology Versus Arthroscopic Microfracture for Cartilage Defects of the Knee

Background: Autologous chondrocyte implantation (ACI) and microfracture are established treatments for large, full-thickness cartilage defects, but there is still a need to expand the clinical and health economic knowledge of these procedures. Purpose: To confirm the noninferiority of ACI compared with microfracture. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Patients were randomized to be treated with matrix-associated ACI using spheroid technology (n = 52) or microfracture (n = 50). Both procedures followed standard methods. Patients were assessed by the Knee injury and Osteoarthritis Outcome Score (KOOS), MOCART (magnetic resonance observation of cartilage repair tissue) scoring system, Bern score, modified Lysholm score, International Cartilage Repair Society (ICRS) rating (histological and immunochemical scoring after rebiopsy 24 months after implantation), and International Knee Documentation Committee (IKDC) examination form. The main assessments were conducted 24 months after study treatment. Results: In the primary intention-to-treat analysis, the overall KOOS score for both ACI and microfracture yielded a statistically significant improvement relative to baseline. According to the between-group analysis, ACI passed the test of noninferiority compared with microfracture; thus, the primary goal of the study was achieved. The KOOS subscores yielded the same qualitative results as the overall KOOS score (ie, for each of these, noninferiority was demonstrated), and in 1 case (Activities of Daily Living subscore), the threshold for superiority was passed. The subgroup analyses did not yield any clear evidence of an association between treatment effect and any of the categories investigated (age, diagnosis, defect localization, sex). A histological analysis of biopsies from 16 patients (ACI: n = 9; microfracture: n = 7) suggested a better quality of repair in the patients treated with ACI. Conclusion: The efficacy of both ACI and microfracture was demonstrated with respect to both functional outcomes and morphological repair. The primary analysis confirmed the statistical hypothesis of the noninferiority of ACI, even for relatively small cartilage defects (1-4 cm2) treated in this study, the indication for which microfracture is generally accepted as the standard of care. ACI showed significant superiority in the KOOS subscores of Activities of Daily Living at 24 months and Knee-related Quality of Life at 12 months. Registration: NCT01222559 (ClinicalTrials.gov identifier).
Oxysterols and Gastrointestinal Cancers Around the Clock

This review focuses on the role of oxidized sterols in three major gastrointestinal cancers (hepatocellular carcinoma, pancreatic, and colon cancer) and how the circadian clock affects the carcinogenesis by regulating the lipid metabolism and beyond. While each field of research (cancer, oxysterols, and circadian clock) is well-studied within their specialty, little is known about the intertwining mechanisms and how these influence the disease etiology in each cancer type. Oxysterols are involved in pathology of these cancers, but final conclusions about their protective or damaging effects are elusive, since the effect depends on the type of oxysterol, concentration, and the cell type. Oxysterol concentrations, the expression of key regulators liver X receptors (LXR), farnesoid X receptor (FXR), and oxysterol-binding proteins (OSBP) family are modulated in tumors and plasma of cancer patients, exposing these proteins and selected oxysterols as new potential biomarkers and drug targets. Evidence about how cholesterol/oxysterol pathways are intertwined with circadian clock is building. Identified key contact points are different forms of retinoic acid receptor related orphan receptors (ROR) and LXRs. RORs and LXRs are both regulated by sterols/oxysterols and the circadian clock and in return also regulate the same pathways, representing a complex interplay between sterol metabolism and the clock. With this in mind, in addition to classical therapies to modulate cholesterol in gastrointestinal cancers, such as the statin therapy, the time is ripe also for therapies where time and duration of the drug application is taken as an important factor for successful therapies. The final goal is the personalized approach with chronotherapy for disease management and treatment in order to increase the positive drug effects.
Sentiment Analysis for Words and Fiction Characters From the Perspective of Computational (Neuro-)Poetics

Two computational studies provide different sentiment analyses for text segments (e.g., “fearful” passages) and figures (e.g., “Voldemort”) from the Harry Potter books (Rowling, 1997, 1998, 1999, 2000, 2003, 2005, 2007) based on a novel simple tool called SentiArt. The tool uses vector space models together with theory-guided, empirically validated label lists to compute the valence of each word in a text by locating its position in a 2d emotion potential space spanned by the words of the vector space model. After testing the tool's accuracy with empirical data from a neurocognitive poetics study, it was applied to compute emotional figure and personality profiles (inspired by the so-called “big five” personality theory) for main characters from the book series. The results of comparative analyses using different machine-learning classifiers (e.g., AdaBoost, Neural Net) show that SentiArt performs very well in predicting the emotion potential of text passages. It also produces plausible predictions regarding the emotional and personality profile of fiction characters which are correctly identified on the basis of eight character features, and it achieves a good cross-validation accuracy in classifying 100 figures into “good” vs. “bad” ones. The results are discussed with regard to potential applications of SentiArt in digital literary, applied reading and neurocognitive poetics studies such as the quantification of the hybrid hero potential of figures.