Miracle-dz/UniFAR-FTUs huggingface dataset:
Human trypsinogens in the pancreas and in cancer

Abstract This study led to the development of monoclonal antibodies and time-resolved immunofluorometric methods recognizing human trypsinogen-1 and -2, respectively. Using these methods in normal sera the concentration of trypsinogen-1 was found to be higher than that of trypsinogen-2. However, in acute pancreatitis the concentration of serum trypsinogen-2 was 50-fold higher than in controls, whereas the difference in trypsinogen-1 concentration was only 15-fold. Serum samples from patients who had undergone pancreatoduodenectomy contained trypsinogen-2, while trypsinogen-1 was detected in only one of nine samples. Furthermore, in human ovarian cyst fluids tumor-associated trypsinogen-2 (TAT-2) is the predominant isoenzyme and in mucinous cyst fluids the levels of TAT-2 were associated with malignancy. These results suggest that (i) trypsinogen-2 could be used as a diagnostic marker for acute pancreatitis, (ii) its expression is not restricted to the pancreas, and (iii) TAT could be involved in ovarian tumor dissemination and breakage of tissue barriers. In ion exchange chromatography, isoelectric variants of the trypsinogen isoenzymes were seen. Mass spectrometric analysis of these revealed that pancreatic trypsinogens are sulfated at tyrosine 154 (Tyr154), whereas TAT-2 from a colon carcinoma cell line is not. Tyr154 is located within the primary substrate binding pocket of trypsin. Thus, Tyr154 sulfation is likely to influence substrate binding. The previously known differences in charge and substrate binding between pancreatic and tumor-associated trypsinogens are suggested to be caused by sulfation of Tyr154 in pancreatic trypsinogens.
Proteomic Analysis of Mitotic RNA Polymerase II Reveals Novel Interactors and Association With Proteins Dysfunctional in Disease*

RNA polymerase II (RNAPII) transcribes protein-coding genes in eukaryotes and interacts with factors involved in chromatin remodeling, transcriptional activation, elongation, and RNA processing. Here, we present the isolation of native RNAPII complexes using mild extraction conditions and immunoaffinity purification. RNAPII complexes were extracted from mitotic cells, where they exist dissociated from chromatin. The proteomic content of native complexes in total and size-fractionated extracts was determined using highly sensitive LC-MS/MS. Protein associations with RNAPII were validated by high-resolution immunolocalization experiments in both mitotic cells and in interphase nuclei. Functional assays of transcriptional activity were performed after siRNA-mediated knockdown. We identify >400 RNAPII associated proteins in mitosis, among these previously uncharacterized proteins for which we show roles in transcriptional elongation. We also identify, as novel functional RNAPII interactors, two proteins involved in human disease, ALMS1 and TFG, emphasizing the importance of gene regulation for normal development and physiology.
Normative Data for the Neurobehavioral Symptom Inventory (NSI) and Post-Concussion Symptom Profiles Among TBI, PTSD, and Nonclinical Samples

The Neurobehavioral Symptom Inventory (NSI) is a self-report measure of symptoms commonly associated with Post-Concussion Syndrome (PCS) that may emerge after mild traumatic brain injury (mTBI). Despite frequent clinical use, no NSI norms have been developed. Thus, the main objective of this study was to establish NSI normative data using the four NSI factors (i.e., vestibular, somatic, cognitive, and affective) identified by Vanderploeg, Silva, et al. (2014) among nonclinical epidemiological samples of deployed and non-deployed Florida National Guard members as well as a reference sample of Guard members with combat-related mTBI. In addition, NSI subscale profile patterns were compared across four distinct subgroups (i.e., non-deployed-nonclinical, deployed-nonclinical, deployed-mTBI, and deployed-PTSD). The deployed-nonclinical group endorsed greater PCS symptom severity than the non-deployed group, and the mTBI group uniformly endorsed more symptoms than both nonclinical groups. However, the PTSD group endorsed higher symptom severity relative to the other three subgroups. As such, this highlights the non-specificity of PCS symptoms and suggests that PTSD is associated with higher symptom endorsement than mTBI.
The Role of Education in Stimulating Economic Development in the Framework of Europe 2020 Strategy: Evidence from South-Eastern Europe

A new model of economic development focused on the encouragement of smart, inclusive and sustainable economic growth is the core of the Europe 2020 strategy. Education is widely acknowledged as being a key factor leading to economic growth and economic development, in the long term. But the impact of different kind of achievements in education on growth has little empirical evidence, especially when examining the South-Eastern European countries. This paper analyses the role played by different types of educational achievements, aggregated at the macroeconomic level, beside a set of other potential socio-economic drivers, on the economic growth and quality of life, in the South Eastern Europe, based on the Eurostat panel dataset. A number of panel data regression models using the GMM and FGLS estimators allow answering our research questions. Our empirical results indicate what policy measures are the most effective to target both the economic growth and quality of life.
It Sounds Like They are Moving: Understanding and Modeling Emphasis-Based Policy Change

Position change is an essential feature of political competition. Implicitly, policy change on an issue dimension is often equated with opinion change on specific issues within that dimension. However, in addition to opinion-based policy change, we highlight that parties and candidates can change their overall position by increasing their emphasis on certain opinions within that issue dimension (emphasis-based policy change). Using party manifesto data, we find that parties differ in their use of each type of policy change based on aspects of party organization, particularly the relative power of leaders and activists. Leader-dominated parties are more likely to engage in opinion-based policy change, also in reaction to systemic policy shifts. In contrast, activist-dominated parties tend to change their overall position in reaction to systemic shifts by emphasizing certain positions more. Our approach links salience-based to spatial models of party competition and has broader implications for how we study party competition.
Lower urinary tract symptoms in female patients with rheumatoid arthritis

Objective: Patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) are associated with an increased severity of lower urinary tract symptoms (LUTS). Recent surveys also reveal that rheumatoid arthritis (RA) is prevalent in patients with interstitial cystitis (IC). Therefore, we have investigated LUTS in patients with RA. Methods: A total of 198 female patients with RA, aged 40 years or older, from the rheumatology outpatient clinic completed this prospective study. The American Urological Association Symptom Index (AUASI) score was used to assess the severity of LUTS and the O'Leary–Sant Symptom Index (ICSI) was used to evaluate IC‐like urinary symptoms in these patients, which were compared to those of 679 age‐matched controls. The possible associations of clinical parameters with LUTS were also explored. Results: The Mean AUASI score and the percentage of individuals reporting severe LUTS (AUASI score⩾20) or IC‐like urinary symptoms (ICSI score⩾12) showed no significant differences between the RA and control groups. However, in the RA group multivariate regression analyses identified patients with secondary SS (n = 21) to be associated with a significantly higher AUASI score (p = 0.007) and a higher percentage of severe LUTS (p = 0.02); these were also significantly higher than those of the control group (p = 0.02 and p = 0.01, respectively). Conclusion: Patients with RA have similar urinary complaints when compared to controls. However, those with secondary SS have a greater severity of LUTS, a finding similar to that observed in patients with primary SS.
A pragmatic randomized controlled trial of a guided self-help intervention versus a waiting list control in a routine primary care mental health service.

OBJECTIVES. To evaluate the effectiveness of a two session guided self-help (GSH) intervention provided by primary care graduate mental health workers (PCGMHWs) in a primary care mental health service. DESIGN. Pragmatic randomized trial, with a wait list control design. METHOD. Patients presenting with significant anxiety and depression problems were given one or more self-help booklets at screening and randomly allocated to an immediate (ITG) or delayed treatment group (DTG). Following this, a two-session GSH intervention was provided by one of two PCGMHWs, with a review session to decide on the need for further intervention. The DTG began the intervention 8 weeks after the screening and the primary outcome was Clinical Outcomes in Routine Evaluation - Outcome Measure (CORE-OM) scores after 8 weeks. RESULTS. A total of 63 patients were allocated to the ITG, 59 to the DTG. Analysis of covariance, carried out on an intention to treat basis, showed a significant treatment effect, F(1,98) = 15, p < . 001, and a comparison of means at 8 weeks showed a significant difference, t(116) = 2.1 (95% CI [1.1, 5.9]), p= . 042 with an effect size, d= 0.375. Taking the two groups together, CORE-OM scores for patients who completed the intervention reduced between screening and the review session by an average of 7.9 (95% CI [6.3, 9.5]), effect size of 1.2. Between screening and the review session, 47% showed a reliable and clinically significant improvement. CONCLUSIONS. The study provides some support for the effectiveness of a two-session GSH intervention and a stepped-care service model.
Fetal and adult human liver differ markedly in the fluidity and lipid composition of their microsomal membranes

The fluidity and lipid composition of the human hepatic microsomal membrane were studied in 11 livers from 16‐ to 21‐week‐old fetuses and in 5 adult livers, and compared with those of fetal and adult rat liver microsomes. Membrane fluidity was analyzed by measurement of fluorescence polarization using the fluorophore 1,6‐diphenyl‐1,3,5‐hexatriene. The lipid apparent microviscosity (\documentclass{article}\pagestyle{empty}\begin{document}$ \overline \eta $\end{document}) of human fetal liver microsomes was 2.17 ± 0.13 poise, as compared with 1.08 ± 0.08 poise in adult liver (p < 0.001). Similar differences in fluidity were found between fetal and adult rat liver microsomes. The more “fluid” adult microsomes had higher phospholipid/cholesterol and phosphatidylcholine/sphingomyelin molar ratios than those of the more “rigid” fetal microsomes. The degree of unsaturation of the adult microsomal lipids was much higher than that of the fetal lipids. The ratios of unsaturated/saturated fatty acids in microsomal lipids highly correlated with the \documentclass{article}\pagestyle{empty}\begin{document}$ \overline \eta $\end{document} values obtained for the combined group of fetal and adult human livers, suggesting that the developmental increase in degree of unsaturation of the microsomal lipids is a major determinant of the increased fluidity of adult as compared with fetal liver microsomes. These differences in fluidity and lipid composition between fetal and adult human liver microsomes may be a critical factor in the regulation of hepatic microsomal drug and carcinogen metabolizing enzyme activity, and could so determine the extent of toxicity and teratogenicity of drugs and/or their metabolites in the developing human fetus.
Ultrastructural Analysis of In Vivo Hypoglycemiant Effect of Two Polyoxometalates in Rats with Streptozotocin-Induced Diabetes

Abstract Two polyoxometalates (POMs), synthesized through a self-assembling method, were used in the treatment of streptozotocin (STZ)-induced diabetic rats. One of these nanocompounds [tris(vanadyl)-substituted tungsto-antimonate(III)-anions—POM1] was previously described in the literature, whereas the second [tris-butyltin-21-tungsto-9-antimonate(III)-anions—POM2], was prepared by us based on our original formula. In rats with STZ-induced diabetes treated with POMs (up to a cumulative dose of 4 mg/kg bodyweight at the end of the treatments), statistically significant reduced levels of blood glucose were measured after 3 weeks, as compared with the diabetic control groups (DCGs). Ultrastructural analysis of pancreatic β-cells (including the mean diameter of secretory vesicles and of their insulin granules) in the treated diabetic rats proved the POMs contribute to limitation of cellular degeneration triggered by STZ, as well as to the presence of increased amounts of insulin-containing vesicles as compared with the DCG. The two POMs also showed hepatoprotective properties when ultrastructural aspects of hepatocytes in the experimental groups of rats were studied. Based on our in vivo studies, we concluded that the two POMs tested achieved hypoglycemiant effects by preventing STZ-triggered apoptosis of pancreatic β-cells and stimulation of insulin synthesis.
Role of B Cell-Activating Factor in Chronic Obstructive Pulmonary Disease.

RATIONALE B cell-activating factor (BAFF) plays a major role in activation of B cells and in adaptive humoral immune responses. In chronic obstructive pulmonary disease (COPD), lymphoid follicles have been associated with disease severity, and overexpression of BAFF has been demonstrated within lymphoid follicles of patients with severe COPD. OBJECTIVES To investigate expression and localization of BAFF in the lungs of patients with COPD and to study the role of BAFF in COPD by antagonizing BAFF in a mouse model of chronic cigarette smoke (CS) exposure. METHODS We quantified and localized BAFF expression in lungs of never-smokers, smokers without COPD, and patients with COPD and in lungs of air- or CS-exposed mice by reverse-transcriptase polymerase chain reaction, ELISA, immunohistochemistry, and confocal imaging. Next, to investigate the role of BAFF in COPD, we antagonized BAFF by prophylactic or therapeutic administration of a soluble fusion protein of the BAFF-receptor, BAFFR-Fc, in mice exposed to air or CS for 24 weeks and evaluated several hallmarks of COPD and polarization of lung macrophages. MEASUREMENTS AND MAIN RESULTS BAFF expression was significantly increased in lungs of patients with COPD and CS-exposed mice. BAFF staining in lymphoid follicles was observed around B cells, CD4(+) cells, dendritic cells, follicular dendritic cells, and fibroblastic reticular cells. Prophylactic and therapeutic administration of BAFFR-Fc in mice reduced pulmonary B-cell numbers and prevented CS-induced formation of lymphoid follicles and increases in immunoglobulin levels. Interestingly, prophylactic BAFFR-Fc administration significantly attenuated pulmonary inflammation and destruction of alveolar walls. Moreover, antagonizing BAFF altered the phenotype of alveolar and interstitial macrophages. CONCLUSIONS BAFF is significantly increased in lungs of patients with COPD and is present around both immune and stromal cells within lymphoid follicles. Antagonizing BAFF in CS-exposed mice attenuates pulmonary inflammation and alveolar destruction.
Synergistic Rescue of Nonsense Mutant Tumor Suppressor p53 by Combination Treatment with Aminoglycosides and Mdm2 Inhibitors

The tumor suppressor gene TP53 is inactivated by mutation in a large fraction of human tumors. Around 10% of TP53 mutations are nonsense mutations that lead to premature termination of translation and expression of truncated unstable and non-functional p53 protein. Aminoglycosides G418 (geneticin) and gentamicin have been shown to induce translational readthrough and expression of full-length p53. However, aminoglycosides have severe side effects that limit their clinical use. Here, we show that combination treatment with a proteasome inhibitor or compounds that disrupt p53-Mdm2 binding can synergistically enhance levels of full-length p53 upon aminoglycoside-induced readthrough of R213X nonsense mutant p53. Full-length p53 expressed upon combination treatment is functionally active as assessed by upregulation of p53 target genes, suppression of cell growth, and induction of cell death. Thus, our results demonstrate that combination treatment with aminoglycosides and compounds that inhibit p53 degradation is synergistic and can provide significantly improved efficacy of readthrough when compared with aminoglycosides alone. This may have implications for future cancer therapy based on reactivation of nonsense mutant TP53.
Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)

To improve the specificity and sensitivity of the clinical diagnosis of progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome), the National Institute of Neurological Disorders and Stroke (NINDS) and the Society for PSP, Inc. (SPSP) sponsored an international workshop to develop an accurate and universally accepted set of criteria for this disorder. The NINDS-SPSP criteria, which were formulated from an extensive review of the literature, comparison with other previously published sets of criteria, and the consensus of experts, were validated on a clinical data set from autopsy-confirmed cases of PSP. The criteria specify three degrees of diagnostic certainty: possible PSP, probable PSP, and definite PSP. Possible PSP requires the presence of a gradually progressive disorder with onset at age 40 or later, either vertical supranuclear gaze palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of onset, as well as no evidence of other diseases that could explain these features. Probable PSP requires vertical supranuclear gaze palsy, prominent postural instability, and falls in the first year of onset, as well as the other features of possible PSP. Definite PSP requires a history of probable or possible PSP and histopathologic evidence of typical PSP. Criteria that support the diagnosis of PSP, and that exclude diseases often confused with PSP, are presented. The criteria for probable PSP are highly specific, making them suitable for therapeutic, analytic epidemiologic, and biologic studies, but not very sensitive. The criteria for possible PSP are substantially sensitive, making them suitable for descriptive epidemiologic studies, but less specific. An appendix provides guidelines for diagnosing and monitoring clinical disability in PSP. NEUROLOGY 1996;47: 1-9
Posterior cingulate hypometabolism in early Alzheimer's disease: what is the contribution of local atrophy versus disconnection?

Sir, Garden et al. (2009) reported an important experimental study highlighting a potential mechanism for neuronal dysfunction distant from the site of damage, specifically a loss of synaptic plasticity in the retrosplenial/posterior cingulate cortex (PCC) after anterior thalamic lesion in the rat. In the discussion section of their article, they make the assumption that this phenomenon plays a role in the early episodic memory impairment characterizing Alzheimer's disease: the PCC would be disconnected from the anterior thalamic nucleus—affected by early neuronal/synaptic loss—through disruption of the cingulum bundle. This would in turn lead to PCC hypometabolism, which occurs very early in Alzheimer's disease and already at the stage of amnestic mild cognitive impairment (Minoshima et al. , 1997; Chetelat et al. , 2003 a , b ). The study by Garden et al. (2009) is therefore important for the understanding of the pathophysiology of the memory impairment that characterizes early Alzheimer's disease, as the proposed underlying synaptic mechanism could be amenable to specific pharmacological modulation. Garden et al. (2009) also allude to the current debate about the relative importance of disconnection versus local atrophy/direct neuronal damage in the PCC hypometabolism observed in amnestic mild cognitive impairment and early Alzheimer's disease. They …
The antagonistic effect of hydroxyl radical on the development of a hypersensitive response in tobacco

Reactive oxygen species (ROS) are important signalling molecules in living cells. It is believed that ROS molecules are the main triggers of the hypersensitive response (HR) in plants. In the present study of the effect of riboflavin, which is excited to generate ROS in light, on the development of the HR induced by the elicitin protein ParA1 in tobacco (Nicotiana tabacum), we found that the extent of the ParA1‐induced HR was diminished by hydroxyl radical (OH•), a type of ROS. As compared with the zones treated with ParA1 only, the HR symptom in the zones that were infiltrated with ParA1 plus riboflavin was significantly diminished when the treated plants were placed in the light. However, this did not occur when the plants were maintained in the dark. Trypan blue staining and the ion leakage measurements confirmed HR suppression in the light. Further experiments proved that HR suppression is attributed to the involvement of the photoexcited riboflavin, and that the suppression can be eliminated with the addition of hydrogen peroxide scavengers or OH• scavengers. Fenton reagent treatment and EPR measurements demonstrated that it is OH• rather than hydrogen peroxide that contributes to HR suppression. Accompanying the endogenous OH• formation, suppression of the ParA1‐induced HR occurred in the tobacco leaves that had been treated with high‐level abscisic acid, and that suppression was also removed by OH• scavengers. These results offer evidence that OH•, an understudied and little appreciated ROS, participates in and modulates biologically relevant signalling in plant cells.