Miracle-dz/UniFAR-FTUs huggingface dataset:
Fisetin, a dietary flavonoid, augments the anti-invasive and anti-metastatic potential of sorafenib in melanoma

Melanoma is the most aggressive and deadly form of cutaneous neoplasm due to its propensity to metastasize. Oncogenic BRAF drives sustained activation of the BRAF/MEK/ERK (MAPK) pathway and cooperates with PI3K/AKT/mTOR (PI3K) signaling to induce epithelial to mesenchymal transition (EMT), leading to cell invasion and metastasis. Therefore, targeting these pathways is a promising preventive/therapeutic strategy. We have shown that fisetin, a flavonoid, reduces human melanoma cell invasion by inhibiting EMT. In addition, fisetin inhibited melanoma cell proliferation and tumor growth by downregulating the PI3K pathway. In this investigation, we aimed to determine whether fisetin can potentiate the anti-invasive and anti-metastatic effects of sorafenib in BRAF-mutated melanoma. We found that combination treatment (fisetin + sorafenib) more effectively reduced the migration and invasion of BRAF-mutated melanoma cells both in vitro and in raft cultures compared to individual agents. Combination treatment also effectively inhibited EMT as observed by a decrease in N-cadherin, vimentin and fibronectin and an increase in E-cadherin both in vitro and in xenograft tumors. Furthermore, combination therapy effectively inhibited Snail1, Twist1, Slug and ZEB1 protein expression compared to monotherapy. The expression of MMP-2 and MMP-9 in xenograft tumors was further reduced in combination treatment compared to individual agents. Bioluminescent imaging of athymic mice, intravenously injected with stably transfected CMV-luciferase-ires-puromycin. T2A.EGFP-tagged A375 melanoma cells, demonstrated fewer lung metastases following combination treatment versus monotherapy. Our findings demonstrate that fisetin potentiates the anti-invasive and anti-metastatic effects of sorafenib. Our data suggest that fisetin may be a worthy adjuvant chemotherapy for the management of melanoma.
Which Are the Most Reliable Methods of Predicting the Meniscal Size for Transplantation?

Background: Although the size of the meniscal allograft is crucial during meniscal transplantation, the accuracy of meniscal measurement methods is still under debate. A number of methods based on radiographic and magnetic resonance imaging (MRI) data as well as on anthropometric data have been proposed, but their reproducibility and reliability are still unclear. Purpose: To compare meniscal length and width as measured by different techniques (anthropometric and plain radiographic) to establish which of these 2 methods is more reliable and cost-effective for determining the meniscal size in comparison to MRI. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: The MRI scans and plain radiographic films of 22 patients (44 knees) from a single institution were studied. The width and length of the medial and lateral menisci were measured using specific techniques. Data on sex, age, body weight, and height were used to develop a regression formula for meniscal measurements (comparing both imaging methods) to establish meniscal dimensions. Data validation was achieved using the Pearson correlation, the intraclass correlation coefficient, and the Wilcoxon nonparametric test for all variables, with a significance level established at 95%. Accuracy was established as a 10% measure discrepancy from the gold standard (MRI) and was considered an average between the right and left knees. Results: No statistically significant difference was observed between the right and left knees on radiographic and MRI measurements. The Pollard technique of radiographic measurement overestimated the width of the lateral meniscus when compared with anthropometric measurements (P < .001), considering MRI as the gold standard. The same was observed for MRI measurements of the length of the lateral meniscus in which not only anthropometric but also plain radiographic measurements using the Yoon technique were significantly smaller than those values found with the Pollard technique (P < .001). The anthropometric method underestimated the width and length of the medial meniscus with an accuracy of 68.2% and 63.6%, respectively. The radiographic method was comparable with MRI in establishing all medial meniscal measurements with an accuracy of 93.2% for length and 77.3% for width. Conclusion: Some viable alternatives to MRI have been suggested. For the lateral meniscus, anthropometric data are an alternative for width, and the Yoon method can be used to assess length. For the medial meniscus, the Pollard method is considered a satisfactory alternative. This study emphasized the importance of measuring the width and length of the meniscus independently during preoperative sizing for a meniscal allograft transplantation procedure. Using MRI as a gold standard, the study also proposed other less costly and satisfactory methods of obtaining such measurements.
A kinase-deficient TrkC receptor isoform activates Arf6–Rac1 signaling through the scaffold protein tamalin

Neurotrophins play an essential role in mammalian development. Most of their functions have been attributed to activation of the kinase-active Trk receptors and the p75 neurotrophin receptor. Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. We show that the neurotrophin-3 (NT3) TrkCT1-truncated receptor binds to the scaffold protein tamalin in a ligand-dependent manner. Moreover, NT3 initiation of this complex leads to activation of the Rac1 GTPase through adenosine diphosphate-ribosylation factor 6 (Arf6). At the cellular level, NT3 binding to TrkCT1–tamalin induces Arf6 translocation to the membrane, which in turn causes membrane ruffling and the formation of cellular protrusions. Thus, our data identify a new signaling pathway elicited by the kinase-deficient TrkCT1 receptor. Moreover, we establish NT3 as an upstream regulator of Arf6.
Neurons with graded response have collective computational properties like those of two-state neurons.

A model for a large network of "neurons" with a graded response (or sigmoid input-output relation) is studied. This deterministic system has collective properties in very close correspondence with the earlier stochastic model based on McCulloch - Pitts neurons. The content- addressable memory and other emergent collective properties of the original model also are present in the graded response model. The idea that such collective properties are used in biological systems is given added credence by the continued presence of such properties for more nearly biological "neurons. " Collective analog electrical circuits of the kind described will certainly function. The collective states of the two models have a simple correspondence. The original model will continue to be useful for simulations, because its connection to graded response systems is established. Equations that include the effect of action potentials in the graded response system are also developed.
Metachromatic Leukodystrophy (MLD) in Hospitalized Adult Schizophrenic Patients Resistant to Drug Treatment

Metachromatic leukodystrophy (MLD) is a rare inherited neurodegenerative disease associated with a defect in the catabolism of sulphatide (galactocerebroside-sulphate) which accumulates in the nervous system. MLD can be diagnosed biochemically by demonstrating deficiency in the activity of the enzyme arylsulphatase A (ASA) and an excess of sulphatide in urine and tissues. Cinically adult MLD may present as a schizophrenic-like psychosis, which typically develops years before the onset of neurologial signs which are not inevitable. Urinary ASA was investigated in 99 chronic hospitalized psychiatric patients (including 77 schizophrenics). Thirteen showed reduced ASA activity. Of the nine who were available for further study, only one evinced reduced ASA activity in other tissues (for example, leukocytes and cultured fibroblasts). However, there was no evidence of sulphatidurea with impaired sulphatide hydrolysis in his intact cultured fibroblasts. Therefore, he tested negative for MLD. This biochemical profile is known as pseudosulphatase deficiency. The possible relationship of pseudosulphatase deficiency to schizophrenic-like conditions is discussed.
A Singular Perturbation Based Global Dynamic High Gain Scaling Control Design for Systems With Nonlinear Input Uncertainties

A general class of uncertain nonlinear systems with input nonlinearities is considered. The system structure includes a core nominal system of triangular structure with additive uncertain nonlinear functions. The control input is allowed to enter non-affinely into the system dynamics as well as to have uncertainties coupled with it in terms of an uncertain nonlinear function of the input and output. The control design is based on dual controller/observer dynamic high-gain scaling with an additional dynamic scaling based on a singular-perturbation-like redesign to address the non-affine and uncertain nature of the input appearance into the system dynamics. The proposed approach yields a global robust adaptive output-feedback control design.
Two User Perspectives in Program Comprehension: End Users and Developer Users

Recent empirical studies identified an interest of software developers in high-level usage information, i.e. Why and how end users employ a software application. Furthermore, recent empirical work found that developers of interactive applications put themselves in the role of users by interacting with the user interface during program comprehension. This paper presents an exploratory case study investigating these two user perspectives in detail. The study focuses on information needs regarding software usage and developers in the role of users during program comprehension. 21 developers from six software companies were observed during program comprehension tasks and interviewed. The resulting observation protocols and interview minutes were analyzed using coding. We found that developers are interested in information about use cases and user behavior, user goals and user needs, failure reproduction steps, and application domain concepts. But such information is rarely available to them during program comprehension. This mismatch indicates a potential to improve program comprehension practices by capturing such information and providing it to developers. Furthermore, we found that developers interact with the user interface of an interactive application to reproduce failures, to find relevant source code, to test changes, to trigger the debugger, and to familiarize with an unknown part of the application. Also, developers conceptually map elements of the user interface to source code, data structures, and algorithms. We call this behavior "UI-based comprehension" and argue that it is part of a broader comprehension strategy together with comprehension activities like reading source code or debugging.
The role of rheumatoid arthritis genetic susceptibility markers in the prediction of erosive disease in patients with early inflammatory polyarthritis: results from the Norfolk Arthritis Register

Objectives. Recent whole-genome and candidate gene association studies in RA have identified a number of single nucleotide polymorphisms (SNPs) that predispose to disease with moderate risk. It remains poorly understood how recently identified genetic factors may contribute to RA severity. We therefore sought to investigate the role of recently identified RA susceptibility SNP markers in predicting erosive outcome in patients with recent-onset inflammatory polyarthritis (IP). Methods. DNA and X-ray data were available for 1049 patients who were registered between 1990 and 2003 with the Norfolk Arthritis Register (NOAR); a primary care-based inception cohort of patients with recent-onset IP. Demographic and clinical data were recorded at inclusion, and at yearly assessments thereafter. Patients were genotyped for 18 SNP markers. The presence of serum anti citrullinated peptide antibodies (ACPAs) was assessed in samples collected at inclusion to the NOAR. The association of serological and genetic markers with poor radiological (Larsen) score at Years 1 and 5, and erosions at Years 1 and 5 was investigated. Results. Baseline ACPA positivity was associated with erosive disease and higher radiological damage. SNP markers within the TRAF1/C5 locus were associated with erosive disease at Year 1 [rs2900180: odds ratio (OR) 1.53 (95% CI 1.14, 2.05)] and Year 5 [rs2900180: OR 1.47 (95% CI 1.07, 2.02)]. None of the SNP markers tested was associated with Larsen score. Conclusion. Our results are in keeping with a previous report and suggest that the TRAF1/C5 region is associated with risk of development of radiological erosions in IP/RA patients. The finding requires replication in other large data sets.
Effectiveness of Postharvest Treatment with Chitosan to Control Citrus Green Mold

Control of green mold, caused by Penicillium digitatum, by fungicides raises several problems, such as emergence of resistant pathogens, as well as concerns about the environment and consumers’ health. As potential alternatives, the effects of chitosan on green mold disease and the quality attributes of citrus fruits were investigated. Fruits were wounded then treated with different concentrations of chitosan 24 h before their inoculation with P. digitatum. The results of in vitro experiment demonstrated that the antifungal activity against P. digitatum was improved in concert to the increase of chitosan concentration. In an in vivo study, green mold was significantly reduced by chitosan treatments. In parallel, chitinase and glucanase activities were enhanced in coated fruits. Evidence suggested that effects of chitosan coating on green mold of mandarin fruits might be related to its fungitoxic properties against the pathogen and/or the elicitation of biochemical defense responses in coated fruits. Further, quality attributes including fruit firmness, surface color, juice content, and total soluble solids, were not affected by chitosan during storage. Moreover, the loss of weight was even less pronounced in chitosan-coated fruit.
Association of Body Mass Index With Increased Cost of Care and Length of Stay for Emergency Department Patients With Chest Pain and Dyspnea

Background—High body mass index (BMI) increases the probability of indeterminate findings on diagnostic studies, length of stay, and cost of care for hospitalized patients. No study has examined the economic and operational impact of BMI in patients with chest complaints presenting to the emergency department (ED). The objective was to measure the association of BMI with the main outcomes of cost of care, length of stay (including time in the ED and time in the wards if admitted), and radiation exposure in patients presenting to the ED with chest pain and dyspnea. Methods and Results—This was a prospective, 4-center, outcomes study. Patients were adults with dyspnea and chest pain, nondiagnostic electrocardiograms, and no obvious diagnosis. Patients were followed for the main outcomes for 90 days. Outcomes that were stratified by BMI in 5 categories, underweight, normal weight, overweight, obese, and morbidly obese, were compared using the Kruskall–Wallis rank test, and the independent predictive value of BMI was tested with multivariate regressions. Compared with medical costs for normal weight patients, costs were 22% higher for overweight patients (P=0.077), 28% higher for obese patients (P=0.020), and 41% higher for morbidly obese patients (P=0.015). Morbidly obese patients without computerized tomographic scanning stayed in the hospital 34% longer than normal weight patients (P=0.073), and morbidly obese patients with computerized tomographic scanning stayed in the hospital 44% longer than normal weight patients (P=0.083). BMI was not a significant predictor of radiation exposure. Morbidly obese patients had the highest proportion (87%) of no significant cardiopulmonary diagnosis for 90 days after computerized tomographic pulmonary angiography. Conclusions—BMI was associated with increases in cost of care and length of hospital stay for patients with chest pain and dyspnea. These results emphasize a need for specific protocols to manage morbidly obese patients presenting to the ED with chest pain and dyspnea. Clinical Trial Registration—http://www.clinicaltrials. gov. Unique identifier: NCT01059500.
Adenylyl Cyclase Signaling in the Developing Chick Heart: The Deranging Effect of Antiarrhythmic Drugs

The adenylyl cyclase (AC) signaling system plays a crucial role in the regulation of cardiac contractility. Here we analyzed the key components of myocardial AC signaling in the developing chick embryo and assessed the impact of selected β-blocking agents on this system. Application of metoprolol and carvedilol, two commonly used β-blockers, at embryonic day (ED) 8 significantly downregulated (by about 40%) expression levels of AC5, the dominant cardiac AC isoform, and the amount of Gsα protein at ED9. Activity of AC stimulated by forskolin was also significantly reduced under these conditions. Interestingly, when administered at ED4, these drugs did not produce such profound changes in the myocardial AC signaling system, except for markedly increased expression of Giα protein. These data indicate that β-blocking agents can strongly derange AC signaling during the first half of embryonic heart development.
Indices of insulin action calculated from fasting glucose and insulin reflect hepatic, not peripheral, insulin sensitivity in African‐American and Caucasian adolescents

Abstract: Insulin stimulates muscle glucose uptake and inhibits hepatic glucose production. Measures of insulin sensitivity or insulin resistance must take both of these actions into account. Homeostatic model assessment of insulin resistance (HOMAIR) and quantitative insulin sensitivity check index (QUICKI) are two simple measures of insulin resistance and insulin sensitivity that are derived from fasting glucose and insulin levels as such it is likely that they reflect primary hepatic insulin action and not muscular effects. To prove this hypothesis, the relationships of HOMAIR and QUICKI to peripheral insulin sensitivity (SI*) and hepatic insulin resistance (HIR) were assessed in 34 adolescents (age 13.5 ± 2.9 yr, body mass index 23.0 ± 5.7, mean ± SD; 16 Caucasian and 14 African‐American). SI* and HIR were determined using the stable‐labeled, frequently sampled intravenous glucose tolerance test (250 mg total glucose/kg, 13% [6,6]‐d2‐glucose). The former was calculated using the one‐compartment minimal model and stable glucose concentration (SI*), and the latter was determined over the last hour of the study by multiplying hepatic glucose production (Steele’s equation) by mean plasma insulin concentration. As expected, HOMAIR and QUICKI were significantly related to HIR (log HOMAIR and log HIR, r = 0.73, p < 0.001; QUICKI and log HIR, r = −0.69, p < 0.001) but not SI*. When both SI* and HIR were included in the equations, only the relationships to log HIR were significant (log HOMAIR, p < 0.001; QUICKI, p < 0.001). The relationships were similar in African‐American and Caucasian subjects. These results demonstrate that in adolescents, HOMAIR and QUICKI assess hepatic but not peripheral insulin action.
Regulatory Role of Gonadotropins and Local Factors Produced by Ovarian Follicles on In Vitro Resistin Expression and Action on Porcine Follicular Steroidogenesis1

ABSTRACT Resistin, a hormone secreted by adipocytes, is thought to be important in reproduction. Our previous study demonstrated resistin expression in porcine ovarian follicles and its direct effect on steroidogenesis. The aim of the current study was to evaluate the effect of gonadotropins and the local ovarian factors, such as insulin-like growth factor type 1 (IGF1) and steroids (progesterone, testosterone, and 17 beta-estradiol), on the expression and secretion of resistin, as well as its steroidogenic action. Porcine ovarian follicles were exposed to follicle-stimulating hormone (FSH) and luteinizing hormone (LH) at 50–150 ng/ml, IGF1 (10–100 ng/ml), and steroids at 10−8 to 10−6 M for 24 h. Then, mRNA, protein expression, and medium concentration of resistin were determined using real-time PCR, Western blot analysis, and ELISA, respectively. In the subsequent experiments, ovarian follicles were exposed to resistin and/or FSH, LH, IGF1, and steroids, and ovarian steroidogenesis was analyzed. Additionally, we examined the direct effect of resistin on the protein expression of receptors for gonadotropins and investigated local factors. The results showed that gonadotropins and steroids have stimulatory effects but that IGF1 has an inhibitory effect on resistin expression and secretion. Resistin decreased gonadotropins and local hormone-induced steroid secretion and inhibited 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and cytochrome P450 aromatase protein expression. Additionally, we demonstrated that resistin increased the expression of receptors for progesterone and testosterone. These findings all show that the expression and function of resistin are regulated by gonadotropins and local factors produced by ovarian follicles.
Selective increase of tumour necrosis factor‐alpha in injured and spared myelinated primary afferents after chronic constrictive injury of rat sciatic nerve

Chronic constriction of the sciatic nerve, leading to a hyperalgesic state, results in a partial lesion wherein some axons are injured and others remain intact. Here we sought to characterize reactive changes which occur in DRG cell bodies of injured and uninjured axons projecting to skin and muscle. Using immunohistochemistry combined with flurorogold and fluororuby retrograde labelling to define DRG cell bodies associated with injured and uninjured axons, we analysed the DRG immunoreactivity (IR) for tumour necrosis factor‐alpha (TNF), interleukin‐10 (IL‐10), the sensory neuron‐specific channel vanilloid receptor 1 (VR1), isolectin B4 (IB4) and calcitonin‐gene‐related peptide (CGRP) 4 days after a unilateral chronic constriction injury (CCI) of the rat sciatic nerve. TNF IR was predominantly localized in neuronal DRG cells. In DRG with an intact nerve, TNF IR was present in 45%, IL‐10 IR in 46%, VR1 IR in 44%, IB4 IR in 51% and CGRP IR in 40% of all neuronal profiles. Four days after CCI, TNF IR was increased in medium‐sized neurons, whereas IR for IL‐10, VR1 and IB4, predominantly present in small neurons, was reduced. Importantly, not only injured but also adjacent spared neurons contributed markedly to increased TNF IR. Neurons projecting to both muscle and skin displayed upregulated TNF IR after CCI. TNF in medium‐sized neurons colocalized with neurofilament and trkB, but not with IB4, trkA or RET, suggesting a selective phenotypic switch in presumably low‐threshold myelinated primary afferents. Spared myelinated fibres with intact sensory functions but upregulated TNF expression may contribute to behavioural changes observed after nerve injury.