Miracle-dz/UniFAR-FTUs huggingface dataset:
Cytotoxic Effects of Diazenes on Tumor Cells in vitro

Background: We have shown previously that diazenecarboxamides (diazenes) were cytotoxic for several tumor cell lines. Their target seems to be the intracellular glutathione (GSH). To improve the solubility and biological activity of these drugs, new compounds have been synthesized. In the present study we examined the cytotoxic effect of six new diazenes: BR-25, UP-39, UP-11, JK-1024, RL-514 and RL-625. Methods: The cytotoxicity of diazenes was tested on nine human tumor cell lines: laryngeal carcinoma HEp2 cells, cervical carcinoma HeLa cells, mammary carcinoma MCF-7 cells, breast adenocarcinoma SK-BR-3 cells, and glioblastoma A1235 cells and their four drug-resistant cell lines. Cytotoxicity was determined using the colorimetric MTT assay. The intracellular GSH content (following the treatment with diazenes) was examined spectrophotometrically in human cervical carcinoma cells by the procedure developed by Tietze. Results: Results show that diazene UP-39 was mostly efficient, significantly reducing the cell survival of all nine cell lines examined, including four drug-resistant cell lines. Diazenes UP-11, RL-514 and BR-25 given in the highest concentrations decreased the survival of some examined cell lines, but to less than 50%. Diazenes RL-625 and JK-1024 had no influence on the cell survival. None of the examined diazenes significantly influenced the intracellular level of GSH. Conclusion: Our results suggest that diazene UP-39 may be a promising new drug for the treatment of tumors and encourage further research on this compound.
Optimizing novel penetration enhancing hybridized vesicles for augmenting the in-vivo effect of an anti-glaucoma drug

Abstract Usually the topical delivery of ocular drugs poses a great challenge. Accordingly, the work in this study comprised the use of different hybrids of generally regarded as safe (GRAS) oils and surfactants in order to develop and optimize novel acetazolamide (AZD) entrapped-vesicular systems aiming at improving its ocular delivery and reaching better therapeutic outcomes in the treatment of glaucoma. The phospholipid/cholesterol bilayer of the vesicles was enriched with hybrids of Tween 80, Labrasol, Transcutol and Labrafac lipophile WL in different masses and proportions according to a mixture design viz. D-optimal mixture design. Three models were generated comprising three responses: particles size, percentage of entrapment efficiency and amount of drug released after 24 hours (Q24h). The results demonstrated the ability of the penetration enhancing hybrids in modulating the three responses compared to the conventional liposomes. Transmission electron microscope was used to characterize the selected formulations. Sterilization of selected formulations was carried out using gamma radiation and the effect of gamma radiations on entrapment, particle size and in vitro release were studied. The selected sterilized formulations were tested in-vivo on the eyes of albino rabbits in order to evaluate the efficiency of the novel delivery systems on the intra-ocular pressure reduction (IOP) compared to drug solution and the conventional liposomes. The novel formulations proved their efficiency in reducing the IOP to lower values compared to the conventional liposomes, which pose new successful platform for ocular delivery of AZD and other anti-glaucoma drug analogs.
A thermodynamic interpretation of malignancy: do the genes come later?

Current theories on cancer development focus on 'unlucky' mutations affecting oncogenes or tumour suppressor genes. In this article a theory will be developed which interprets cancer as an adaptive phenomenon -- a response to cellular stress induced by an energetic overload which would ultimately lead to an increase in cellular entropy. One of these adaptive mechanisms is paneuploid polyploidization, a phenomenon frequently described in malignant tumours. This inherent property of the genome to multiply with limited sequence variability may be involved just to make new proteins which are more appropriate to manage the harmful situation of energetic overload. Another important mechanism to prevent increasing entropy is the change in chirality of proteins and carbon hydrates because the use of enantiomers with higher intrinsic energy ultimately reduces entropy of the cell. These chiral alterations in turn affect the molecular structures of proteins and DNA, resulting in abnormal function of the former and disturbances of replication, transcription and repair of the latter. Moreover, the altered proteins may -- as a secondary step -- induce structural changes of the DNA. Because changes in chirality affect the structure of a cell randomly, one can expect alterations of multiple genes or proteins, and this is exactly what has been described in the literature. Therefore, this hypothesis may help to clarify confusing findings of tumour genetics accumulated over the last two decades. Cancer could be seen as a reaction of a cell to entrap energy which reduces entropy, or, in other words, cancer may best be regarded as entropic devolution.
Waiting for the Barbarians

For decades the Magistrate has run the affairs of a tiny frontier settlement, ignoring the impending war between the barbarians and the Empire, whose servant he is. But when the interrogation experts arrive, he is jolted into sympathy with the victims and into a quixotic act of rebellion which lands him in prison, branded as an enemy of the state. Waiting for the Barbarians is an allegory of oppressor and oppressed. Not just a man living through a crisis of conscience in an obscure place in remote times, the Magistrate is an analogue of all men living in complicity with regimes that ignore justice and decency.
Rapamycin Impairs In Vivo Proliferation of Islet Beta-Cells

Background. Progressive graft dysfunction is commonly observed in recipients of islet allografts treated with high doses of rapamycin. This study aimed at evaluating the effect of rapamycin on pancreatic islet cell proliferation in vivo. Methods. The murine pregnancy model was utilized, since a high rate of &bgr;-cell proliferation occurs in a well-defined time frame. Rapamycin (0.2 mg/kg/day) was given to C57BL/6 mice for 5–7 days starting on day 7.5 of pregnancy. Cell proliferation was evaluated by detection of bromodeoxyuridine incorporation by immunohistochemistry. Results. Pregnancy led to increased &bgr;-cell proliferation and islet yield with skewing in islet size distribution as well as higher pancreatic insulin content, when compared to that of nonpregnant females. These effects of pregnancy on &bgr;-cell proliferation and mass were significantly blunted by rapamycin treatment. Minimal effect of rapamycin was observed on islet function both in vivo and in vitro. Rapamycin treatment of islets in vitro resulted in reduced p70s6k phosphorylation, which was paralleled by increased ERK1/2 phosphorylation. Conclusions. Rapamycin treatment reduces the rate of &bgr;-cell proliferation in vivo. This phenomenon may contribute to impair &bgr;-cell renewal in transplanted patients and to the progressive dysfunction observed in islet graft recipients.
Estimated GFR and incident cardiovascular disease events in American Indians: the Strong Heart Study.

BACKGROUND In populations with high prevalences of diabetes and obesity, estimating glomerular filtration rate (GFR) by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation may predict cardiovascular disease (CVD) risk better than by using the Modification of Diet in Renal Disease (MDRD) Study equation. STUDY DESIGN Longitudinal cohort study comparing the association of GFR estimated using either the CKD-EPI or MDRD Study equation with incident CVD outcomes. SETTING & PARTICIPANTS American Indians participating in the Strong Heart Study, a longitudinal population-based cohort with high prevalences of diabetes, CVD, and CKD. PREDICTOR Estimated GFR (eGFR) predicted using the CKD-EPI and MDRD Study equations. OUTCOMES Fatal and nonfatal cardiovascular events, consisting of coronary heart disease, stroke, and heart failure. MEASUREMENTS The association between eGFR and outcomes was explored in Cox proportional hazards models adjusted for traditional risk factors and albuminuria; the net reclassification index and integrated discrimination improvement were determined for the CKD-EPI versus MDRD Study equations. RESULTS In 4,549 participants, diabetes was present in 45%; CVD, in 7%; and stages 3-5 CKD, in 10%. During a median of 15 years, there were 1,280 cases of incident CVD, 929 cases of incident coronary heart disease, 305 cases of incident stroke, and 381 cases of incident heart failure. Reduced eGFR (<90 mL/min/1.73 m2) was associated with adverse events in most models. Compared with the MDRD Study equation, the CKD-EPI equation correctly reclassified 17.0% of 2,151 participants without incident CVD to a lower risk (higher eGFR) category and 1.3% (n=28) were reclassified incorrectly to a higher risk (lower eGFR) category. LIMITATIONS Single measurements of eGFR and albuminuria at study visits. CONCLUSIONS Although eGFR based on either equation had similar associations with incident CVD, coronary heart disease, stroke, and heart failure events, in those not having events, reclassification of participants to eGFR categories was superior using the CKD-EPI equation compared with the MDRD Study equation.
A new technique of hepatic vein reconstruction in partial liver transplantation

The shortage of pediatric donor livers has stimulated the development of advanced surgical approaches such as partial liver transplantation, which produces the same results as whole organ replacement. Differences in body weight between donor and recipient of more than four times, however, usually necessitate extended reduction hepatectomy and modified ways of performing vascular reconstruction. Therefore, following ex vivo “trisegmentectomy”, a new technique of hepatic venous drainage was developed with an end-to-side anastomosis of the left donor hepatic vein to the preserved recipient inferior vena cava. This operative technique was applied to four children, one of whom had a retransplantation performed in exactly the same fashion. There were no specific complications related to this particular surgical technique. From our preliminary experience we conclude that reduced-size liver transplantation can be safely performed with the described type of hepatic vein reconstruction, especially when large donor organs have to be used for small children.
Effect of valproic acid on radiation-induced DNA damage in euchromatic and heterochromatic compartments

The distinction between heterochromatin and euchromatin in the double-strand break (DSB) damage pathway is of interest, recent reports indicate that chromatin is not created equally nor is it acquiescent to DSBs. Using the classical histone deacetylase inhibitor, Trichostatin A, we have previously demonstrated that chromatin represents a heterogeneous substrate with respect to histone tail modification by histone deacetylase inhibitors and consequent responses to DNA damage and repair. Here, we extended the initial findings by investigating the radiation sensitizing properties of the widely used antiepileptic, valproic acid. Clonogenic survival assays confirm that valproic acid is an efficient sensitizer of radiation-induced cell death. The radiosensitizing effect is correlated with valproic acid-mediated histone hyperacetylation, chromatin decondensation and enhanced formation of radiation-induced γH2AX preferentially on euchromatic alleles. Heterochromatin was much more resistant to histone tail modification, changes in chromatin architecture and DNA damage. These findings are consolidated by studies with the structurally related analogue, valpromide, which does not inhibit histone deacetylase enzymes. At a relatively low concentration (1 mM) valpromide did not cause chromatin modifications and radiation sensitivity, providing further evidence that the radiation sensitizing properties of valproic acid are at least in part, due to histone modification-dependent effects on euchromatin. When higher concentrations (5 mM) were used, both compounds resulted in significant radiation sensitivity, albeit, with differing efficacy (dose modifying factors of 1.5 and 1.2 for valproic acid and valpromide, respectively). The findings imply that histone-modification independent mechanisms also contribute to the radiation sensitizing properties of valproic acid. Overall, our findings are consistent with the emerging interest in the use histone deacetylase inhibitors in combination with radiotherapy for the treatment of cancer.
Live Fast, Die Young: Experimental Evidence of Population Extinction Risk due to Climate Change

Evidence has accumulated in recent decades on the drastic impact of climate change on biodiversity. Warming temperatures have induced changes in species physiology, phenology, and have decreased body size. Such modifications can impact population dynamics and could lead to changes in life cycle and demography. More specifically, conceptual frameworks predict that global warming will severely threaten tropical ectotherms while temperate ectotherms should resist or even benefit from higher temperatures. However, experimental studies measuring the impacts of future warming trends on temperate ectotherms' life cycle and population persistence are lacking. Here we investigate the impacts of future climates on a model vertebrate ectotherm species using a large-scale warming experiment. We manipulated climatic conditions in 18 seminatural populations over two years to obtain a present climate treatment and a warm climate treatment matching IPCC predictions for future climate. Warmer temperatures caused a faster body growth, an earlier reproductive onset, and an increased voltinism, leading to a highly accelerated life cycle but also to a decrease in adult survival. A matrix population model predicts that warm climate populations in our experiment should go extinct in around 20 y. Comparing our experimental climatic conditions to conditions encountered by populations across Europe, we suggest that warming climates should threaten a significant number of populations at the southern range of the distribution. Our findings stress the importance of experimental approaches on the entire life cycle to more accurately predict population and species persistence in future climates.
Interleukin-33 stimulates GM-CSF and M-CSF production by human endothelial cells

Summary Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in various inflammatory conditions targeting amongst other cells the endothelium. Besides regulating the maturation and functions of myeloid cells, granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) have been shown to play a role in such pathologies too. It was the aim of our study to investigate a possible influence of IL-33 on GM-CSF and M–CSF production by human endothelial cells. IL-33, but not IL-18 or IL-37, stimulated GM-CSF and M-CSF mRNA expression and protein production by human umbilical vein endothelial cells (HUVECs) and human coronary artery ECs (HCAECs) through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in an IL–1-independent way. This effect was inhibited by the soluble form of ST2 (sST2), which is known to act as a decoy receptor for IL-33. The 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor fluvastatin could also be shown to moderately reduce the IL-33-mediated effect on M-CSF, but not on GM-CSF expression. In addition, IL–33, IL-1β, GM-CSF and M-CSF were detected in endothelial cells of human carotid atherosclerotic plaques using immunofluorescence. Upregulation of GM-CSF and M–CSF production by human endothelial cells, an effect that appears to be mediated by NF–κB and to be independent of IL-1, may be an additional mechanism through which IL-33 contributes to inflammatory activation of the vessel wall. Supplementary Material to this article is available online at www.thrombosis-online.com.
Stimulation of Expression for the Adenosine A2A Receptor Gene by Hypoxia in PC12 Cells

The purpose of this study was to examine the regulation of adenosine A2A receptor (A2AR) gene expression during hypoxia in pheochromocytoma (PC12) cells. Northern blot analysis revealed that the A2AR mRNA level was substantially increased after a 3-h exposure to hypoxia (5% O2), which reached a peak at 12 h. Immunoblot analysis showed that the A2AR protein level was also increased during hypoxia. Inhibition of de novo protein synthesis blocked A2AR induction by hypoxia. In addition, removal of extracellular free Ca2+, chelation of intracellular free Ca2+, and pretreatment with protein kinase C inhibitors prevented A2AR induction by hypoxia. Moreover, depletion of protein kinase C activity by prolonged treatment with phorbol 12-myristate 13-acetate significantly inhibited the hypoxic induction of A2AR. A2AR antagonists led to a significant enhancement of A2AR mRNA levels during hypoxia, whereas A2AR agonists caused down-regulation of A2AR expression during hypoxia. This suggests that A2AR regulates its own expression during hypoxia by feedback mechanisms. We further found that activation of A2AR enhances cell viability during hypoxia and also inhibits vascular endothelial growth factor expression in PC12 cells. Thus, increased expression of A2AR during hypoxia might protect cells against hypoxia and may act to inhibit hypoxia-induced angiogenic activity mediated by vascular endothelial growth factor.
Recognition between flexible protein molecules: induced and assisted folding †

This review focuses on a very important but little understood type of molecular recognition — the recognition between highly flexible molecular structures. The formation of a specific complex in this case is a dynamic process that can occur through sequential steps of mutual conformational adaptation. This allows modulation of specificity and affinity of interaction in extremely broad ranges. The interacting partners can interact together to form a complex with entirely new properties and produce conformational signal transduction at substantial distance. We show that this type of recognition is frequent in formation of different protein–protein and protein–nucleic acid complexes. It is also characteristic for self‐assembly of protein molecules from their unfolded fragments as well as for interaction of molecular chaperones with their substrates and it can be the origin of ‘protein misfolding’ diseases. Thermodynamic and kinetic features of this type of dynamic recognition and the principles underlying their modeling and analysis are discussed. Copyright © 2001 John Wiley & Sons, Ltd.
Monitoring ovarian cycles, pregnancy and post-partum in captive marsh deer (Blastocerus dichotomus) by measuring fecal steroids

Lay summary: This study aimed to characterize some aspects of the reproductive physiology of female marsh deer, such as length and fecal progestins profile of estrous cycle, pregnancy and post parturition periods, information that we consider an important and decisive factor for the elaboration of conservation actions of Neotropical deer species.
System management recovery protocol for MPSoCs

The advances in silicon technology lead to systems with hundreds of processors, the NoC-based MPSoCs. However, the higher fault probability in deep sub-micron technologies shortens the integrated circuits lifetime. Operating systems enable to execute distributed applications in the MPSoC processing elements (PEs). Large systems require PEs dedicated to management purposes, for example, execute the task mapping, handle monitoring data, and run self-awareness adaptation. This paper addresses an MPSoC hierarchically organized: PEs with an embedded operating system executing the applications (SpE) and dedicated PEs manage at runtime the system resources (Mpe). A rich literature presents fault-tolerant proposals for the hardware and software components of the MPSoC, but there is a significant gap related to fault-tolerant approaches at the system level, i.e., related to the PEs with the function to manage the system. Consider for example an Mpe responsible for managing a set of SpE s. A fault in an Mpe prevents the access to the set of SpE s to execute new applications. The goal of this paper is to present a method to determine when an Mpe became faulty, and propose a protocol to migrate the management software safely to an Spe. The management data is preserved, without saving the context in redundant structures. The proposal is transparent to the applications executing in the system, with a small execution overhead observed during the management migration, presented in the results Section.
Mollicutes-wall-less bacteria with internal cytoskeletons.

The structure and motility of the Mollicutes (Spiroplasma, Mycoplasma, and Acholeplasma) are briefly reviewed. The data are presented from the perspective of prokaryotic and eukaryotic motors, cytoskeletons, and cell motility. The Mollicutes are eubacteria derived from Clostridia by regressive evolution and genome reduction to produce the smallest and simplest free-living and self-replicating cells. Structurally, the Mollicutes are characterized by a complete lack of a cell wall and the presence of an internal cytoskeleton. Spiroplasma, which are helical cells with a flat, ribbon-like cytoskeleton, are amenable to structural and geometrical analysis. Motility and shape changes can be explained and modeled by the cytoskeleton acting as a linear motor.
ENDURING INFLUENCE OF EARLY TEMPERAMENT ON NEURAL MECHANISMS MEDIATING ATTENTION–EMOTION CONFLICT IN ADULTS

Behavioral inhibition, a temperament identified in early childhood, is often associated with dysregulated attention and affective processing, particularly in response to threat. Longitudinal studies find that the manifestation of perturbed attention and affective processing often dissipates with age. Yet, childhood behavioral inhibition continues to predict perturbed brain function into adulthood. This suggests that adults with childhood behavioral inhibition may engage compensatory processes to effectively regulate emotion‐related attention. However, it is unknown whether perturbations in brain function reflect compensation for attention bias to emotional stimuli generally, or to threatening contexts more specifically. The present study tests these possibilities.
A low energy consumption routing protocol for mobile sensor networks with a path-constrained mobile sink

Installing a mobile sink on the public vehicle, which is a path-constrained vehicle, to collect data in a mobile sensor network can lower maintenance cost. However, immediately sending the data packet to the mobile sink when it arrives does not guarantee the shortest path, leading to high energy consumption. Meanwhile, immediately sending the data packet to the closest future position of the mobile sink can guarantee the shortest path. However, the mobile sensor node, which buffers the data packet while waiting for the mobile sink to arrive, may move away from the trajectory, resulting in reduction of delivery ratio. Therefore, we shall propose to delay sending the data packet until the mobile sink approaches the position with the shortest path. It not only guarantees the shortest path but also exhibits robustness with dynamic node mobility. Via extensive simulations, we show that our proposed scheme can effectively reduce energy consumption and increase delivery ratio even for the high-speed mobile sink.