Miracle-dz/UniFAR-FTUs huggingface dataset:
Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

Significance The role of signal transducer and activator of transcription 3 (STAT3) pathway in hepatic stellate cells (HSCs) remains unclear. Using sorafenib and its derivative SC-1, we demonstrated the significant role of STAT3 pathway in liver fibrogenesis. We further found that STAT3 pathway of HSCs overexpressed in chronic hepatitis B patients with advanced fibrosis, therefore STAT3 may serve as a promising fibrotic biomarker and target. Furthermore, SHP-1 phosphatase-direct STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery. Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery.
Changes in the Abundance of Grassland Species in Monocultures versus Mixtures and Their Relation to Biodiversity Effects

Numerous studies have reported positive effects of species richness on plant community productivity. Such biodiversity effects are usually quantified by comparing the performance of plant mixtures with reference monocultures. However, several mechanisms, such as the lack of resource complementarity and facilitation or the accumulation of detrimental agents, suggest that monocultures are more likely than mixtures to deteriorate over time. Increasing biodiversity effects over time could therefore result from declining monocultures instead of reflecting increases in the functioning of mixtures. Commonly, the latter is assumed when positive trends in biodiversity effects occur. Here, we analysed the performance of 60 grassland species growing in monocultures and mixtures over 9 years in a biodiversity experiment to clarify whether their temporal biomass dynamics differed and whether a potential decline of monocultures contributed significantly to the positive net biodiversity effect observed. Surprisingly, individual species’ populations produced, on average, significantly more biomass per unit area when growing in monoculture than when growing in mixture. Over time, productivity of species decreased at a rate that was, on average, slightly more negative in monocultures than in mixtures. The mean net biodiversity effect across all mixtures was continuously positive and ranged between 64–217 g per m2. Short-term increases in the mean net biodiversity effect were only partly due to deteriorating monocultures and were strongly affected by particular species gaining dominance in mixtures in the respective years. We conclude that our species performed, on average, comparably in monocultures and mixtures; monoculture populations being slightly more productive than mixture populations but this trend decreased over time. This suggested that negative feedbacks had not yet affected monocultures strongly but could potentially become more evident in the future. Positive biodiversity effects on aboveground productivity were heavily driven by a small, but changing, set of species that behaved differently from the average species.
Gab-1-mediated IGF-1 Signaling in IRS-1-deficient 3T3 Fibroblasts*

The insulin receptor substrate (IRS) family of proteins mediate a variety of intracellular signaling events by serving as signaling platforms downstream of several receptor tyrosine kinases including the insulin and insulin-like growth factor-1 (IGF-1) receptors. Recently, several new members of this family have been identified including IRS-3, IRS-4, and growth factor receptor-binding protein 2-associated binder-1 (Gab-1). 3T3 cell lines derived from IRS-1-deficient embryos exhibit a 70–80% reduction in IGF-1-stimulated S-phase entry and a parallel decrease in the induction of the immediate-early genes c-fos and egr-1but unaltered activation of the mitogen-activated protein kinases extracellular signal-regulated kinase-1 and extracellular signal-regulated kinase-2. Reconstitution of IRS-1 expression in IRS-1-deficient fibroblasts by retroviral mediated gene transduction is capable of restoring these defects. Overexpression of Gab-1 in IRS-1-deficient fibroblasts also results in the restoration ofegr-1 induction to levels similar to those achieved by IRS-1 reconstitution and markedly increases IGF-1-stimulated S-phase progression. Gab-1 is capable of regulating these biological end points despite the absence of IGF-1 stimulated tyrosine phosphorylation. These data provide evidence that Gab-1 may serve as a unique signaling intermediate in insulin/IGF-1 signaling for induction of early gene expression and stimulation of mitogenesis without direct tyrosine phosphorylation.
Ursodeoxycholic Acid in Primary Biliary Cirrhosis

In patients with primary biliary cirrhosis (PBC), ursodeoxycholic acid (ursodiol) improves laboratory test markers of cholestasis and hepatic inflammation as well as some hepatic histological features; it also delays histological progression in the early stages of PBC. Ursodiol is well tolerated and safe. Less well substantiated are that ursodiol either improves the quality of life or prevents liver transplantation or that it prolongs survival without transplantation. There are favorable trends for ursodiol in preventing transplantation and prolonging survival, but in the absence of randomized, placebo-controlled trials of sufficient duration, there remain impressions rather than statistically proved, strong conclusions.
Combining Image Reconstruction and Image Analysis with an Application to Two-Dimensional Tomography

The tasks of image reconstruction from measured data and the analysis of the resulting images are more or less strictly separated. One group of scientists computes by applying reconstruction algorithms to the images; the other then operates on these images to enhance the analysis. First attempts at combining image reconstruction and image analysis, in a nonsystematic way, are known as Lambda tomography or Tikhonov-Phillips methods with $\ell_1$-norms or with level-set methods. The aim of this paper is to provide a general tool to combine these two steps; i.e., even in the reconstruction step the future image analysis step is taken into account, leading to a new reconstruction kernel. Here we concentrate on linear methods. As a practical example we consider the image reconstruction problem in computerized tomography followed by an edge detection. We calculate a new reconstruction kernel and present results from simulations.
A new and generalized model for the multitaper detector with nonzero mean signals

The problem of spectrum sensing for cognitive radio networks has attracted much interest in the research community. The Multitaper detector has its unique importance and was highly recommended for spectrum sensing in cognitive radio systems. In this paper, we investigate the Multitaper detector for the generalized nonzero-mean case. We analyze the Hermitian form of the Multitaper estimate to obtain the detector performance for nonzero-mean primary signals. The difficulty in this case arises from finding an expression for the noncentrality parameters associated with the diagonalized form of the quadratic representation of the Multitaper estimate. We provide closed form expressions for the noncentrality parameters, which also turned to be a function of the eigenvalues of the quadratic form. The validity of the derived mathematical model is verified through Monte-Carlo simulations.
Dietary hemoglobin rescues young piglets from severe iron deficiency anemia: Duodenal expression profile of genes involved in heme iron absorption

Heme is an efficient source of iron in the diet, and heme preparations are used to prevent and cure iron deficiency anemia in humans and animals. However, the molecular mechanisms responsible for heme absorption remain only partially characterized. Here, we employed young iron-deficient piglets as a convenient animal model to determine the efficacy of oral heme iron supplementation and investigate the pathways of heme iron absorption. The use of bovine hemoglobin as a dietary source of heme iron was found to efficiently counteract the development of iron deficiency anemia in piglets, although it did not fully rebalance their iron status. Our results revealed a concerted increase in the expression of genes responsible for apical and basolateral heme transport in the duodenum of piglets fed a heme-enriched diet. In these animals the catalytic activity of heme oxygenase 1 contributed to the release of elemental iron from the protoporphyrin ring of heme within enterocytes, which may then be transported by the strongly expressed ferroportin across the basolateral membrane to the circulation. We hypothesize that the well-recognized high bioavailability of heme iron may depend on a split pathway mediating the transport of heme-derived elemental iron and intact heme from the interior of duodenal enterocytes to the bloodstream.
Efficient software performance estimation methods for hardware/software codesign

The performance estimation of a target system at a higher level of abstraction is very important in hardware/software codesign. We focus on software performance estimation, including both the execution time and the code size. We present two estimation methods at different levels of abstraction for use in the POLIS hardware/software codesign system. The experimental results show that the accuracy of our methods is usually within /spl plusmn/20%.
Matrix‐Gla protein promotes osteosarcoma lung metastasis and associates with poor prognosis

Osteosarcoma (OS) is the most prevalent osseous tumour in children and adolescents and, within this, lung metastases remain one of the factors associated with a dismal prognosis. At present, the genetic determinants driving pulmonary metastasis are poorly understood. We adopted a novel strategy using robust filtering analysis of transcriptomic profiling in tumour osteoblastic cell populations derived from human chemo‐naive primary tumours displaying extreme phenotypes (indolent versus metastatic) to uncover predictors associated with metastasis and poor survival. We identified MGP, encoding matrix‐Gla protein (MGP), a non‐collagenous matrix protein previously associated with the inhibition of arterial calcification. Using different orthotopic models, we found that ectopic expression of Mgp in murine and human OS cells led to a marked increase in lung metastasis. This effect was independent of the carboxylation of glutamic acid residues required for its physiological role. Abrogation of Mgp prevented lung metastatic activity, an effect that was rescued by forced expression. Mgp levels dramatically altered endothelial adhesion, trans‐endothelial migration in vitro and tumour cell extravasation ability in vivo. Furthermore, Mgp modulated metalloproteinase activities and TGFβ‐induced Smad2/3 phosphorylation. In the clinical setting, OS patients who developed lung metastases had high serum levels of MGP at diagnosis. Thus, MGP represents a novel adverse prognostic factor and a potential therapeutic target in OS. Microarray datasets may be found at: http://bioinfow.dep. usal.es/osteosarcoma/ Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Waste not, want not: resource-based garbage collection in a shared environment

To achieve optimal performance, garbage-collected applications must balance the sizes of their heaps dynamically. Sizing the heap too small can reduce throughput by increasing the number of garbage collections that must be performed. Too large a heap, however, can cause the system to page and drag down the overall throughput. In today's multicore, multiprocessor machines, multiple garbage-collected applications may run simultaneously. As a result, each virtual machine (VM) must adjust its memory demands to reflect not only the behavior of the application it is running, but also the behavior of the peer applications running on the system. We present a memory management system that enables VMs to react to memory demands dynamically. Our approach allows the applications' heaps to remain small enough to avoid the negative impacts of paging, while still taking advantage of any memory that is available within the system. This memory manager, which we call Poor Richard's Memory Manager, focuses on optimizing overall system performance by allowing applications to share data and make system-wide decisions. We describe the design of our memory management system, show how it can be added to existing VMs with little effort, and document that it has almost no impact on performance when memory is plentiful. Using both homogenous and heterogenous Java workloads, we then show that Poor Richard's memory manager improves average performance by up to a factor 5.5 when the system is paging. We further show that this result is not specific to any garbage collection algorithm, but that this improvement is observed for every garbage collector on which we test it. We finally demonstrate the versatility of our memory manager by using it to improve the performance of a conservative whole-heap garbage collector used in executing . Net applications.
Comparing inclusion techniques on chemical engineering problems

Solving general nonlinear systems of equations and/or finding the global optimum of nonconvex functions constitute an important part of the everyday practice in chemical engineering. Standard methods cannot provide theoretical guarantee for convergence to a solution, cannot find multiple solutions, and cannot prove non-existence of solutions. This is the main motive to apply interval methods. Interval analysis has been applied to a wide variety of problems in chemical engineering, e.g. [1]. Similarly impressive results can be achieved with αBB, a fairly general global optimization method [2, 3]. Computing steady states of multistage separation processes requires solving large-scale nonlinear systems of equations. Despite of the outstanding results referred above, computation of these problems with interval arithmetic have not yet been considered in the literature, according to the authors’ best knowledge. The only globally convergent methods used in this area seem to be the homotopy-continuation methods [4]. Leading edge software packages, such as [5], are also available to find zeros of nonlinear systems. Unfortunately, finding all solutions can be guaranteed only in special cases e.g. polynomial systems with no constraints [6]. The authors aim to compute steady states of homogeneous and heterogeneous azeotropic distillation columns with interval methods, keeping the algorithm as problem independent as possible. The results achieved so far are presented here. Numerical evidence published in the literature, e.g. [7, 8], seem to indicate superiority of the linear interval approximation (LIA, L(x) = Ax+b, A is a real matrix), proposed by Kolev in a number of publications e.g. [9], compared to the traditional interval linear approximation (ILA, L(x ) = A(x − z) + f(z), A is an interval matrix) such as the interval Newton method. LIA has the following advantages over ILA when applied to root-finding. (i) The solution set of the LIA has a much simpler form, the hull solution is straightforward: X ∩ − Ab. (ii) Linear programming is directly applicable to prune the current box. The automatic
Synergistic effect of adenovirus type 1 and nontypeable Haemophilus influenzae in a chinchilla model of experimental otitis media

We recently reported the development of a chinchilla model of experimental otitis media (OM) that uses a pediatric clinical isolate of adenovirus type 1 (4) and in which an active infection with the wild-type strain was demonstrated. To expand upon these findings, this study was designed to determine whether we could demonstrate adenovirus infection-induced predisposition to bacterial OM in the chinchilla, as has been shown in human epidemiological studies (D. A. Clements, F. W. Henderson, and E. C. Neebe, p. 27-29, in D. J. Lim, C. D. Bluestone, J. O. Klein, D. J. Nelson, and P. L. Ogra, ed., Proceedings of the Fifth International Symposium on Recent Advances in Otitis Media, 1993; F. W. Henderson, A. M. Collier, M. A. Sanyai, et al., N. Engl. J. Med. 306:1377-1383, 1982). In addition, we were interested in determining whether altering the order of pathogen acquisition would further affect the outcome of disease incidence and severity. Toward this end, cohorts of chinchillas were inoculated intranasally with a strain of nontypeable Haemophilus influenzae (NTHi) (86-028NP) which colonizes the chinchilla nasopharynx but does not consistently induce culture-positive OM when inoculated intranasally (L. O. Bakaletz, T. M. Hoepf, D. J. Lim, and B. Tallan, Abstr. 90th Annu. Meet. Am. Soc. Microbiol. 1990, abstr. B-66, p. 37, 1990), adenovirus type 1 and then inoculated 7 days later with NTHi, NTHi and then inoculated 7 days later with adenovirus type 1, or both pathogens concurrently. All cohorts were observed over a 35-day period and assessed for incidence and severity of OM by several methodologies. The data collectively indicated that all animals receiving both pathogens developed OM of greater severity than those receiving only a single agent. Adenovirus inoculation followed 7 days later by NTHi inoculation was the order of pathogen acquisition which induced the most prolonged presence of NTHi in both the nasopharynx and the middle ear, the most severe tympanic membrane inflammation overall, and the most significant damage to and altered function of both middle ear and eustachian tube mucosae.
Histologic and In Situ Viral Findings in the Myocardium in Cases of Sudden, Unexpected Death

The purpose of this study was to do in situ viral detection in myocardial tissues of individuals who suffered sudden unexpected death and to correlate the results with the postmortem histopathologic findings. Thirteen cases were identified and the heart tissues were analyzed for adenovirus, cytomegalovirus, Epstein Barr virus, herpes simplex virus 1 and 2, human immunodeficiency virus 1 (HIV-1), influenza A, influenza B, parvovirus, rotavirus, picornavirus (including separate primers for enterovirus and Coxsackie virus A and B), varicella zoster virus, and respiratory syncytial virus. Thirteen individuals aged 2 to 67 years were studied. In each case, polymerase chain reaction–amplified viral RNA was detected in situ: Coxsackie virus B (5 cases), rotavirus (4 cases), HIV-1 (2 cases), influenza A (1 case), and influenza B (1 case). Immunohistochemical detection of viral proteins was found in the five Coxsackie virus cases and four rotavirus cases. The mononuclear inflammatory infiltrate was diffuse and marked only in the cases of influenza A and HIV-1, as well as one of the Coxsackie virus and rotavirus cases, respectively. Immunohistochemical analysis showed that the most common cell type in the inflammatory infiltrates was CD68-positive macrophages. Direct myocyte infection was most prominent in the cases of Coxsackie virus infection. In summary, in situ viral detection was documented in each case of idiopathic myocarditis associated with sudden, unexpected death; in 6/13 cases, the myocarditis was focal and minimal. Although Coxsackie virus was, as expected, the most common virus noted, other viruses including rotavirus and HIV-1 were also observed, highlighting the need for comprehensive viral and histologic analyses in such cases.
Circulating levels of reactive oxygen species in patients with nonproliferative diabetic retinopathy and the influence of antioxidant supplementation: 6-month follow-up

Aims: The aim was to evaluate circulating levels of reactive oxygen species (ROS) and changes in central macular thickness (CMT) in patients with nonproliferative diabetic retinopathy (NPDR) after antioxidant supplementation. Materials and Methods: A total of 68 patients (68 eyes) with NPDR were enrolled. Patients were randomly divided into two groups: Treated with antioxidant supplement (Group A) and untreated control group (Group B). Each tablet, for oral administration, containing pycnogenol 50 mg, Vitamin E 30 mg and coenzyme Q10 20 mg. CMT and free oxygen radical test (FORT) were analyzed at baseline (T0), 3 (T1) and 6 (T2) months in both groups. Results: In Group A, FORT levels and CMT were significantly reduced over time (P < 0.001 for both). In Group B, FORT levels were increased (P < 0.001) and CMT did not vary significantly (P = 0.81) over 3 time points. Conclusions: This is the first study showing the reduction of ROS levels in patients with NPDR thanks to antioxidant therapy. Moreover, our findings have suggested also an influence on retinal thickness.
Resveratrol Attenuates Acute Inflammatory Injury in Experimental Subarachnoid Hemorrhage in Rats via Inhibition of TLR4 Pathway

Toll-like receptor 4 (TLR4) has been proven to play a critical role in neuroinflammation and to represent an important therapeutic target following subarachnoid hemorrhage (SAH). Resveratrol (RSV), a natural occurring polyphenolic compound, has a powerful anti-inflammatory property. However, the underlying molecular mechanisms of RSV in protecting against early brain injury (EBI) after SAH remain obscure. The purpose of this study was to investigate the effects of RSV on the TLR4-related inflammatory signaling pathway and EBI in rats after SAH. A prechiasmatic cistern SAH model was used in our experiment. The expressions of TLR4, high-mobility group box 1 (HMGB1), myeloid differentiation factor 88 (MyD88), and nuclear factor-κB (NF-κB) were evaluated by Western blot and immunohistochemistry. The expressions of Iba-1 and pro-inflammatory cytokines in brain cortex were determined by Western blot, immunofluorescence staining, or enzyme-linked immunosorbent assay. Neural apoptosis, brain edema, and neurological function were further evaluated to investigate the development of EBI. We found that post-SAH treatment with RSV could markedly inhibit the expressions of TLR4, HMGB1, MyD88, and NF-κB. Meanwhile, RSV significantly reduced microglia activation, as well as inflammatory cytokines leading to the amelioration of neural apoptosis, brain edema, and neurological behavior impairment at 24 h after SAH. However, RSV treatment failed to alleviate brain edema and neurological deficits at 72 h after SAH. These results indicated that RSV treatment could alleviate EBI after SAH, at least in part, via inhibition of TLR4-mediated inflammatory signaling pathway.