Miracle-dz/UniFAR-FTUs huggingface dataset:
Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations.

Drug transport in the central nervous system is highly regulated not only by the blood-brain and the blood-cerebrospinal fluid barriers but also in brain parenchyma. The novel localization of drug transporters in brain parenchyma cells, such as microglia and astrocytes, suggest a reconsideration of the present conceptualization of brain barriers as it relates to drug transport. That is, the cellular membranes of parenchyma cells act as a second "barrier" to drug permeability and express transporters whose properties appear similar to those localized at the conventional brain barriers. This review will focus on the molecular characteristics, localization, and substrate specificities of several classes of well known membrane drug transporters (i.e., the organic cation, organic anion, nucleoside, P-glycoprotein, and multidrug resistance proteins) in the brain. Comparisons to similar transporters localized within the peripheral system and clinical implications of the functional expression of specific drug transport families will be discussed when appropriate. Nutrient and neurotransmitter transporters, whose characteristics have been reviewed extensively elsewhere, will not be considered in this review.
Molecular constituents of the postsynaptic density fraction revealed by proteomic analysis using multidimensional liquid chromatography‐tandem mass spectrometry

Protein constituents of the postsynaptic density (PSD) fraction were analysed using an integrated liquid chromatography (LC)‐based protein identification system, which was constructed by coupling microscale two‐dimensional liquid chromatography (2DLC) with electrospray ionization (ESI) tandem mass spectrometry (MS/MS) and an automated data analysis system. The PSD fraction prepared from rat forebrain was solubilized in 6 m guanidium hydrochloride, and the proteins were digested with trypsin after S‐carbamoylmethylation under reducing conditions. The tryptic peptide mixture was then analysed with the 2DLC‐MS/MS system in a data‐dependent mode, and the resultant spectral data were automatically processed to search a genome sequence database for protein identification. In triplicate analyses, the system allowed assignments of 5264 peptides, which could finally be attributed to 492 proteins. The PSD contained various proteins involved in signalling transduction, including receptors, ion channel proteins, protein kinases and phosphatases, G‐protein and related proteins, scaffold proteins, and adaptor proteins. Structural proteins, including membrane proteins involved in cell adhesion and cell–cell interaction, proteins involved in endocytosis, motor proteins, and cytoskeletal proteins were also abundant. These results provide basic data on a major protein set associated with the PSD and a basis for future functional studies of this important neural machinery.
Cancer Research

THE twenty-seventh annual report of the Imperial Cancer Research Fund contains, in addition to the usual survey of the work published from the laboratory during the year, an unusual feature in the form of a review by Dr. W. Cramer of certain aspects of experimental carcinogenesis. It is proposed to include such critical commentaries in future reports, and there can be no doubt that this policy will enhance the value of these publications, for in no branch of medical research is it more necessary to pause from time to time to order our conceptions of the central problems.
A Light Transport Framework for Lenslet Light Field Cameras

Light field cameras capture full spatio-angular information of the light field, and enable many novel photographic and scientific applications. It is often stated that there is a fundamental trade-off between spatial and angular resolution, but there has been limited understanding of this trade-off theoretically or numerically. Moreover, it is very difficult to evaluate the design of a light field camera because a new design is usually reported with its prototype and rendering algorithm, both of which affect resolution. In this article, we develop a light transport framework for understanding the fundamental limits of light field camera resolution. We first derive the prefiltering model of lenslet-based light field cameras. The main novelty of our model is in considering the full space-angle sensitivity profile of the photosensor—in particular, real pixels have nonuniform angular sensitivity, responding more to light along the optical axis rather than at grazing angles. We show that the full sensor profile plays an important role in defining the performance of a light field camera. The proposed method can model all existing lenslet-based light field cameras and allows to compare them in a unified way in simulation, independent of the practical differences between particular prototypes. We further extend our framework to analyze the performance of two rendering methods: the simple projection-based method and the inverse light transport process. We validate our framework with both flatland simulation and real data from the Lytro light field camera.
International Guidelines for Management of Metastatic Breast Cancer: Can Metastatic Breast Cancer Be Cured?

A distinctive subset of metastatic breast cancer (MBC) is oligometastatic disease, which is characterized by single or few detectable metastatic lesions. The existing treatment guidelines for patients with localized MBC include surgery, radiotherapy, and regional chemotherapy. The European School of Oncology–Metastatic Breast Cancer Task Force addressed the management of these patients in its first consensus recommendations published in 2007. The Task Force endorsed the possibility of a more aggressive and multidisciplinary approach for patients with oligometastatic disease, stressing also the need for clinical trials in this patient population. At the sixth European Breast Cancer Conference, held in Berlin in March 2008, the second public session on MBC guidelines addressed the controversial issue of whether MBC can be cured. In this commentary, we summarize the discussion and related recommendations regarding the available therapeutic options that are possibly associated with cure in these patients. In particular, data on local (surgery and radiotherapy) and chemotherapy options are discussed. Large retrospective series show an association between surgical removal of the primary tumor or of lung metastases and improved long-term outcome in patients with oligometastatic disease. In the absence of data from prospective randomized studies, removal of the primary tumor or isolated metastatic lesions may be an attractive therapeutic strategy in this subset of patients, offering rapid disease control and potential for survival benefit. Some improvement in outcome may also be achieved with optimization of systemic therapies, possibly in combination with optimal local treatment.
Rhegmatogenous retinal detachment in children 16 years of age or younger

Purpose To study the anatomical and visual outcomes and prognostic factors that may predict the outcomes of rhegmatogenous retinal detachment (RRD) in children. Methods A retrospective chart review was performed for patients 16 years of age or younger who underwent retinal reattachment surgery for RRD at the King Abdulaziz University Hospital from 1996 to 2005 and the King Khalid Eye Specialist Hospital from 2002 to 2006, Riyadh, Saudi Arabia. Good visual outcome was defined as ≥20/200. The association between two categorical variables was evaluated with the Chi-squared test or the exact test, as appropriate. Predictors for RRD and good final visual acuity were identified by conducting stepwise logistic regression analysis. P < 0.05 was statistically significant. Results The study population comprised 148 patients (166 eyes). There were 104 (70%) males and 44 (30%) females. Mean age at presentation was 8.33 ± 3.26 years (range 1.5–16 years). The retina was reattached after one surgical procedure in 106 (63.8%) eyes and reattached in 130 (78.3%) eyes after multiple surgeries. Factors predicting recurrence after the first surgery were myopia (P = 0.028), proliferative vitreoretinopathy (PVR) at presentation (P = 0.024), and total retinal detachment (P = 0.032). Good final visual outcome was achieved in 60 (44.4%) eyes. Predictors of good visual acuity were: good visual acuity at presentation (P < 0.001); absence of PVR at presentation (P < 0.001); one quadrant of retinal detachment (P = 0.0024); macula on (P = 0.0107); absence of primary repair of a ruptured globe (P = 0.0059); no pars plana vitrectomy (PPV) (P = 0.0123); clear phakic lens at follow-up (P < 0.001); absence of postoperative complications (P < 0.001); absence of recurrence of RRD (P < 0.001); and absence of epiretinal membrane (P = 0.0088). Logistic regression analysis indicated that recurrence of RRD was associated with myopia and previous congenital cataract surgery; good final visual outcome was associated with macula on detachment and poor visual outcome was associated with recurrence of RRD and occurrence of postoperative complications and previous repair of a ruptured globe. Conclusion RRD in children is usually associated with a predisposing factor, a high rate of PVR, and total retinal detachment. Despite late diagnosis and the presence of PVR, favorable anatomical and visual outcomes can be achieved.
Unified hierarchical multi-object tracking using global data association

This paper presents a unified hierarchical multi-object tracking scheme. The problem of simultaneously tracking multiple objects is cast as a global MAP problem which aims at maximizing the probability of trajectories given the observations in each frame. Directly solving this problem is infeasible, due to computational considerations and the difficulty of reliably estimate necessary transition probabilities. Without breaking the MAP formulation, we propose a three stage hierarchical tracking framework which makes solving the MAP feasible. In addition, using a hierarchical framework allows for modeling inter-object occlusions. Occlusion handling thus smoothly and implicitly integrates into the proposed framework without any explicit occlusion reasoning. Finally, we evaluate the proposed method on the publicly available PETS 2009 tracking data and show improvements over the current state of the art for most sequences.
SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis

Constitutive fibroblast activation is responsible for organ fibrosis in fibrotic disorders including systemic sclerosis (SSc), but the underlying mechanisms are not fully understood, and effective therapies are lacking. We investigated the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and its modulation by hexafluoro, a novel fluorinated synthetic honokiol analogue, in the context of fibrosis. We find that augmenting cellular SIRT3 by forced expression in normal lung and skin fibroblasts, or by hexafluoro treatment, blocked intracellular TGF-ß signaling and fibrotic responses, and mitigated the activated phenotype of SSc fibroblasts. Moreover, hexafluoro attenuated mitochondrial and cytosolic reactive oxygen species (ROS) accumulation in TGF-β-treated fibroblasts. Remarkably, we found that the expression of SIRT3 was significantly reduced in SSc skin biopsies and explanted fibroblasts, and was suppressed by TGF-β treatment in normal fibroblasts. Moreover, tissue levels of acetylated MnSOD, a sensitive marker of reduced SIRT3 activity, were dramatically enhanced in lesional skin and lung biopsies from SSc patients. Mice treated with hexafluoro showed substantial attenuation of bleomycin-induced fibrosis in the lung and skin. Our findings reveal a cell-autonomous function for SIRT3 in modulating fibrotic responses, and demonstrate the ability of a novel pharmacological SIRT3 agonist to attenuate fibrosis in vitro and in vivo. In light of the impaired expression and activity of SIRT3 associated with organ fibrosis in SSc, pharmacological approaches for augmenting SIRT3 might have therapeutic potential.
Coblockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts.

We have developed an in vitro system in which C57BL/6 donor splenocytes are exposed to B10.BR host alloantigens in the context of deficient CD28:B7 signaling as a means of preventing graft-versus-host disease (GVHD). Although 54% to 82% of MLR alloresponse was inhibited by cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig treatment of host stimulator cells, treated splenocytes were still capable of causing GVHD when infused in vivo. By adding anti-leukocyte function antigen 1 (anti-LFA1) antibody to hCTLA4-Ig in vitro to coblock the LFA1:intercellular adhesion molecule (ICAM) signaling, splenic alloresponse was inhibited by > or = 89%, yet GVHD induction capabilities were retained. Because antigen-primed cells might be more susceptible to CD28:B7 blockade, we investigated whether hCTLA4-Ig alone, anti-LFA1 antibody alone, or the combination of both added to donor-antihost in vitro primed cells could reduce GVHD. To facilitate hyporesponsiveness induction and to block B7 and ICAM ligands that are upregulated during GVHD, these reagents were also administered to recipients post-BMT. We have shown that hCTLA4-Ig plus anti-LFA1 antibody is highly effective in preventing GVHD-induced lethality (88% to 100% of treated mice surviving versus 0% to 28% of controls surviving). For optimal prevention, both hCTLA4-Ig and anti-LFA1 must be used in vitro in the context of donor-antihost primed splenocytes and continued in vivo. This in vitro-in vivo combined approach was associated with donor engraftment, and recipients were not globally immunosuppressed. We conclude that blocking both the CD28/B7 and the LFA1:ICAM pathways are critical to effective GVHD prevention and may offer advantages to in vitro donor T-cell removal.
Polymorphisms of −174G>C and −572G>C in the Interleukin 6 (IL-6) Gene and Coronary Heart Disease Risk: A Meta-Analysis of 27 Research Studies

Objective Elevated serum IL-6 level is a risk factor for coronary heart disease (CHD). The −174G>C and −572G>C polymorphisms in the IL-6 gene have previously been shown to modulate IL-6 levels. But the association between the −174G>C and −572G>C polymorphisms and the risk of CHD is still unclear. A meta-analysis of all eligible studies was carried out to clarify the role of IL-6 gene polymorphisms in CHD. Methods and Results PubMed, EMBASE, Vip, CNKI and CBM-disc were searched for eligible articles in English and Chinese that were published before October 2010. 27 studies involving 11580 patients with CHD and 17103 controls were included. A meta-analysis was performed for the included articles using the RevMan 5.0 and Stata 10.0 softwares. Overall, the −174C allele was not significantly associated with CHD risk (ORs = 1.04, 95%CI = 0.98 to 1.10) when compared with the −174G allele in the additive model, and meta-analysis under other genetic models (dominant, recessive, CC versus GG, and GC versus GG) also did not reveal any significant association. On the contrary, the −572C allele was associated with a decreased risk of CHD when compared with the −572G allele (ORs = 0.79, 95%CI = 0.68 to 0.93). Furthermore, analyses under the recessive model (ORs = 0.69, 95% = 0.59 to 0.80) and the allele contrast model (genotype of CC versus GG, ORs = 0.49, 95% = 0.35 to 0.70) yielded similar results. However, statistical significance was not found when the meta-analysis was restricted to studies focusing on European populations, studies with large sample size, and cohort studies by using subgroup analysis. Conclusions The −174G>C polymorphism in the IL-6 gene is not significantly associated with increased risks of CHD. However, The −572G>C polymorphism may contribute to CHD development. Future investigations with better study design and large number of subjects are needed.
As Time goes by: Long-term evaluation of social presence in robotic companions

Given the recent advances in robot and synthetic character technology, many researchers are now focused on ways of establishing social relations between these agents and humans over long periods of time. Early studies have shown that the novelty effect of robots and agents quickly wears out and that people change their attitudes and preferences towards them over time. In this paper, we study the role of social presence in long-term human-robot interactions. We conducted a study where children played chess exercises with a social robot over a five week period. With this experiment, we identified possible key issues that should be considered when designing social robots for long-term interactions.
Post‐Reunification Restructuring and Corporate Re‐bundling in the Bitterfeld‐Wolfen Chemical Industry, East Germany

While earlier research has shown that regional restructuring after reunification has ledto broad de-industrialization processes in eastern Germany’s chemical industry, thisarticle focuses on how re-bundling processes at the corporate level have stimulatedadjustments to the changing economic and political environment leading to a renewedregional development trajectory. The analysis is based on a conceptualization thatassesses diachronic processes of rupture and re-bundling by applying a bottom-upperspective of how corporate adjustments and restructuring processes generatere-bundling types that manifest themselves in broader regional re-bundling scenarios.The empirical analysis focuses on a qualitative case study of Bitterfeld-Wolfen, theeastern region with the largest chemical industry. The research provides evidence that,although new firm formation has remained weak and acquisitions of chemicalmultinationals have generated structures only tenuously embedded in the regionaleconomy, modernization and re-bundling process have contributed to a renewed, smalleryet stable, regional chemical industry. The analysis further shows that the associatedprocesses depended on the roles of individual industrial leaders in the region, who actedas network builders, mobilized joint action and stimulated the development of acollective regional spirit.
Ecological genetics of range size variation in Boechera spp. (Brassicaceae)

Abstract Many taxonomic groups contain both rare and widespread species, which indicates that range size can evolve quickly. Many studies have compared molecular genetic diversity, plasticity, or phenotypic traits between rare and widespread species; however, a suite of genetic attributes that unites rare species remains elusive. Here, using two rare and two widespread Boechera (Brassicaceae) species, we conduct a simultaneous comparison of quantitative trait diversity, genetic diversity, and population structure among species with highly divergent range sizes. Consistent with previous studies, we do not find strong associations between range size and within‐population genetic diversity. In contrast, we find that both the degree of phenotypic plasticity and quantitative trait structure (Q ST) were positively correlated with range size. We also found higher F ST: Q ST ratios in rare species, indicative of either a greater response to stabilizing selection or a lack of additive genetic variation. While widespread species occupy more ecological and climactic space and have diverged at both traits and markers, rare species display constrained levels of population differentiation and phenotypic plasticity. Combined, our results provide evidence for a specialization–generalization trade‐off across three orders of magnitude of range size variation in the ecological model genus, Boechera.
Why Do Software Firms Fail? Capabilities, Competitive Actions, and Firm Survival in the Software Industry from 1995 to 2007

This study examines why firms fail or survive in the volatile software industry. We provide a novel perspective by considering how software firms' capabilities and their competitive actions affect their ultimate survival. Drawing on the resource-based view (RBV), we conceptualize capabilities as a firm's ability to efficiently transform input resources into outputs, relative to its peers. We define three critical capabilities of software-producing firms---research and development (RD), marketing (MK), and operations (OP)---and hypothesize that in the dynamic, high-technology software industry, RD and MK capabilities are most important for firm survival. We then draw on the competitive dynamics literature to theorize that competitive actions distinguished by a greater emphasis on innovation-related moves will increase firm survival more than actions emphasizing resource-related moves. Finally, we postulate that firms' capabilities will complement their competitive actions in affecting firm survival. Our empirical evaluation examines a cross-sectional, time series panel of 5,827 observations on 870 software companies from 1995 to 2007. We use a stochastic frontier production function to measure the capability for each software firm in each time period. We then use the Cox proportional hazard regression technique to relate capabilities and competitive actions to software firms' failure rates. Unexpectedly, our results reveal that higher OP capability increases software firm survival more than higher MK and RD capabilities. Further, firms with a greater emphasis on innovation-related than resource-related competitive actions have a greater likelihood of survival, and this likelihood increases even further when these firms have higher MK and OP capabilities. Additional analyses of subsectors within the software industry reveal that firms producing visual applications (e.g., graphical and video game software) have the highest MK capability but the lowest OP and RD capabilities and make twice as many innovation-related as resource-related moves. These firms have the highest market values but the worst Altman Z scores, suggesting that they are valued highly but also are at high risk for failure, and indeed the firms in this sector fail at a greater rate than expected. In contrast, firms producing traditional decision-support applications and infrastructure software have different capabilities and make different competitive moves. Our findings suggest that the firms that persist and survive over the long term in the dynamic software industry are able to capitalize on their competitive actions because of their greater capabilities, and particularly OP capabilities.