Miracle-dz/UniFAR-FTUs huggingface dataset:
Electron-electron interactions in bilayer graphene. 1. Broken symmetry states and divergent resistance in suspended bilayer graphene

1. Broken symmetry states and divergent resistance in suspended bilayer graphene Benjamin E. Feldman, Jens Martin, Amir Yacoby, arXiv:0909.2883, Nature Physics 5, 889 (2009) 2. Local Compressibility Measurements of Correlated States in Suspended Bilayer Graphene Jens Martin, Benjamin E. Feldman, R. Thomas Weitz, Monica T. Allen, Amir Yacoby, arXiv:1009.2069, Phys. Rev. Lett. 105, 256806 (2010) 3. Interaction-Driven Spectrum Reconstruction in Bilayer Graphene A. S. Mayorov, D. C. Elias, M. Mucha-Kruczynski, R. V. Gorbachev, T. Tudorovskiy, A. Zhukov, S. V. Morozov, M. I. Katsnelson, V. I. Fal’ko, A. K. Geim, K. S. Novoselov, arXiv:1108.1742, Science 333, 860 (2011) 4. Transport Spectroscopy of Symmetry-Broken Insulating States in Bilayer Graphene J. Velasco Jr., L. Jing, W. Bao, Y. Lee, P. Kratz, V. Aji, M. Bockrath, C.N. Lau, C. Varma, R. Stillwell, D. Smirnov, Fan Zhang, J. Jung, A.H. MacDonald arXiv:1108.1609
Phonological Processing in Chinese–english Bilingual Biscriptals: an Fmri Study

Different activation loci have been reported for language processing in unilingual Chinese and unilingual English participants, as well as in bilingual readers of English and French, two alphabetic languages. Nevertheless, the extant imaging work on Mandarin – English bilin-guals favors common neural substrates for English and Chinese, languages with contrasting oral and written forms. We investigated the phonological processes in reading for English – Chinese biscriptals using a homophone matching task with parallel behavioral (n = 28) and fMRI (n = 6) experiments. Unlike previous reports, we observed distinct regions of activation for Mandarin in the left and right frontal lobes, the left temporal lobe, and the right occipital lobe, plus distinct regions of activation for English bilaterally in both the frontal and parietal lobes. The implications of these novel findings are discussed with reference to language representation in bilinguals.
Intra-Vitreal Administration of Microvesicles Derived from Human Adipose-Derived Multipotent Stromal Cells Improves Retinal Functionality in Dogs with Retinal Degeneration

This study was designed to determine the influence of microvesicles (MVs) derived from multipotent stromal cells isolated from human adipose tissue (hASCs) on retinal functionality in dogs with various types of retinal degeneration. The biological properties of hASC-MVs were first determined using an in vitro model of retinal Muller-like cells (CaMLCs). The in vitro assays included analysis of hASC-MVs influence on cell viability and metabolism. Brain-derived neurotrophic factor (BDNF) expression was also determined. Evaluation of the hASC-MVs was performed under normal and oxidative stress conditions. Preliminary clinical studies were performed on ten dogs with retinal degeneration. The clinical studies included behavioral tests, fundoscopy and electroretinography before and after hASC-MVs intra-vitreal injection. The in vitro study showed that CaMLCs treated with hASC-MVs were characterized by improved viability and mitochondrial potential, both under normal and oxidative stress conditions. Additionally, hASC-MVs under oxidative stress conditions reduced the number of senescence-associated markers, correlating with the increased expression of BDNF. The preliminary clinical study showed that the intra-vitreal administration of hASC-MVs significantly improved the dogs’ general behavior and tracking ability. Furthermore, fundoscopy demonstrated that the retinal blood vessels appeared to be less attenuated, and electroretinography using HMsERG demonstrated an increase in a- and b-wave amplitude after treatment. These results shed promising light on the application of cell-free therapies in veterinary medicine for retinal degenerative disorders treatment.
Compton PET: a layered structure PET detector with high performance

In most high-resolution PET detector designs, there is an inherent trade-off between spatial resolution and detector efficiency. We have developed and tested a new geometry for the detector module which avoids this trade-off. The module uses a layered structure, in which four crystal slabs are stacked in the depth direction and optically separated by enhanced specular reflector (ESR) film. The scintillation light within each layer is measured by 16 SiPMs located on the four sides of the crystal. Analog signals from all SiPMs (4 × 16) on the four sides of the crystal are digitized individually using a 64-channel TOFPET-2 module. The four-sided readout method reduces the problem of light trapping resulting from total internal reflection when reading out the end(s) of traditional scintillation crystal arrays, thus increasing the light collection efficiency. In this work, we demonstrate the readout of a complete layered detector with 4 layers. The high light collection efficiency results in a FWHM energy resolution of 10.3%, and a FWHM timing resolution of 348 ps. The distribution of scintillation light detected by the SiPMs was used to decode the interaction position of each gamma ray using a trained neural network. A FWHM spatial resolution of 1.1 ± 0.1 mm was achieved. This design allows the detection efficiency of the module to be increased by adding additional crystal slabs along the depth direction. Since the position, energy, and timing are measured for each layer independently, increasing the system sensitivity by adding more layers will not affect the spatial/energy/timing resolution. Furthermore, the layered structure allows partial recovery of position information for events that undergo Compton scatter within the detector.
Mast Cell Protease 7 Promotes Angiogenesis by Degradation of Integrin Subunits

Previous studies from our laboratory have shown that during angiogenesis in vitro, rmMCP-7 (recombinant mouse mast cell protease-7) stimulates endothelial cell spreading and induces their penetration into the matrix. The ability of rmMCP-7 to induce angiogenesis in vivo was assessed in the present study using a directed in vivo angiogenesis assay (DIVAA™). Vessel invasion of the angioreactor was observed in the presence of rmMCP-7 but was not seen in the control. Since integrins are involved in endothelial cell migration, the relationship between rmMCP-7 and integrins during angiogenesis was investigated. Incubation with rmMCP-7 resulted in a reduction in the levels of integrin subunits αv and β1 on SVEC4-10 endothelial cells during angiogenesis in vitro. Furthermore, the degradation of integrin subunits occurs both through the direct action of rmMCP-7 and indirectly via the ubiquitin/proteasome system. Even in the presence of a proteasome inhibitor, incubation of endothelial cells with rmMCP-7 induced cell migration and tube formation as well as the beginning of loop formation. These data indicate that the direct degradation of the integrin subunits by rmMCP-7 is sufficient to initiate angiogenesis. The results demonstrate, for the first time, that mMCP-7 acts in angiogenesis through integrin degradation.
Beliefs About Advanced Cancer Curability in Older Patients, Their Caregivers, and Oncologists.

BACKGROUND Ensuring older patients with advanced cancer and their oncologists have similar beliefs about curability is important. We investigated discordance in beliefs about curability in patient-oncologist and caregiver-oncologist dyads. MATERIALS AND METHODS We used baseline data from a cluster randomized trial assessing whether geriatric assessment improves communication and quality of life in older patients with advanced cancer and their caregivers. Patients were aged ≥70 years with incurable cancer from community oncology practices. Patients, caregivers, and oncologists were asked: "What do you believe are the chances the cancer will go away and never come back with treatment? " Options were 100%, >50%, 50/50, <50%, and 0% (5-point scale). Discordance in beliefs about curability was defined as any difference in scale scores (≥3 points were severe). We used multivariate logistic regressions to describe correlates of discordance. RESULTS Discordance was present in 60% (15% severe) of the 336 patient-oncologist dyads and 52% (16% severe) of the 245 caregiver-oncologist dyads. Discordance was less common in patient-oncologist dyads when oncologists practiced longer (adjusted odds ratio [AOR] 0.90, 95% confidence interval [CI] 0.84-0.97) and more common in non-Hispanic white patients (AOR 5.77, CI 1.90-17.50) and when patients had lung (AOR 1.95, CI 1.29-2.94) or gastrointestinal (AOR 1.55, CI 1.09-2.21) compared with breast cancer. Severe discordance was more common when patients were non-Hispanic white, had lower income, and had impaired social support. Caregiver-oncologist discordance was more common when caregivers were non-Hispanic white (AOR 3.32, CI 1.01-10.94) and reported lower physical health (AOR 0.88, CI 0.78-1.00). Severe discordance was more common when caregivers had lower income and lower anxiety level. CONCLUSION Discordance in beliefs about curability is common, occasionally severe, and correlated with patient, caregiver, and oncologist characteristics. IMPLICATIONS FOR PRACTICE Ensuring older patients with advanced cancer and their caregivers have similar beliefs about curability as the oncologist is important. This study investigated discordance in beliefs about curability in patient-oncologist (PO) and caregiver-oncologist (CO) dyads. It found that discordance was present in 60% (15% severe) of PO dyads and 52% (16% severe) of CO dyads, raising serious questions about the process by which patients consent to treatment. This study supports the need for interventions targeted at the oncologist, patient, caregiver, and societal levels to improve the delivery of prognostic information and patients'/caregivers' understanding and acceptance of prognosis.
Fibroblasts rescue oral squamous cancer cell from metformin-induced apoptosis via alleviating metabolic disbalance and inhibiting AMPK pathway

ABSTRACT Metformin is an antidiabetic drug widely used for the treatment of type 2 diabetes. Growing evidence suggests that it may exert antitumor effects in vivo and in vitro. However, even with the promising potency on defeating cancer cells, the pre-clinical and epidemiological studies of metformin on various kinds of cancers are not satisfactory, and the reasons and underlying mechanisms remain unknown. Since cancer is a complex system, dependent on a promoting microenvironment, we hypothesize that the interactions between cancer cells and their neighborhood fibroblasts are essential for metformin resistance. To test this, we used a cell co-culture model closely mimicking the in vivo interactions and metabolic exchanges between normal stromal cells (NOFs) and oral squamous cancer cells (OSCC). Here we show that while metformin can significantly inhibit cell growth and induce apoptosis of OSCC cultured alone in a dose-dependent manner through activating p-AMPKT172 and modulating Bcl-2, Bax, and cleaved PARP. However, when OSCC are co-cultured with NOFs the metformin effects on OSCC cells are annihilated. NOFs are rescuing OSCC from metformin – induced apoptosis, at least partially, through inhibiting the activity of AMPK and PARP, maintaining mitochondrial membrane potential and increasing the oxidative stress. Our results indicate that metformin effects on oral cancer cells are modulated by the microenvironment and that this has to be taken into consideration in the context of developing a new combination of drugs for oral cancer treatment.
Updates on enzymatic and structural properties of human glutamine: fructose-6-phosphate amidotransferase 2 (hGFAT2)

Glycoconjugates play a central role in several cellular processes and alteration in their composition is associated to human pathologies. The hexosamine biosynthetic pathway is a route through which cells obtain substrates for cellular glycosylation, and is controlled by the glutamine: fructose-6-phosphate amidotransferase (GFAT). Human isoform 2 GFAT (hGFAT2) has been implicated in diabetes and cancer, however, there is no information about structural and enzymatic properties of this enzyme. Here, we report a successful expression and purification of a catalytically active recombinant hGFAT2 (rhGFAT2) in E. coli cells fused or not to a HisTag at the C-terminal end. Our enzyme kinetics data suggest that hGFAT2 does not follow the ordered bi-bi mechanism, and performs the glucosamine-6-phosphate synthesis much slowly than previously reported for other GFATs. In addition, hGFAT2 is able to isomerase fructose-6-phosphate into glucose-6-phosphate even in presence of equimolar amounts of glutamine, in an unproductive glutamine hydrolysis. Structural analysis of the generated three-dimensional model rhGFAT2, corroborated by circular dichroism data, indicated the presence of a partially structured loop in glutaminase domain, whose sequence is present in eukaryotic enzymes but absent in the E. coli homolog. Molecular dynamics simulations show such loop as the most flexible portion of the protein, which interacts with the protein mainly through the interdomain region, and plays a key role on conformational states of hGFAT2. Altogether, our study provides the first comprehensive set of data on the structure, kinetics and mechanics of hGFAT2, which will certainly contribute for further studies focusing on drug development targeting hGFAT2.
eprosartan-based hypertension therapy, systolic arterial blood pressure and cognitive function: analysis of Middle east data from the OscAR study

Background: Studies have indicated a relationship between hypertension and cognitive function. The possible effect of antihypertensive therapy on cognitive disorders is therefore a matter of interest. Materials and methods: The Observational Study on Cognitive function And SBP Reduction (OSCAR) was an open-label, multinational trial designed to evaluate the impact of eprosartan-based antihypertensive therapy on cognitive function in patients with essential hypertension. Eprosartan 600 mg/day for 6 months (with provision for additional medication as needed) was initiated in hypertensive subjects aged $ 50 years. A total of 853 patients in an intention-to-treat cohort from seven countries of the Middle East was identified for subgroup analysis. Results: Arterial blood pressure was reduced significantly ( P , 0.001) during the study: At the end of 6 months of eprosartan-based therapy, the mean ( ± SD) reduction from baseline was 32.1 ± 14.3/14.6. 3 ± 8.6 mmHg ( P , 0.001). Mean pulse pressure was reduced by 18.3 ± 13.1 mmHg ( P , 0.0001 vs baseline). Blood pressure was normalized (systolic , 140 mmHg and diastolic , 90 mmHg) in 68.2% of patients. The overall mean Mini-Mental State Examination (MMSE) score after 6 months of eprosartan-based therapy was one-point higher than at baseline ( P , 0.001). MMSE score on completion of 6 months’ follow-up was either unchanged or increased from baseline in 793 (93%) individuals and decreased in 60 (7%). Factors associated with stability of or improvement in cognitive function included MMSE score at baseline, diastolic blood pressure (DBP) at baseline, and treatment-induced change in DBP. Conclusion: Results from the Middle East subgroup of OSCAR are supportive of the hypothesis that antihypertensive therapy based on angiotensin-receptor blocker therapy with eprosartan may be associated with preservation or improvement of cognitive function.
Mechanisms of Action of Ruxolitinib in Murine Models of Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the over-activation of T cells and macrophages that excessively produce pro-inflammatory cytokines, including interferon-γ (IFNγ). Previously, we reported that the Janus kinase (JAK) inhibitor ruxolitinib dampens T cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1 -/-) mice are infected with Lymphocytic Choriomeningitis Virus (LCMV). Ruxolitinib inhibits signaling downstream of IFNγ as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting its beneficial effects in HLH by inhibiting IFNγ signaling or instead by targeting signaling initiated by other pro-inflammatory cytokines. To address this question, here we compared the effects of ruxolitinib with those obtained using an IFNγ-neutralizing antibody (αIFNγ) in two murine HLH models. In both models, ruxolitinib and αIFNγ reduced inflammation-associated anemia indicating that ruxolitinib operates in an IFNγ-dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, and their infiltration into tissues, were significantly lessened following treatment with ruxolitinib but remained unchanged or were increased following treatment with αIFNγ. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1 -/- mice exhibited enhanced survival compared to mice that discontinued αIFNγ. This protective effect could be mimicked by transient treatment with αIFNγ and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFNγ-dependent and independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.
A Metadynamics-Based Protocol for the Determination of GPCR-Ligand Binding Modes

G protein-coupled receptors (GPCRs) are a main drug target and therefore a hot topic in pharmaceutical research. One important prerequisite to understand how a certain ligand affects a GPCR is precise knowledge about its binding mode and the specific underlying interactions. If no crystal structure of the respective complex is available, computational methods can be used to deduce the binding site. One of them are metadynamics simulations which have the advantage of an enhanced sampling compared to conventional molecular dynamics simulations. However, the enhanced sampling of higher-energy states hampers identification of the preferred binding mode. Here, we present a novel protocol based on clustering of multiple walker metadynamics simulations which allows identifying the preferential binding mode from such conformational ensembles. We tested this strategy for three different model systems namely the histamine H1 receptor in combination with its physiological ligand histamine, as well as the β2 adrenoceptor with its agonist adrenaline and its antagonist alprenolol. For all three systems, the proposed protocol was able to reproduce the correct binding mode known from the literature suggesting that the approach can more generally be applied to the prediction of GPCR ligand binding in future.
Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma.

PURPOSE SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort. PATIENTS AND METHODS This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS. RESULTS Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation. CONCLUSION The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.
A scalable database of organ doses for common diagnostic fluoroscopy examinations of children: procedures of current practice at the University of Florida

Of all the medical imaging modalities that utilize ionizing radiation, fluoroscopy proves to be the most difficult to assess values of patient organ dose owing to the dynamic and patient-specific nature of the irradiation geometry and its associated x-ray beam characteristics. With the introduction of the radiation dose structured report (RDSR) in the mid-2000s, however, computational tools have been developed to extract patient and procedure-specific data for each irradiation event of the study, and when coupled to a computational phantom of the patient, values of skin and internal organ dose may be assessed. Unfortunately, many legacy and even current diagnostic fluoroscopy units do not have RDSR reporting capabilities, thus limiting these dosimetry reporting advances. Nevertheless, knowledge of patient organ doses for patient care, as well as for radiation epidemiology studies, remains a research and regulatory priority. In this study, we created procedural outlines which document all radiation exposure information required for organ dose assessment, akin to a reference RDSR, for six common diagnostic fluoroscopy procedures performed at the University of Florida (UF) Shands Pediatric Hospital. These procedures include the voiding cystourethrogram, the gastrostomy-tube placement, the lower gastrointestinal study, the rehabilitation swallow, the upper gastrointestinal study, and the upper gastrointestinal study with follow through. These procedural outlines were used to develop an extensive database of organ doses for the 162-member UF/NCI (National Cancer Institute) library of pediatric hybrid phantoms, with each member varying combinations of sex, height, and weight. The organ dose assessment accounts for the varying x-ray fields, fluoroscopy time, relative concentration of x-ray contrast in the organs, and changes in the fluoroscope output due to patient size. Furthermore, we are also reporting organ doses normalized to total fluoroscopy time, reference point air kerma, and kerma-area product, effectively providing procedure dose coefficients. The extensive organ dose library produced in this study may be used prospectively for patient organ dose reporting or retrospectively in epidemiological studies of radiation-associated health risks.