New York, NY, United States
New York, NY, United States

Rimed snow refers to snowflakes that are partially or completely coated in tiny frozen water droplets called 'rime'. Rime forms on a snowflake when it passes through a super-cooled cloud. Snowflakes that are heavily rimed typically produce very heavy and wet snow, with snow to liquid ratios in the 5-1 to 9-1 range.Rimed snow has been found to provide greater initial stability for a snow layer. However, it also allows thicker, and therefore less stable, snow layers to build up. It could be argued that these cancel each other out.There has been research into the effect of rimed snow on avalanches. Wikipedia.


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Barnes C.O.,University of Pittsburgh | Calero M.,University of Pittsburgh | Malik I.,Texas A&M University | Graham B.W.,University of Pittsburgh | And 11 more authors.
Molecular Cell | Year: 2015

Notwithstanding numerous published structures of RNA Polymerase II (Pol II), structural details of Pol II engaging a complete nucleic acid scaffold have been lacking. Here, we report the structures of TFIIF-stabilized transcribing Pol II complexes, revealing the upstream duplex and full transcription bubble. The upstream duplex lies over a wedge-shaped loop from Rpb2 that engages its minor groove, providing part of the structural framework for DNA tracking during elongation. At the upstream transcription bubble fork, rudder and fork loop 1 residues spatially coordinate strand annealing and the nascent RNA transcript. At the downstream fork, a network of Pol II interactions with the non-template strand forms a rigid domain with the trigger loop (TL), allowing visualization of its open state. Overall, our observations suggest that "open/closed" conformational transitions of the TL may be linked to interactions with the non-template strand, possibly in a synchronized ratcheting manner conducive to polymerase translocation. © 2015 Elsevier Inc.


Lee J.J.,University of Pittsburgh | D'Ancona G.,Mediterranean Institute for Transplantation and Advanced Specialized Therapies ISMETT | Amaducci A.,Mediterranean Institute for Transplantation and Advanced Specialized Therapies ISMETT | Follis F.,Mediterranean Institute for Transplantation and Advanced Specialized Therapies ISMETT | And 2 more authors.
Journal of Cardiac Surgery | Year: 2014

Thoracic aortic diseases are life-threatening conditions causing significant mortality and morbidity despite advances in diagnostic and surgical treatments. Computational methods combined with imaging techniques provide quantitative information of disease progression, which may improve clinical treatments and therapeutic strategies for clinical practice. Since hemodynamic and wall mechanics play important roles in the natural history and progression of aortic diseases, we reviewed the potential application of computational modeling of the thoracic aorta. We placed emphasis on the clinical relevance of these techniques for the assessment of aortic dissection, thoracic aortic aneurysm, and aortic coarctation. Current clinical guidelines and treatment are also described. © 2014 Wiley Periodicals, Inc.


Cascio S.,University of Palermo | Cascio S.,Rimed | D'Andrea A.,University of Palermo | Ferla R.,University of Palermo | And 9 more authors.
Journal of Cellular Physiology | Year: 2010

MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of different genes, including genes involved in cancer progression. A functional link between hypoxia, a key feature of the tumor microenvironment, and miRNA expression has been documented. We investigated whether and how miR-20b can regulate the expression of vascular endothelial growth factor (VEGF) in MCF-7 breast cancer cells under normoxic and hypoxia-mimicking conditions (CoCl 2 exposure). Using immunoblotting, ELISA, and quantitative real-time PCR, we demonstrated that miR-20b decreased VEGF protein levels at 4 and 24 h following CoCl2 treatment, and VEGF mRNA at 4 h of treatment. In addition, miR-20b reduced VEGF protein expression in untreated cells. Next, we investigated the molecular mechanism by which pre-miR-20b can affect VEGF transcription, focusing on hypoxia inducible factor 1 (HIF-1) and signal transducer and activator of transcription 3 (STAT3), transcriptional inducers of VEGF and putative targets of miR-20b. Downregulation of VEGF mRNA by miR-20b under a 4 h of CoCl2 treatment was associated with reduced levels of nuclear HIF-1α subunit and STAT3. Chromatin immunoprecipitation (ChIP) assays revealed that HIF-1α, but not STAT3, was recruited to the VEGF promoter following the 4 h of CoCl2 treatment. This effect was inhibited by transfection of cells with pre-miR-20b. In addition, using siRNA knockdown, we demonstrated that the presence of STAT3 is necessary for CoCl 2-mediated HIF-1α nuclear accumulation and recruitment on VEGF promoter. In summary, this report demonstrates, for the first time, that the VEGF expression in breast cancer cells is mediated by HIF-1 and STAT3 in a miR-20b-dependent manner. © 2010 Wiley-Liss, Inc.


Marigliano M.,Childrens Hospital of Pittsburgh | Marigliano M.,Salesis Hospital | Bertera S.,Childrens Hospital of Pittsburgh | Grupillo M.,Childrens Hospital of Pittsburgh | And 3 more authors.
Current Diabetes Reports | Year: 2011

The therapy of type 1 diabetes is an open challenging problem. The restoration of normoglycemia and insulin independence in immunosuppressed type 1 diabetic recipients of islet allotransplantation has shown the potential of a cell-based diabetes therapy. Even if successful, this approach poses a problem of scarce tissue supply. Xenotransplantation can be the answer to this limited donor availability and, among possible candidate tissues for xenotransplantation, porcine islets are the closest to a future clinical application. Xenotransplantation, with pigs as donors, offers the possibility of using healthy, living, and genetically modified islets from pathogen-free animals available in unlimited number of islets. Several studies in the pig-to-nonhuman primate model demonstrated the feasibility of successful preclinical islet xenotransplantation and have provided insights into the critical events and possible mechanisms of immune recognition and rejection of xenogeneic islet grafts. Particularly promising results in the achievement of prolonged insulin independence were obtained with newly developed, genetically modified pigs islets able to produce immunoregulatory products, using different implantation sites, and new immunotherapeutic strategies. Nonetheless, further efforts are needed to generate additional safety and efficacy data in nonhuman primate models to safely translate these findings into the clinic. © Springer Science+Business Media, LLC 2011.


Pasta S.,Rimed | Pasta S.,University of Pittsburgh | Pasta S.,McGowan Institute for Regenerative Medicine | Phillippi J.A.,McGowan Institute for Regenerative Medicine | And 5 more authors.
Journal of Thoracic and Cardiovascular Surgery | Year: 2012

Objectives: The acute dissection of an ascending thoracic aortic aneurysm (ATAA) represents a devastating separation of elastic layers occurring when the hemodynamic loads on the diseased wall exceed the adhesive strength between layers. At present, the mechanics underlying aortic dissection are largely unclear, and the biomechanical delamination properties of the aneurysmal aorta are not defined. Individuals with bicuspid aortic valve (BAV) are particularly predisposed to ascending aortic aneurysm formation, with a marked risk of aortic dissection. The purpose of this study was to evaluate and compare the dissection properties of nonaneurysmal and aneurysmal human ascending thoracic aorta from patients with BAV morphology or normal tricuspid aortic valve (TAV) morphology using biomechanical delamination testing. Methods: The influence on the delamination strength (S d) of the aorta associated with BAV was compared with that in patients with TAV. After complete delamination of ATAA tissue samples, tensile tests were performed on each delaminated half for comparison of their tensile strengths. Results: The results showed that the aneurysmal aortas with BAV and TAV have lower S d than nonaneurysmal aortas and that ATAA with BAV has a lower S d than that with TAV. We have found a significant difference in S d between longitudinal and circumferential directions of the nondiseased aorta, suggesting anisotropic dissection properties. Conclusions: The tensile testing results suggest that the weaker intimal half of the aortic wall might fail before the outer adventitial half. Scanning electron microscope analyses suggest different failure modalities of dissection between the two morphologies, and the lower S d in ATAAs appears to be associated with a disorganized microstructure. BAV ATAAs have a lower S d than TAV ATAAs, suggesting a greater propensity for aortic dissection. © 2012 by The American Association for Thoracic Surgery.


Di Caro V.,University of Pittsburgh | Di Caro V.,Rimed | Phillips B.,Pennsylvania State University | Engman C.,University of Pittsburgh | And 3 more authors.
Clinical and Experimental Immunology | Year: 2013

While much is known about tolerogenic dendritic cell effects on forkhead box protein 3 (FoxP3)+ regulatory T cells, virtually nothing is known about their effects on another arm of immunoregulation that is mediated by a subpopulation of immunosuppressive B cells. These cells suppress rheumatoid arthritis, lupus and inflammatory bowel disease in mice, and functional defects have been reported in human lupus. We show that co-stimulation-impaired tolerogenic dendritic cells that prevent and reverse type 1 diabetes mellitus induce the proliferation of human immunosuppressive B cells in vitro. We also show that the suppressive properties of these B cells concentrate inside the CD19+CD24+ B cell population and more specifically inside the CD19+CD24+CD38+ regulatory B cell population. We discovered that B cell conversion into suppressive cells in vitro is partially dependent on dendritic cell production of retinoic acid and also that CD19+CD24+CD38+ B regulatory cells express retinoic acid receptors. Taken together, our data suggest a model whereby part of the immunosuppressive properties of human tolerogenic dendritic cells could be mediated by retinoic acid which, in addition to its known role in favouring T cell differentiation to FoxP3+ regulatory T cells, acts to convert B cells into immunosuppressive cells. © 2013 British Society for Immunology.


Di Caro V.,University of Pittsburgh | Di Caro V.,Rimed | Phillips B.,Pennsylvania State University | Engman C.,University of Pittsburgh | And 3 more authors.
PLoS ONE | Year: 2014

The objective of the study was to identify immune cell populations, in addition to Foxp3+ T-regulatory cells, that participate in the mechanisms of action of tolerogenic dendritic cells shown to prevent and reverse type 1 diabetes in the Non-Obese Diabetic (NOD) mouse strain. Co-culture experiments using tolerogenic dendritic cells and B-cells from NOD as well as transgenic interleukin-10 promoter-reporter mice along with transfer of tolerogenic dendritic cells and CD19+ B-cells into NOD and transgenic mice, showed that these dendritic cells increased the frequency and numbers of interleukin-10-expressing B-cells in vitro and in vivo. The expansion of these cells was a consequence of both the proliferation of preexisting interleukin-10-expressing B-lymphocytes and the conversion of CD19+ B-lymphcytes into interleukin-10-expressing cells. The tolerogenic dendritic cells did not affect the suppressive activity of these B-cells. Furthermore, we discovered that the suppressive murine B-lymphocytes expressed receptors for retinoic acid which is produced by the tolerogenic dendritic cells. These data assist in identifying the nature of the B-cell population increased in response to the tolerogenic dendritic cells in a clinical trial and also validate very recent findings demonstrating a mechanistic link between human tolerogenic dendritic cells and immunosuppressive regulatory B-cells. © 2014 Di Caro et al.


Francipane M.G.,McGowan Institute for Regenerative Medicine | Francipane M.G.,Rimed | Lagasse E.,McGowan Institute for Regenerative Medicine
Oncotarget | Year: 2013

Metastatic colorectal cancer (CRC) is incurable for most patients. Since mammalian target of rapamycin (mTOR) has been suggested as a crucial modulator of tumor biology, we aimed at evaluating the effectiveness of mTOR targeting for CRC therapy. To this purpose, we analyzed mTOR expression and the effect of mTOR inhibition in cancer stem-like cells isolated from three human metastatic CRCs (CoCSCs). CoCSCs exhibited a strong mTOR complex 2 (mTORC2) expression, and a rare expression of mTOR complex 1 (mTORC1). This latter correlated with differentiation, being expressed in CoCSC-derived xenografts. We indicate Serum/glucocorticoid-regulated kinase 1 (SGK1) as the possible main mTORC2 effector in CoCSCs, as highlighted by the negative effect on cancer properties following its knockdown. mTOR inhibitors affected CoCSCs differently, resulting in proliferation, autophagy as well as apoptosis induction. The apoptosis-inducing mTOR inhibitor Torin-1 hindered growth, motility, invasion, and survival of CoCSCs in vitro, and suppressed tumor growth in vivo with a concomitant reduction in vessel formation. Torin-1 also affected the expression of markers for cell proliferation, angio-/lympho-genesis, and stemness in vivo, including Ki67, DLL1, DLL4, Notch, Lgr5, and CD44. Importantly, Torin-1 did not affect the survival of normal colon stem cells in vivo, suggesting its selectivity towards cancer cells. Thus, we propose Torin-1 as a powerful drug candidate for metastatic CRC therapy.


Sepe S.,Erasmus Medical Center | Payan-Gomez C.,Erasmus Medical Center | Payan-Gomez C.,El Rosario University | Milanese C.,Erasmus Medical Center | And 3 more authors.
DNA Repair | Year: 2013

Impaired DNA repair involving the nucleotide excision repair (NER)/transcription-coupled repair (TCR) pathway cause human pathologies associated with severe neurological symptoms. These clinical observations suggest that defective NER/TCR might also play a critical role in chronic neurodegenerative disorders (ND), such as Alzheimer's and Parkinson's disease. Involvement of NER/TCR in these disorders is also substantiated by the evidence that aging constitutes the principal risk factor for chronic ND and that this DNA repair mechanism is very relevant for the aging process itself. Our understanding of the exact role of NER/TCR in chronic ND, however, is extremely rudimentary; while there is no doubt that defective NER/TCR can lead to neuronal death, evidence for its participation in the etiopathogenesis of ND is inconclusive thus far. Here we summarize the experimental observations supporting a role for NER/TCR in chronic ND and suggest questions and lines of investigation that might help in addressing this important issue. We also present a preliminary yet unprecedented meta-analysis on human brain microarray data to understand the expression levels of the various NER factors in the anatomical areas relevant for chronic ND pathogenesis. In summary, this review intends to highlight elements supporting a role of NER/TCR in these devastating disorders and to propose potential strategies of investigation. © 2013 Elsevier B.V.


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