Oblique projection for scalable rank-adaptive reduced-order modeling of nonlinear stochastic PDEs with time-dependent bases

Time-dependent basis reduced order models (TDB ROMs) have successfully been used for approximating the solution to nonlinear stochastic partial differential equations (PDEs). For many practical problems of interest, discretizing these PDEs results in massive matrix differential equations (MDEs) that are too expensive to solve using conventional methods. While TDB ROMs have the potential to significantly reduce this computational burden, they still suffer from the following challenges: (i) inefficient for general nonlinearities, (ii) intrusive implementation, (iii) ill-conditioned in the presence of small singular values, and (iv) error accumulation due to fixed rank. To this end, we present a scalable method based on oblique projections for solving TDB ROMs that is computationally efficient, minimally intrusive, robust in the presence of small singular values, rank-adaptive, and highly parallelizable. These favorable properties are achieved via low-rank approximation of the time discrete MDE. Using the discrete empirical interpolation method (DEIM), a low-rank decomposition is computed at each iteration of the time stepping scheme, enabling a near-optimal approximation at a fraction of the cost. We coin the new approach TDB-CUR since it is equivalent to a CUR decomposition based on sparse row and column samples of the MDE. We also propose a rank-adaptive procedure to control the error on-the-fly. Numerical results demonstrate the accuracy, efficiency, and robustness of the new method for a diverse set of problems

Lung adenocarcinoma originates from retrovirus infection of proliferating type 2 pneumocytes during pulmonary post-natal development or tissue repair

Jaagsiekte sheep retrovirus (JSRV) is a unique oncogenic virus with distinctive biological properties. JSRV is the only virus causing a naturally occurring lung cancer (ovine pulmonary adenocarcinoma, OPA) and possessing a major structural protein that functions as a dominant oncoprotein. Lung cancer is the major cause of death among cancer patients. OPA can be an extremely useful animal model in order to identify the cells originating lung adenocarcinoma and to study the early events of pulmonary carcinogenesis. In this study, we demonstrated that lung adenocarcinoma in sheep originates from infection and transformation of proliferating type 2 pneumocytes (termed here lung alveolar proliferating cells, LAPCs). We excluded that OPA originates from a bronchioalveolar stem cell, or from mature post-mitotic type 2 pneumocytes or from either proliferating or non-proliferating Clara cells. We show that young animals possess abundant LAPCs and are highly susceptible to JSRV infection and transformation. On the contrary, healthy adult sheep, which are normally resistant to experimental OPA induction, exhibit a relatively low number of LAPCs and are resistant to JSRV infection of the respiratory epithelium. Importantly, induction of lung injury increased dramatically the number of LAPCs in adult sheep and rendered these animals fully susceptible to JSRV infection and transformation. Furthermore, we show that JSRV preferentially infects actively dividing cell in vitro. Overall, our study provides unique insights into pulmonary biology and carcinogenesis and suggests that JSRV and its host have reached an evolutionary equilibrium in which productive infection (and transformation) can occur only in cells that are scarce for most of the lifespan of the sheep. Our data also indicate that, at least in this model, inflammation can predispose to retroviral infection and cancer

A Novel Inhibitor of Human La Protein with Anti-HBV Activity Discovered by Structure-Based Virtual Screening and In Vitro Evaluation

Background: Over 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. Current therapeutic agents are highly effective, but are also associated with development of viral resistance. Therefore, strategies for identifying other anti-HBV agents with specific, but distinctive mechanisms of action are needed. The human La (hLa) protein, which forms a stabilizing complex with HBV RNA ribonucleoprotein to promote HBV replication, is a promising target of molecular therapy. Aims: This study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression. Methods: A multistage molecular docking approach was used to screen a Specs database and an in-house library against hLa binding sites. Sequential in vitro evaluations were performed to detect potential compounds with high scores in HepG2.2.15 cells. Results: Of the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50 % with P,0.05. Six had significant inhibition of HBV e antigen (HBeAg) levels, and 13 had significant inhibition of HBV surface antigen (HBsAg) levels by in vitro assays. Compounds HBSC-11, HBSC-15 and HBSC-34 (HBSC is system prefix for active compounds screened by the library) were selected for evaluation. HBSC-11 was found to have an obvious inhibitory effect on hLa transcription and expression

The G1613A Mutation in the HBV Genome Affects HBeAg Expression and Viral Replication through Altered Core Promoter Activity

Infection of hepatitis B virus (HBV) causes acute and chronic hepatitis and is closely associated with the development of cirrhosis and hepatocellular carcinoma (HCC). Previously, we demonstrated that the G1613A mutation in the HBV negative regulatory element (NRE) is a hotspot mutation in HCC patients. In this study, we further investigated the functional consequences of this mutation in the context of the full length HBV genome and its replication. We showed that the G1613A mutation significantly suppresses the secretion of e antigen (HBeAg) and enhances the synthesis of viral DNA, which is in consistence to our clinical result that the G1613A mutation associates with high viral load in chronic HBV carriers. To further investigate the molecular mechanism of the mutation, we performed the electrophoretic mobility shift assay with the recombinant RFX1 protein, a trans-activator that was shown to interact with the NRE of HBV. Intriguingly, RFX1 binds to the G1613A mutant with higher affinity than the wild-type sequence, indicating that the mutation possesses the trans-activating effect to the core promoter via NRE. The trans-activating effect was further validated by the enhancement of the core promoter activity after overexpression of RFX1 in liver cell line. In summary, our results suggest the functional consequences of the hotspot G1613A mutation found in HBV. We also provide a possible molecular mechanism of this hotspot mutation to the increased viral load of HBV carriers, which increases the risk to HCC

Targeting cells with single vectors using multiple-feature Boolean logic

Precisely defining the roles of specific cell types is an intriguing frontier in the study of intact biological systems and has stimulated the rapid development of genetically encoded tools for observation and control. However, targeting these tools with adequate specificity remains challenging: most cell types are best defined by the intersection of two or more features such as active promoter elements, location and connectivity. Here we have combined engineered introns with specific recombinases to achieve expression of genetically encoded tools that is conditional upon multiple cell-type features, using Boolean logical operations all governed by a single versatile vector. We used this approach to target intersectionally specified populations of inhibitory interneurons in mammalian hippocampus and neurons of the ventral tegmental area defined by both genetic and wiring properties. This flexible and modular approach may expand the application of genetically encoded interventional and observational tools for intact-systems biology

I manoscritti medievali di Padova e Provincia

Si tratta del catalogo dei manoscritti miniati delle biblioteche della provincia di Padova (esclusa la Biblioteca del Seminario Vescovile sulla quale \ue8 uscito un volume monografico). Federica Toniolo ha visionato tutto il materiale miniato ed \ue8 autrice della voce relativa alla Miniatura di parte delle schede di catalogo

I manoscritti della Biblioteca del Seminario Vescovile di Padova

Volume interamente dedicato ai codici medievali della Biblioteca del Seminario Vescovile di Padova. Federica Toniolo ha visionato tutto il materiale miniato ed \ue8 autrice della voce miniatura di alcune schede

Wounds difficult to heal: An effective treatment strategy

Objective: Treatment of wounds difficult to heal concerns 50% of the elderly population in Italy and is therefore a relevant social burden. The present study shows how the treatment with autologous leuco-platelets reduces the healing time of wounds improving the functional recovery. Patients and Methods: Patients (n=100) with ulcers of the legs were divided in two groups: 1) 50 patients treated with conventional therapies; 2) 50 patients treated with autologous leuco-platelet concentrate (LPC) and hyaluronic acid (HIAFF, Hyalofill-F®) as a scaffold. Results: After 2 months, a 49% reduction in wound area was observed in the second group and in about 65% wound reduction was achieved in 15 days (4 LPC dressings). In contrast, patients treated by conventional therapies, showed a longer healing time and a greater percentage of failures. Morphometric analysis of biopsy samples obtained from the edge as well as from the bottom of the lesions obtained from the LPC group, detected an abundant presence of neoformed capillaries, characterized by a cubic, “reactive endothelium”, close to the site of LPC infiltration. Conclusion: These results suggest that healing was promoted not only by limiting bacterial infections but also by the release of chemotactic and proangiogenic factors from leukocytes and platelets, improving the neoformation of capillaries

Somatic gene transfer of cAMP response element-binding protein attenuates memory impairment in aging rats

cAMP response element-binding protein (CREB) is important for the formation and facilitation of long-term memory in diverse models. However, to our knowledge, involvement of CREB in age-associated memory impairment has not been reported. Here, we use a recombinant adeno-associated virus vector to obtain stable transgenic expression of CREB as well as the inducible cAMP early repressor (ICER) in the hippocampus of adult rats. In a longitudinal study, we show that somatic gene transfer of both CREB and ICER does not alter long-term memory in young (3-month-old) rats. However, at 15 months of age, the same CREB-transduced rats show significantly better long-term memory in spatial-navigation and passive-avoidance tasks compared with their equally aged control littermates, and a threshold effect is evident. In contrast, the aged ICER-transduced rats demonstrate significantly reduced memory in comparison with the same control group. Hippocampal CREB gene transfer prevented the aging-related decrease in long-term memory found in the control rats. These data suggest that elevation of CREB protein levels in a subset of hippocampal neurons as achieved by somatic cell gene transfer might compensate for general deficits in molecular mechanisms underlying age-related memory loss in rats and, therefore, attenuate long-term-memory impairment during normal aging