Diethyl 2,6-dimethyl-4-(5-phenyl-1H-pyrazol-4-yl)-1,4-dihydro­pyridine-3,5-dicarboxyl­ate

In the title compound, C22H25N3O4, the dihydro­pyridine ring adopts a flattened boat conformation. The pyrazole ring makes a dihedral angle of 29.04 (5)° with the benzene ring. The mol­ecular structure is stabilized by an intra­molecular C—H⋯O hydrogen bond which generates an S(9) ring motif. In the crystal, mol­ecules are linked via N—H⋯O and C—H⋯N hydrogen bonds into a two-dimensional network parallel to the ab plane. The crystal structure is further consolidated by weak C—H⋯π inter­actions

Macro-physical, optical and radiative properties of tropical cirrus clouds and its temperature dependence at Gadanki (13.5° N, 79.2° E) observed by ground based lidar

The macro-physical and optical properties of cirrus clouds and its temperature dependencies have been investigated at the National Atmospheric Research Laboratory (NARL; 13.5° N, 79.2° E), Gadanki, Andhra Pradesh, India; an inland tropical station during the period of observation January to December 2009 using a ground based pulsed monostatic lidar system data and radiosonde measurements. Based on the analysis of measurements the cirrus macrophysical properties such as occurrence height, mid cloud temperature, cloud geometrical thickness, and optical properties such as extinction coefficient, optical depth, depolarization ratio and lidar ratio have been determined. The variation of cirrus macrophysical and optical properties with mid cloud temperature have also been studied. The cirrus clouds mean height has been generally observed in the range of 9-17 km with a peak occurrence at 13-14 km. The cirrus mid cloud temperatures were in the range from -81 °C to -46 °C. The cirrus geometrical thickness ranges from 0.9-4.5 km and 56% of cirrus occurrences have thickness 1.0 -2.7 km. The monthly cirrus optical depth ranges from 0.01-0.47, but most (>80%) of the cirrus have values less than 0.1. The monthly mean cirrus extinction ranges from 2.8E-06 to 8E-05 and depolarization ratio and lidar ratio varies from 0.13 to 0.77 and 2 to 52 respectively. The temperature and thickness dependencies on cirrus optical properties have also been studied. A maximum cirrus geometrical thickness of 4.5 km is found at temperatures around – 46 °C with an indication that optical depth increases with increasing thickness and mid cloud temperature. The cloud radiative properties such as outgoing long-wave radiation (OLR) flux and cirrus IR forcing are studied. OLR flux during the cirrus occurrence days ranged from 348-456 W/m2 with a low value in the monsoon period. The cirrus IR forcing varied from 3.13 – 110.54 W/m2 and shows a peak at monsoon period

Elastic shape matching of parameterized surfaces using square root normal fields.

In this paper we define a new methodology for shape analysis of parameterized surfaces, where the main issues are: (1) choice of metric for shape comparisons and (2) invariance to reparameterization. We begin by defining a general elastic metric on the space of parameterized surfaces. The main advantages of this metric are twofold. First, it provides a natural interpretation of elastic shape deformations that are being quantified. Second, this metric is invariant under the action of the reparameterization group. We also introduce a novel representation of surfaces termed square root normal fields or SRNFs. This representation is convenient for shape analysis because, under this representation, a reduced version of the general elastic metric becomes the simple \ensuremathL2\ensuremathL2 metric. Thus, this transformation greatly simplifies the implementation of our framework. We validate our approach using multiple shape analysis examples for quadrilateral and spherical surfaces. We also compare the current results with those of Kurtek et al. [1]. We show that the proposed method results in more natural shape matchings, and furthermore, has some theoretical advantages over previous methods

Atomistic Mechanisms for the Thermal Relaxation of Au -hyperdoped Si

Au-hyperdoped Si produced by ion implantation and pulsed laser melting exhibits sub-band-gap absorption in the near infrared, a property that is interesting for Si photonics. However, the sub-band-gap absorption has previously been shown to be thermally metastable. In this work, we study the atomistic processes that occur during the thermal relaxation of Au-hyperdoped Si. We show that the first step in thermal relaxation is the release of substitutional Au from lattice sites. This process is characterized by an activation energy of around 1.6 eV, a value similar to that associated with Au diffusion in Si, suggesting that both processes could be rate limited by the exchange of substitutional and interstitial Au atoms. As the system further relaxes, Au is found to locally diffuse and become trapped at nearby lattice defects, notably vacancies and vacancy complexes. In fact, density-functional theory results suggest that the formation of Au dimers is energetically favourable after the Au becomes locally trapped. The dimers could subsequently evolve into trimers, etc., as other diffusing Au atoms become trapped at the dimer. At low Au concentrations, this clustering process does not form visible precipitation after annealing at 750 ◦C for 3 min. In contrast, spherical Au precipitates are found in samples with higher Au concentrations (>0.14 at. %), where the Au atoms and the associated lattice defect distributions are laterally inhomogeneous.Funding from the U.S. Army under Contract No. FA5209-16-P-0104 is acknowledged for partial support of this work. This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Coordinated Infrastructure Network (NNCI), which is supported by the National Science Foundation under NSF Grant No. 1541959. CNS is part of Harvard University

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Mouse genomic screen reveals novel host regulator of metastasis

Tumor cells have to overcome challenges in the host tissue microenvironment to metastasize successfully to distant organs. In a recent Nature study, a genome-wide functional screen demonstrated that deficiency of the sphingosine-1-phoshate (S1P) transporter gene Spns2 in endothelium increased immune-mediated cell killing by T cells and natural killer (NK) cells, thereby suppressing metastatic colonization

Combination Lenalidomide and Azacitidine: A Novel Salvage Therapy in Patients Who Relapse After Allogeneic Stem-Cell Transplantation for Acute Myeloid Leukemia.

Purpose Salvage options for patients who relapse after allogeneic stem-cell transplantation (allo-SCT) for acute myeloid leukemia (AML) and myelodysplasia (MDS) remain limited, and novel treatment strategies are required. Both lenalidomide (LEN) and azacitidine (AZA) possess significant antitumor activity effect in AML. Administration of LEN post-transplantation is associated with excessive rates of graft-versus-host disease (GVHD), but AZA has been shown to ameliorate GVHD in murine transplantation models. We therefore examined the tolerability and activity of combined LEN/AZA administration in post-transplantation relapse.Patients and methods Twenty-nine patients who had relapsed after allo-SCT for AML (n = 24) or MDS (n = 5) were treated with sequential AZA (75 mg/m2 for 7 days) followed by escalating doses of LEN on days 10 to 30. Dose allocation and maximum tolerated dose (MTD) estimation were guided by a modified Bayesian continuous reassessment method (CRM).Results Sequential AZA and LEN therapy was well tolerated. The MTD of post-transplantation LEN, in combination with AZA, was determined as 25 mg daily. Three patients developed grade 2 to 4 GVHD. There was no GVHD-related mortality. Seven of 15 (47%) patients achieved a major clinical response after LEN/AZA therapy. CD8+ T cells demonstrated impaired interferon-γ/tumor necrosis factor-α production at relapse, which was not reversed during LEN/AZA administration.Conclusion We conclude LEN can be administered safely post-allograft in conjunction with AZA, and this combination demonstrates clinical activity in relapsed AML/MDS without reversing biologic features of T-cell exhaustion. The use of a CRM model delivered improved efficiency in MTD assessment and provided additional flexibility. Combined LEN/AZA therapy represents a novel and active salvage therapy in patients who had relapsed post-allograft

The UCSC Genome Browser database: extensions and updates 2011

The University of California Santa Cruz Genome Browser (http://genome.ucsc.edu) offers online public access to a growing database of genomic sequence and annotations for a wide variety of organisms. The Browser is an integrated tool set for visualizing, comparing, analyzing and sharing both publicly available and user-generated genomic data sets. In the past year, the local database has been updated with four new species assemblies, and we anticipate another four will be released by the end of 2011. Further, a large number of annotation tracks have been either added, updated by contributors, or remapped to the latest human reference genome. Among these are new phenotype and disease annotations, UCSC genes, and a major dbSNP update, which required new visualization methods. Growing beyond the local database, this year we have introduced ‘track data hubs’, which allow the Genome Browser to provide access to remotely located sets of annotations. This feature is designed to significantly extend the number and variety of annotation tracks that are publicly available for visualization and analysis from within our site. We have also introduced several usability features including track search and a context-sensitive menu of options available with a right-click anywhere on the Browser's image