Complex macrocycle exploration: parallel, heuristic, and constraint-based conformer generation using ForceGen.

ForceGen is a template-free, non-stochastic approach for 2D to 3D structure generation and conformational elaboration for small molecules, including both non-macrocycles and macrocycles. For conformational search of non-macrocycles, ForceGen is both faster and more accurate than the best of all tested methods on a very large, independently curated benchmark of 2859 PDB ligands. In this study, the primary results are on macrocycles, including results for 431 unique examples from four separate benchmarks. These include complex peptide and peptide-like cases that can form networks of internal hydrogen bonds. By making use of new physical movements ("flips" of near-linear sub-cycles and explicit formation of hydrogen bonds), ForceGen exhibited statistically significantly better performance for overall RMS deviation from experimental coordinates than all other approaches. The algorithmic approach offers natural parallelization across multiple computing-cores. On a modest multi-core workstation, for all but the most complex macrocycles, median wall-clock times were generally under a minute in fast search mode and under 2 min using thorough search. On the most complex cases (roughly cyclic decapeptides and larger) explicit exploration of likely hydrogen bonding networks yielded marked improvements, but with calculation times increasing to several minutes and in some cases to roughly an hour for fast search. In complex cases, utilization of NMR data to constrain conformational search produces accurate conformational ensembles representative of solution state macrocycle behavior. On macrocycles of typical complexity (up to 21 rotatable macrocyclic and exocyclic bonds), design-focused macrocycle optimization can be practically supported by computational chemistry at interactive time-scales, with conformational ensemble accuracy equaling what is seen with non-macrocyclic ligands. For more complex macrocycles, inclusion of sparse biophysical data is a helpful adjunct to computation

Numerical Models of Binary Neutron Star System Mergers. I.: Numerical Methods and Equilibrium Data for Newtonian Models

The numerical modeling of binary neutron star mergers has become a subject of much interest in recent years. While a full and accurate model of this phenomenon would require the evolution of the equations of relativistic hydrodynamics along with the Einstein field equations, a qualitative study of the early stages on inspiral can be accomplished by either Newtonian or post-Newtonian models, which are more tractable. In this paper we offer a comparison of results from both rotating and non-rotating (inertial) frame Newtonian calculations. We find that the rotating frame calculations offer significantly improved accuracy as compared with the inertial frame models. Furthermore, we show that inertial frame models exhibit significant and erroneous angular momentum loss during the simulations that leads to an unphysical inspiral of the two neutron stars. We also examine the dependence of the models on initial conditions by considering initial configurations that consist of spherical neutron stars as well as stars that are in equilibrium and which are tidally distorted. We compare our models those of Rasio & Shapiro (1992,1994a) and New & Tohline (1997). Finally, we investigate the use of the isolated star approximation for the construction of initial data.Comment: 32 pages, 19 gif figures, manuscript with postscript figures available at http://www.astro.sunysb.edu/dswesty/docs/nspap1.p

Human cytomegalovirus: taking the strain

In celebrating the 60th anniversary of the first isolation of human cytomegalovirus (HCMV), we reflect on the merits and limitations of the viral strains currently being used to develop urgently needed treatments. HCMV research has been dependent for decades on the high-passage strains AD169 and Towne, heavily exploiting their capacity to replicate efficiently in fibroblasts. However, the genetic integrity of these strains is so severely compromised that great caution needs to be exercised when considering their past and future use. It is now evident that wild-type HCMV strains are not readily propagated in vitro. HCMV mutants are rapidly selected during isolation in fibroblasts, reproducibly affecting gene RL13, the UL128 locus (which includes genes UL128, UL130 and UL131A) and often the UL/b′ region. As a result, the virus becomes less cell associated, altered in tropism and less pathogenic. This problem is not restricted to high-passage strains, as even low-passage strains can harbour biologically significant mutations. Cloning and manipulation of the HCMV genome as a bacterial artificial chromosome (BAC) offers a means of working with stable, genetically defined strains. To this end, the low-passage strain Merlin genome was cloned as a BAC and sequentially repaired to match the viral sequence in the original clinical sample from which Merlin was derived. Restoration of UL128L to wild type was detrimental to growth in fibroblasts, whereas restoration of RL13 impaired growth in all cell types tested. Stable propagation of phenotypically wild-type virus could be achieved only by placing both regions under conditional expression. In addition to the development of these tools, the Merlin transcriptome and proteome have been characterized in unparalleled detail. Although Merlin may be representative of the clinical agent, high-throughput whole-genome deep sequencing studies have highlighted the remarkable high level of interstrain variation present in circulating virus. There is a need to develop systems capable of addressing the significance of this diversity, free from the confounding effects of genetic changes associated with in vitro adaptation. The generation of a set of BAC clones, each containing the genome of a different HCMV strain repaired to match the sequence in the clinical sample, would provide a pathway to address the biological and clinical effects of natural variation in wild-type HCMV

Supermassive black holes with high accretion rates in active galactic nuclei. XIII. Ultraviolet time lag of Hβ emission in Mrk 142

Funding: We acknowledge the support of the Natural Sciences and Engineering Research Council of Canada (NSERC), Discovery Grant RGPIN/04157. V.C.K. acknowledges the support of the Ontario Graduate Scholarships. C.H. acknowledges support from the National Science Foundation of China (12122305). The research of V.C.K. was partially supported by the New Technologies for Canadian Observatories, an NSERC CREATE program.We performed a rigorous reverberation-mapping analysis of the broad-line region (BLR) in a highly accreting (L/LEdd = 0.74–3.4) active galactic nucleus, Markarian 142 (Mrk 142), for the first time using concurrent observations of the inner accretion disk and the BLR to determine a time lag for the Hβ λ4861 emission relative to the ultraviolet (UV) continuum variations. We used continuum data taken with the Niel Gehrels Swift Observatory in the UVW2 band, and the Las Cumbres Observatory, Dan Zowada Memorial Observatory, and Liverpool Telescope in the g band, as part of the broader Mrk 142 multi-wavelength monitoring campaign in 2019. We obtained new spectroscopic observations covering the Hβ broad emission line in the optical from the Gemini North Telescope and the Lijiang 2.4-meter Telescope for a total of 102 epochs (over a period of eight months) contemporaneous to the continuum data. Our primary result states a UV-to-Hβ time lag of 8.68+0.75−0.72 days in Mrk 142 obtained from light-curve analysis with a Python-based Running Optimal Average algorithm. We placed our new measurements for Mrk 142 on the optical and UV radius-luminosity relations for NGC 5548 to understand the nature of the continuum driver. The positions of Mrk 142 on the scaling relations suggest that UV is closer to the “true” driving continuum than the optical. Furthermore, we obtain log(M•/M⊙) = 6.32 ± 0.29 assuming UV as the primary driving continuum.Publisher PDFPeer reviewe

The electronic properties of bilayer graphene

We review the electronic properties of bilayer graphene, beginning with a description of the tight-binding model of bilayer graphene and the derivation of the effective Hamiltonian describing massive chiral quasiparticles in two parabolic bands at low energy. We take into account five tight-binding parameters of the Slonczewski-Weiss-McClure model of bulk graphite plus intra- and interlayer asymmetry between atomic sites which induce band gaps in the low-energy spectrum. The Hartree model of screening and band-gap opening due to interlayer asymmetry in the presence of external gates is presented. The tight-binding model is used to describe optical and transport properties including the integer quantum Hall effect, and we also discuss orbital magnetism, phonons and the influence of strain on electronic properties. We conclude with an overview of electronic interaction effects.Comment: review, 31 pages, 15 figure

Microgeometry capture using an elastomeric sensor

We describe a system for capturing microscopic surface geometry. The system extends the retrographic sensor [Johnson and Adelson 2009] to the microscopic domain, demonstrating spatial resolution as small as 2 microns. In contrast to existing microgeometry capture techniques, the system is not affected by the optical characteristics of the surface being measured---it captures the same geometry whether the object is matte, glossy, or transparent. In addition, the hardware design allows for a variety of form factors, including a hand-held device that can be used to capture high-resolution surface geometry in the field. We achieve these results with a combination of improved sensor materials, illumination design, and reconstruction algorithm, as compared to the original sensor of Johnson and Adelson [2009].National Science Foundation (U.S.) (Grant 0739255)National Institutes of Health (U.S.) (Contract 1-R01-EY019292-01

Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts

Aims: Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia. Methods and Results: FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased. Conclusion: In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia