Convergence and Perturbation Resilience of Dynamic String-Averaging Projection Methods

We consider the convex feasibility problem (CFP) in Hilbert space and concentrate on the study of string-averaging projection (SAP) methods for the CFP, analyzing their convergence and their perturbation resilience. In the past, SAP methods were formulated with a single predetermined set of strings and a single predetermined set of weights. Here we extend the scope of the family of SAP methods to allow iteration-index-dependent variable strings and weights and term such methods dynamic string-averaging projection (DSAP) methods. The bounded perturbation resilience of DSAP methods is relevant and important for their possible use in the framework of the recently developed superiorization heuristic methodology for constrained minimization problems.Comment: Computational Optimization and Applications, accepted for publicatio

Photoswitchable diacylglycerols enable optical control of protein kinase C.

Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling

Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy

Although immunotherapy can offer profound clinical benefit for patients with a variety of difficult-to-treat cancers, many tumors either do not respond to upfront treatment with immune checkpoint inhibitors (ICIs) or progressive/recurrent disease occurs after an interval of initial control. Improved response rates have been demonstrated with the addition of ICIs to cytotoxic therapies, leading to approvals from the US Food and Drug Administration and regulatory agencies in other countries for ICI-chemotherapy combinations in a number of solid tumor indications, including breast, head and neck, gastric, and lung cancer. Designing trials for patients with tumors that do not respond or stop responding to treatment with immunotherapy combinations, however, is challenging without uniform definitions of resistance. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-programmed cell death protein 1 (PD-1). To provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of ICIs and chemotherapies. Definitions for resistance to ICIs in combination with targeted therapies and with other ICIs will be published in companion volumes to this paper

Variations on Debris Disks II. Icy Planet Formation as a Function of the Bulk Properties and Initial Sizes of Planetesimals

We describe comprehensive calculations of the formation of icy planets and debris disks at 30-150 AU around 1-3 solar mass stars. Disks composed of large, strong planetesimals produce more massive planets than disks composed of small, weak planetesimals. The maximum radius of icy planets ranges from roughly 1500 km to 11,500 km. The formation rate of 1000 km objects - `Plutos' - is a useful proxy for the efficiency of icy planet formation. Plutos form more efficiently in massive disks, in disks with small planetesimals, and in disks with a range of planetesimal sizes. Although Plutos form throughout massive disks, Pluto production is usually concentrated in the inner disk. Despite the large number of Plutos produced in many calculations, icy planet formation is inefficient. At the end of the main sequence lifetime of the central star, Plutos contain less than 10% of the initial mass in solid material. This conclusion is independent of the initial mass in the disk or the properties of planetesimals. Debris disk formation coincides with the formation of planetary systems containing Plutos. As Plutos form, they stir leftover planetesimals to large velocities. A cascade of collisions then grinds the leftovers to dust, forming an observable debris disk. In disks with small (< 1-10 km) planetesimals, collisional cascades produce luminous debris disks with maximum luminosity roughly 0.01 times the stellar luminosity. Disks with larger planetesimals produce much less luminous debris disks. Observations of debris disks around A-type and G-type stars strongly favor models with small planetesimals. In these models, our predictions for the time evolution and detection frequency of debris disks agree with published observations. We suggest several critical observations that can test key features of our calculations.Comment: 61 pages of text, 24 tables, and 34 figures; submitted to ApJS; comments welcome; revised version accepted to ApJS, changed text, modified tables, added references, no major changes to conclusion

Self-Similarity in General Relativity \endtitle

The different kinds of self-similarity in general relativity are discussed, with special emphasis on similarity of the ``first'' kind, corresponding to spacetimes admitting a homothetic vector. We then survey the various classes of self-similar solutions to Einstein's field equations and the different mathematical approaches used in studying them. We focus mainly on spatially homogenous and spherically symmetric self-similar solutions, emphasizing their possible roles as asymptotic states for more general models. Perfect fluid spherically symmetric similarity solutions have recently been completely classified, and we discuss various astrophysical and cosmological applications of such solutions. Finally we consider more general types of self-similar models.Comment: TeX document, 53 page

Governor of the glnAp2 promoter of Escherichia coli

Low-affinity sites for the activator NRI∼P (NtrC∼P) that map between the enhancer and the glnAp2 promoter were responsible for limiting promoter activity at high concentrations of NRI∼P in intact cells and in an in vitro transcription system consisting of purified bacterial components. That is, the low-affinity sites constitute a ‘governor’, limiting the maximum promoter activity. As the governor sites are themselves far from the promoter, they apparently act either by preventing the formation of the activation DNA loop that brings the enhancer-bound activator and the promoter-bound polymerase into proximity or by preventing a productive interaction between the enhancer-bound activator and polymerase. The combination of potent enhancer and governor sites at the glnAp2 promoter provides for efficient activation of the promoter when the activator concentration is low, while limiting the maximum level of promoter activity when the activator concentration is high.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75402/1/j.1365-2958.2002.03211.x.pd

Template-Directed Ligation of Tethered Mononucleotides by T4 DNA Ligase for Kinase Ribozyme Selection

Background: In vitro selection of kinase ribozymes for small molecule metabolites, such as free nucleosides, will require partition systems that discriminate active from inactive RNA species. While nucleic acid catalysis of phosphoryl transfer is well established for phosphorylation of 59 or 29 OH of oligonucleotide substrates, phosphorylation of diffusible small molecules has not been demonstrated. Methodology/Principal Findings: This study demonstrates the ability of T4 DNA ligase to capture RNA strands in which a tethered monodeoxynucleoside has acquired a 59 phosphate. The ligation reaction therefore mimics the partition step of a selection for nucleoside kinase (deoxy)ribozymes. Ligation with tethered substrates was considerably slower than with nicked, fully duplex DNA, even though the deoxynucleotides at the ligation junction were Watson-Crick base paired in the tethered substrate. Ligation increased markedly when the bridging template strand contained unpaired spacer nucleotides across from the flexible tether, according to the trends: A2.A1.A3.A4.A0.A6.A8.A10 and T2.T3.T4.T6&lt;T1.T8.T10. Bridging T’s generally gave higher yield of ligated product than bridging A’s. ATP concentrations above 33 mM accumulated adenylated intermediate and decreased yields of the gap-sealed product, likely due to re-adenylation of dissociated enzyme. Under optimized conditions, T4 DNA ligase efficiently (.90%) joined a correctly paired, or T:G wobble-paired, substrate on the 39 side of the ligation junction while discriminating approximately 100-fold against most mispaire

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres

Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the $α_1$ subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase $α_1$–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the $α_1$ and $β_1$ subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG