Two Warm Super-Earths Transiting the Nearby M Dwarf TOI-2095

We report the detection and validation of two planets orbiting TOI-2095 (TIC 235678745). The host star is a 3700K M1V dwarf with a high proper motion. The star lies at a distance of 42 pc in a sparsely populated portion of the sky and is bright in the infrared (K=9). With data from 24 Sectors of observation during TESS's Cycles 2 and 4, TOI-2095 exhibits two sets of transits associated with super-Earth-sized planets. The planets have orbital periods of 17.7 days and 28.2 days and radii of 1.30 and 1.39 Earth radii, respectively. Archival data, preliminary follow-up observations, and vetting analyses support the planetary interpretation of the detected transit signals. The pair of planets have estimated equilibrium temperatures of approximately 400 K, with stellar insolations of 3.23 and 1.73 times that of Earth, placing them in the Venus zone. The planets also lie in a radius regime signaling the transition between rock-dominated and volatile-rich compositions. They are thus prime targets for follow-up mass measurements to better understand the properties of warm, transition radius planets. The relatively long orbital periods of these two planets provide crucial data that can help shed light on the processes that shape the composition of small planets orbiting M dwarfs.Comment: Submitted to AAS Journal

A Unique Role for Nonmuscle Myosin Heavy Chain IIA in Regulation of Epithelial Apical Junctions

The integrity and function of the epithelial barrier is dependent on the apical junctional complex (AJC) composed of tight and adherens junctions and regulated by the underlying actin filaments. A major F-actin motor, myosin II, was previously implicated in regulation of the AJC, however direct evidence of the involvement of myosin II in AJC dynamics are lacking and the molecular identity of the myosin II motor that regulates formation and disassembly of apical junctions in mammalian epithelia is unknown. We investigated the role of nonmuscle myosin II (NMMII) heavy chain isoforms, A, B, and C in regulation of epithelial AJC dynamics and function. Expression of the three NMMII isoforms was observed in model intestinal epithelial cell lines, where all isoforms accumulated within the perijunctional F-actin belt. siRNA-mediated downregulation of NMMIIA, but not NMMIIB or NMMIIC expression in SK-CO15 colonic epithelial cells resulted in profound changes of cell morphology and cell-cell adhesions. These changes included acquisition of a fibroblast-like cell shape, defective paracellular barrier, and substantial attenuation of the assembly and disassembly of both adherens and tight junctions. Impaired assembly of the AJC observed after NMMIIA knock-down involved dramatic disorganization of perijunctional actin filaments. These findings provide the first direct non-pharmacological evidence of myosin II-dependent regulation of AJC dynamics in mammalian epithelia and highlight a unique role of NMMIIA in junctional biogenesis

A Generic Program for Multistate Protein Design

Some protein design tasks cannot be modeled by the traditional single state design strategy of finding a sequence that is optimal for a single fixed backbone. Such cases require multistate design, where a single sequence is threaded onto multiple backbones (states) and evaluated for its strengths and weaknesses on each backbone. For example, to design a protein that can switch between two specific conformations, it is necessary to to find a sequence that is compatible with both backbone conformations. We present in this paper a generic implementation of multistate design that is suited for a wide range of protein design tasks and demonstrate in silico its capabilities at two design tasks: one of redesigning an obligate homodimer into an obligate heterodimer such that the new monomers would not homodimerize, and one of redesigning a promiscuous interface to bind to only a single partner and to no longer bind the rest of its partners. Both tasks contained negative design in that multistate design was asked to find sequences that would produce high energies for several of the states being modeled. Success at negative design was assessed by computationally redocking the undesired protein-pair interactions; we found that multistate design's accuracy improved as the diversity of conformations for the undesired protein-pair interactions increased. The paper concludes with a discussion of the pitfalls of negative design, which has proven considerably more challenging than positive design

Pharmacology and acute toxicity of antirheumatic and immunologic therapy

https://scholarlycommons.pacific.edu/phs-facbooks/1021/thumbnail.jp

Pharmacology and acute toxicity of antirheumatic and immunologic therapy

https://scholarlycommons.pacific.edu/phs-facbooks/1021/thumbnail.jp

Pharmacology and acute toxicity of antirheumatic and immunologic therapy

https://scholarlycommons.pacific.edu/phs-facbooks/1021/thumbnail.jp

Tophus resolution in patients with chronic refractory gout who have persistent urate-lowering responses to pegloticase

Abstract Background Pegloticase is a recombinant mammalian uricase conjugated to polyethylene glycol approved in the United States for treatment of chronic refractory gout. It can profoundly decrease serum urate to < 1 mg/dl. In patients receiving pegloticase who did not generate high-titer antidrug antibodies (responders), the serum urate remained low for the duration of therapy, 6 months in the phase III clinical trials plus the open-label extension. The objective of this study was to assess the velocity of tophus resolution in subjects treated with pegloticase. Methods Data from two randomized controlled trials of pegloticase in chronic refractory gout were analyzed. Tophi were assessed by computer-assisted measurements of standardized digital photographs. Subjects were designated as responders and nonresponders based on maintenance of serum urate < 6 mg/dl at months 3 and 6 of treatment. The projected time of complete resolution of all tophi was determined by linear regression analysis. Results The mean total tophus area at baseline was 585.8 mm2 for responders, 661.5 mm2 for nonresponders, and 674.4 mm2 for placebo-treated patients. Complete resolution at 6 months of at least one tophus was achieved by 69.6% of 23 responders, 27.9% of 43 nonresponders, and 14.3% of 21 patients who received placebo. Complete resolution of all photographed tophi was achieved by 34.8% of biochemical responders, 11.6% of nonresponders, and 0% of placebo-treated patients. The mean velocity of resolution of all tophi was 60.1 mm2/month in responders with a mean projected time of complete resolution of 9.9 months (4.6–32.6 months). There was a significant inverse correlation between serum urate AUC and tophus resolution velocity (r = − 0.40, P = 0.0002), although considerable heterogeneity in the velocity of resolution was noted. The only patient characteristic that correlated with the velocity of tophus resolution was the baseline tophus area. Conclusions Pegloticase treatment caused a rapid resolution of tophi in responders that correlated with the serum urate lowering associated with this therapy