Alexandrov groupoids and the nuclear dimension of twisted groupoid C∗\mathrm{C}^*-algebras

We consider a twist $E$ over an \'etale groupoid $G$. When $G$ is principal, we prove that the nuclear dimension of the reduced twisted groupoid $\mathrm{C}^*$-algebra is bounded by a number depending on the dynamic asymptotic dimension of $G$ and the topological covering dimension of its unit space. This generalizes an analogous theorem by Guentner, Willett, and Yu for the $\mathrm{C}^*$-algebra of $G$. Our proof uses a reduction to the unital case where $G$ has compact unit space, via a construction of ``groupoid unitizations'' $\widetilde{G}$ and $\widetilde{E}$ of $G$ and $E$ such that $\widetilde{E}$ is a twist over $\widetilde{G}$. The construction of $\widetilde G$ is for r-discrete (hence \'etale) groupoids $G$ which are not necessarily principal. When $G$ is \'etale, the dynamic asymptotic dimension of $G$ and $\widetilde{G}$ coincide. We show that the minimal unitizations of the full and reduced twisted groupoid $\mathrm{C}^*$-algebras of the twist over $G$ are isomorphic to the twisted groupoid $\mathrm{C}^*$-algebras of the twist over $\widetilde{G}$. We apply our result about the nuclear dimension of the twisted groupoid $\mathrm{C}^*$-algebra to obtain a similar bound on the nuclear dimension of the $\mathrm{C}^*$-algebra of an \'etale groupoid with closed orbits and abelian stability subgroups that vary continuously.Comment: 41 page

A phosphorylation switch controls the spatiotemporal activation of Rho GTPases in directional cell migration

Although cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood. Here we report that a phosphorylationmediated molecular switch comprising deleted in liver cancer 1(DLC1), tensin-3(TNS3), phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase (PI3K) controls the spatiotemporal activation of the small GTPases, Rac1 and RhoA, thereby initiating directional cell migration induced by growth factors. On epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) stimulation, TNS3 and PTEN are phosphorylated at specific Thr residues, which trigger the rearrangement of the TNS3-DLC1 and PTEN-PI3K complexes into the TNS3-PI3K and PTEN-DLC1 complexes. Subsequently, the TNS3-PI3K complex translocates to the leading edge of a migrating cell to promote Rac1 activation, whereas PTEN-DLC1 translocates to the posterior for localized RhoA activation. Our work identifies a core signalling mechanism by which an external motility stimulus is coupled to the spatiotemporal activation of Rac1 and RhoA to drive directional cell migration

Erratum: A phosphorylation switch controls the spatiotemporal activation of Rho GTPases in directional cell migration

Although cell migration plays a central role in development and disease, the underlying molecular mechanism is not fully understood. Here we report that a phosphorylation-mediated molecular switch comprising deleted in liver cancer 1 (DLC1), tensin-3 (TNS3), phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase (PI3K) controls the spatiotemporal activation of the small GTPases, Rac1 and RhoA, thereby initiating directional cell migration induced by growth factors. On epidermal growth factor (EGF) or platelet-derived growth factor (PDGF) stimulation, TNS3 and PTEN are phosphorylated at specific Thr residues, which trigger the rearrangement of the TNS3–DLC1 and PTEN–PI3K complexes into the TNS3–PI3K and PTEN–DLC1 complexes. Subsequently, the TNS3–PI3K complex translocates to the leading edge of a migrating cell to promote Rac1 activation, whereas PTEN–DLC1 translocates to the posterior for localized RhoA activation. Our work identifies a core signalling mechanism by which an external motility stimulus is coupled to the spatiotemporal activation of Rac1 and RhoA to drive directional cell migration

(Arg) 9 -SH2 superbinder: A novel promising anticancer therapy to melanoma by blocking phosphotyrosine signaling

Background: Melanoma is a malignant tumor with high misdiagnosis rate and poor prognosis. The bio-targeted therapy is a prevailing method in the treatment of melanoma; however, the accompanying drug resistance is inevitable. SH2 superbinder, a triple-mutant of the Src Homology 2 (SH2) domain, shows potent antitumor ability by replacing natural SH2-containing proteins and blocking multiple pY-based signaling pathways. Polyarginine (Arg) 9 , a powerful vector for intracellular delivery of large molecules, could transport therapeutic agents across cell membrane. The purpose of this study is to construct (Arg) 9 -SH2 superbinder and investigate its effects on melanoma cells, expecting to provide potential new approaches for anti-cancer therapy and overcoming the unavoidable drug resistance of single-targeted antitumor agents. Methods: (Arg) 9 and SH2 superbinder were fused to form (Arg) 9 -SH2 superbinder via genetic engineering. Pull down assay was performed to identify that (Arg) 9 -SH2 superbinder could capture a wide variety of pY proteins. Immunofluorescence was used to detect the efficiency of (Arg) 9 -SH2 superbinder entering cells. The proliferation ability was assessed by MTT and colony formation assay. In addition, wound healing and transwell assay were performed to evaluate migration of B16F10, A375 and A375/DDP cells. Moreover, apoptosis caused by (Arg) 9 -SH2 superbinder was analyzed by flow cytometry-based Annexin V/PI. Furthermore, western blot revealed that (Arg) 9 -SH2 superbinder influenced some pY-related signaling pathways. Finally, B16F10 xenograft model was established to confirm whether (Arg) 9 -SH2 superbinder could restrain the growth of tumor. Results: Our data showed that (Arg) 9 -SH2 superbinder had the ability to enter melanoma cells effectively and displayed strong affinities for various pY proteins. Furthermore, (Arg) 9 -SH2 superbinder could repress proliferation, migration and induce apoptosis of melanoma cells by regulating PI3K/AKT, MAPK/ERK and JAK/STAT signaling pathways. Importantly, (Arg) 9 -SH2 superbinder could significantly inhibit the growth of tumor in mice. Conclusions: (Arg) 9 -SH2 superbinder exhibited high affinities for pY proteins, which showed effective anticancer ability by replacing SH2-containing proteins and blocking diverse pY-based pathways. The remarkable ability of (Arg) 9 -SH2 superbinder to inhibit cancer cell proliferation and tumor growth might open the door to explore the SH2 superbinder as a therapeutic agent for cancer treatment

Antibody Therapies for the Treatment of Acute Myeloid Leukemia: Exploring Current and Emerging Therapeutic Targets

INTRODUCTION: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients. AREAS COVERED: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials. EXPERT OPINION: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions

Acute effects of kisspeptin administration on bone metabolism in healthy men

CONTEXT: Osteoporosis results from disturbances in bone formation and resorption. Recent non-human data suggests that the reproductive hormone, kisspeptin, directly stimulates osteoblast differentiation in vitro and thus could have clinical therapeutic potential. However, the effects of kisspeptin on human bone metabolism are currently unknown. OBJECTIVE: To assess the effects of kisspeptin on human bone metabolism in vitro and in vivo. DESIGN: In vitro study: Mono- and co-cultures of human osteoblasts and osteoclasts treated with kisspeptin. Clinical study: Randomized, placebo-controlled, double-blind, two-way crossover clinical study in twenty-six men investigating the effects of acute kisspeptin administration (90 minutes) on human bone metabolism, with blood sampling every 30 minutes to +90 minutes. PARTICIPANTS: In vitro study: Twelve male blood donors and eight patients undergoing hip replacement surgery. Clinical Study: Twenty-six healthy eugonadal men (age 26.8±5.8 years). INTERVENTION: Kisspeptin (versus placebo). MAIN OUTCOME MEASURES: Changes in bone parameters and turnover markers. RESULTS: Incubation with kisspeptin in vitro increased alkaline phosphatase levels in human bone marrow mesenchymal stem cells by 41.1% (P=0.0022), and robustly inhibited osteoclastic resorptive activity by up to 53.4% (P<0.0001), in a dose-dependent manner. Kisspeptin administration to healthy men increased osteoblast activity, as evidenced by a 20.3% maximal increase in total osteocalcin (P=0.021) and 24.3% maximal increase in carboxylated osteocalcin levels (P=0.014). CONCLUSIONS: Collectively, these data provide the first human evidence that kisspeptin promotes osteogenic differentiation of osteoblast progenitors and inhibits bone resorption in vitro. Furthermore, kisspeptin acutely increases the bone formation marker osteocalcin but not resorption markers in healthy men, independent of downstream sex-steroid levels. Kisspeptin could therefore have clinical therapeutic application in the treatment of osteoporosis

The APOKASC Catalog: An Asteroseismic and Spectroscopic Joint Survey of Targets in the Kepler Fields

We present the first APOKASC catalog of spectroscopic and asteroseismic properties of 1916 red giants observed in the Kepler fields. The spectroscopic parameters provided from the Apache Point Observatory Galactic Evolution Experiment project are complemented with asteroseismic surface gravities, masses, radii, and mean densities determined by members of the Kepler Asteroseismology Science Consortium. We assess both random and systematic sources of error and include a discussion of sample selection for giants in the Kepler fields. Total uncertainties in the main catalog properties are of order 80 K in Teff , 0.06 dex in [M/H], 0.014 dex in log g, and 12% and 5% in mass and radius, respectively; these reflect a combination of systematic and random errors. Asteroseismic surface gravities are substantially more precise and accurate than spectroscopic ones, and we find good agreement between their mean values and the calibrated spectroscopic surface gravities. There are, however, systematic underlying trends with Teff and log g. Our effective temperature scale is between 0-200 K cooler than that expected from the Infrared Flux Method, depending on the adopted extinction map, which provides evidence for a lower value on average than that inferred for the Kepler Input Catalog (KIC). We find a reasonable correspondence between the photometric KIC and spectroscopic APOKASC metallicity scales, with increased dispersion in KIC metallicities as the absolute metal abundance decreases, and offsets in Teff and log g consistent with those derived in the literature. We present mean fitting relations between APOKASC and KIC observables and discuss future prospects, strengths, and limitations of the catalog data.Comment: 49 pages. ApJSupp, in press. Full machine-readable ascii files available under ancillary data. Categories: Kepler targets, asteroseismology, large spectroscopic survey

Planet Populations as a Function of Stellar Properties

Exoplanets around different types of stars provide a window into the diverse environments in which planets form. This chapter describes the observed relations between exoplanet populations and stellar properties and how they connect to planet formation in protoplanetary disks. Giant planets occur more frequently around more metal-rich and more massive stars. These findings support the core accretion theory of planet formation, in which the cores of giant planets form more rapidly in more metal-rich and more massive protoplanetary disks. Smaller planets, those with sizes roughly between Earth and Neptune, exhibit different scaling relations with stellar properties. These planets are found around stars with a wide range of metallicities and occur more frequently around lower mass stars. This indicates that planet formation takes place in a wide range of environments, yet it is not clear why planets form more efficiently around low mass stars. Going forward, exoplanet surveys targeting M dwarfs will characterize the exoplanet population around the lowest mass stars. In combination with ongoing stellar characterization, this will help us understand the formation of planets in a large range of environments.Comment: Accepted for Publication in the Handbook of Exoplanet