Cooperation of Gq, Gi, and G12/13 in Protein Kinase D Activation and Phosphorylation Induced by Lysophosphatidic Acid

To examine the contribution of different G-protein pathways to lysophosphatidic acid (LPA)-induced protein kinase D (PKD) activation, we tested the effect of LPA on PKD activity in murine embryonic cell lines deficient in Galpha q/11 (Galpha q/11 KO cells) or Galpha 12/13 (Galpha 12/13 KO cells) and used cells lacking rhodopsin kinase (RK cells) as a control. In RK and Galpha 12/13 KO cells, LPA induced PKD activation through a phospholipase C/protein kinase C pathway in a concentration-dependent fashion with maximal stimulation (6-fold for RK cells and 4-fold for Galpha 12/13 KO cells in autophosphorylation activity) achieved at 3 µM. In contrast, LPA did not induce any significant increase in PKD activity in Galpha q/11 KO cells. However, LPA induced a significantly increased PKD activity when Galpha q/11 KO cells were transfected with Galpha q. LPA-induced PKD activation was modestly attenuated by prior exposure of RK cells to pertussis toxin (PTx) but abolished by the combination treatments of PTx and Clostridium difficile toxin B. Surprisingly, PTx alone strikingly inhibited LPA-induced PKD activation in a concentration-dependent fashion in Galpha 12/13 KO cells. Similar results were obtained when activation loop phosphorylation at Ser-744 was determined using an antibody that detects the phosphorylated state of this residue. Our results indicate that Gq is necessary but not sufficient to mediate LPA-induced PKD activation. In addition to Gq, LPA requires additional G-protein pathways to elicit a maximal response with Gi playing a critical role in Galpha 12/13 KO cells. We conclude that LPA induces PKD activation through Gq, Gi, and G12 and propose that PKD activation is a point of convergence in the action of multiple G-protein pathways

Symmetry indicators in commensurate magnetic flux

We derive a framework to apply topological quantum chemistry in systems subject to magnetic flux. We start by deriving the action of spatial symmetry operators in a uniform magnetic field, which extends Zak's magnetic translation groups to all crystal symmetry groups. Ultimately, the magnetic symmetries form a projective representation of the crystal symmetry group. As a consequence, band representations acquire an extra gauge invariant phase compared to the non-magnetic theory. Thus, the theory of symmetry indicators is distinct from the non-magnetic case. We give examples of new symmetry indicators that appear at $\pi$ flux. Finally, we apply our results to an obstructed atomic insulator with corner states in a magnetic field. The symmetry indicators reveal a topological-to-trivial phase transition at finite flux, which is confirmed by a Hofstadter butterfly calculation. The bulk phase transition provides a new probe of higher order topology in certain obstructed atomic insulators.Comment: 24 pages, 7 figure

The Continuing Evolution of Precision Health in Type 2 Diabetes: Achievements and Challenges

Purpose of Review The purpose of this review was to summarize recent advances in the genomics of type 2 diabetes (T2D) and to highlight current initiatives to advance precision health. Recent Findings Generation of multi-omic data to measure each of the “biologic layers,” developments in describing genomic function and annotation in T2D relevant tissue, along with the increasing recognition that T2D is a heterogeneous disease, and large-scale collaborations have all contributed to advancing our understanding of the molecular basis of T2D. Summary Substantial advances have been made in understanding the molecular basis of T2D pathogenesis, such that precision health diabetes is increasingly becoming a reality. For precision diabetes to become a routine in clinical and public health, additional large-scale multi-omic initiatives are needed along with better assessment of our environment to delineate an individual’s diabetes subtype for improved detection and management

Improving Identification of SSI in SNF

Educational deficit in basic wound assessment can lead to failure to recognize early signs of infection or wound deterioration. Despite many challenges towards wound care, there are potential opportunities to reduce patient injury and clinical outcomes through continuing education. The purpose of this paper is to review literature on current wound care knowledge in nurses and assess existing wound care knowledge in nurses at a skilled nursing facility. A 10-question pre-test wound assessment quiz based on the Bates-Jensen Wound Assessment Tool (BWAT) selected by the Wound Care Coordinator (WCC)/Wound Care Specialist (WCS) was given to 22 nurses: 5 Registered Nurses (RN) and 17 Licensed Vocational Nurses (LVN) working at this SNF. Results showed that only 13% (3) scored higher than 75%. Additional clinical education was provided according to knowledge deficits. A post-test was then given with the same questions as the pre-test. Results showed that 77 percent (17) scored equal or higher than 97%, and 22.7 percent (5) scored 77 percent. There was an increase of 32 percent in correctly answered questions. This shows that education has a significant impact on enhancing clinical knowledge

Intravital Multiphoton Microscopy with Fluorescent Bile Salts in Rats as an In Vivo Biomarker for Hepatobiliary Transport Inhibition

The bile salt export pump (BSEP) is expressed at the canalicular domain of hepatocytes, where it mediates the elimination of monovalent bile salts into the bile. Inhibition of BSEP is considered a susceptibility factor for drug-induced liver injury that often goes undetected during nonclinical testing. Although in vitro assays exist for screening BSEP inhibition, a reliable and specific method for confirming Bsep inhibition in vivo would be a valuable follow up to a BSEP screening strategy, helping to put a translatable context around in vitro inhibition data, incorporating processes such as metabolism, protein binding, and other exposure properties that are lacking in most in vitro BSEP models. Here, we describe studies in which methods of quantitative intravital microscopy were used to identify dose-dependent effects of two known BSEP/Bsep inhibitors, 2-[4-[4-(butylcarbamoyl)-2-[(2,4-dichlorophenyl)sulfonylamino]phenoxy]-3-methoxyphenyl]acetic acid (AMG-009) and bosentan, on hepatocellular transport of the fluorescent bile salts cholylglycyl amidofluorescein and cholyl-lysyl-fluorescein in rats. Results of these studies demonstrate that the intravital microscopy approach is capable of detecting Bsep inhibition at drug doses well below those found to increase serum bile acid levels, and also indicate that basolateral efflux transporters play a significant role in preventing cytosolic accumulation of bile acids under conditions of Bsep inhibition in rats. Studies of this kind can both improve our understanding of exposures needed to inhibit Bsep in vivo and provide unique insights into drug effects in ways that can improve our ability interpret animal studies for the prediction of human drug hepatotoxicity

Does Format Matter? Reader Preferences in an Academic Library Context

Although many academic libraries have dramatically increased their e‐book acquisitions in recent years, questions linger about format preference. When a scholarly monograph is made available in both print and electronic formats, which format will users prefer? Does format even matter? At the University of Toronto Libraries, we analyzed usage data for scholarly monographs from three key university presses, covering thousands of titles over several years of publication. By comparing print and e‐book usage patterns of identical titles, our goal was to examine format preferences and determine if there are differences in usage across subject disciplines or publishers. Through this analysis, our aim is to question whether continued acquisition of the same content in multiple formats is necessary and desirable, especially in an era of rapid technological change, increased pressure on library acquisitions budgets, and diminishing physical storage space

Quantum geometry induced nonlinear transport in altermagnets

Quantum geometry plays a pivotal role in the second-order response of $\cal PT$-symmetric antiferromagnets. Here we study the nonlinear response of 2D altermagnets protected by $C_n\cal T$ symmetry and show that their leading nonlinear response is third-order. Furthermore, we show that the contributions from the quantum metric and Berry curvature enter separately: the longitudinal response for all planar altermagnets \emph{only} has a contribution from the quantum metric quadrupole (QMQ), while transverse responses in general have contributions from both the Berry curvature quadrupole (BCQ) and QMQ. We show that for the well-known example of $d$-wave altermagnets the Hall response is dominated by the BCQ. Both longitudinal and transverse responses are strongly dependent on the crystalline anisotropy. While altermagnets are strictly defined in the limit of vanishing SOC, real altermagnets exhibit weak SOC, which is essential to observe this response. Specifically, SOC gaps the spin-group protected nodal line, generating a response peak that is sharpest when SOC is weak. Two Dirac nodes also contribute a divergence to the nonlinear response, whose scaling changes as a function of SOC. Finally, we apply our results to thin films of the 3D altermagnet RuO$_2$. Our work uncovers distinct features of altermagnets in nonlinear transport, providing experimental signatures as well as a guide to disentangling the different components of their quantum geometry.Comment: 4 figures, 6+12, Supplementary materials include