Phosphorylation of the Arp2 subunit relieves auto-inhibitory interactions for Arp2/3 complex activation.

Actin filament assembly by the actin-related protein (Arp) 2/3 complex is necessary to build many cellular structures, including lamellipodia at the leading edge of motile cells and phagocytic cups, and to move endosomes and intracellular pathogens. The crucial role of the Arp2/3 complex in cellular processes requires precise spatiotemporal regulation of its activity. While binding of nucleation-promoting factors (NPFs) has long been considered essential to Arp2/3 complex activity, we recently showed that phosphorylation of the Arp2 subunit is also necessary for Arp2/3 complex activation. Using molecular dynamics simulations and biochemical assays with recombinant Arp2/3 complex, we now show how phosphorylation of Arp2 induces conformational changes permitting activation. The simulations suggest that phosphorylation causes reorientation of Arp2 relative to Arp3 by destabilizing a network of salt-bridge interactions at the interface of the Arp2, Arp3, and ARPC4 subunits. Simulations also suggest a gain-of-function ARPC4 mutant that we show experimentally to have substantial activity in the absence of NPFs. We propose a model in which a network of auto-inhibitory salt-bridge interactions holds the Arp2 subunit in an inactive orientation. These auto-inhibitory interactions are destabilized upon phosphorylation of Arp2, allowing Arp2 to reorient to an activation-competent state

Summer Engagement in Cyber Undergraduate Research Experiences (SECURE)

Background: This virtual initiative, called Summer Engagement in Cyber Undergraduate Research Experiences (SECURE), was established as a response to support students who may have lost summer internships and/or have financial hardships due to COVID-19. Several students in the program were NSF S-STEM scholars, a mix of computer engineering, cyber security engineering, electrical engineering and software engineering students.Purpose/Hypothesis: The main question addressed by this initiative was whether we could build a virtual undergraduate research experience that enabled students to apply their studies and knowledge similarly as they would in a traditional summer internship. Goals for the experience included providing small-group mentoring as well as broader opportunities for students to learn about design and research skills and to collaborate across projects.Design/Method: Sixteen paid students were assigned to one of ten projects. Several students were classified as sophomores, and others were more advanced. Projects were proposed by faculty mentors with an emphasis on the development of educational experiences using research and/or design approaches. Several projects revolved around cyber security. We introduced students to the research process, while adapting to the limitations of a virtual program. While our main goal was to support students and provide summer work, we also made progress on projects that were established before the program.Results: The SECURE program operated from May 18 through July 31, 2020. The program was funded using funds remaining in an NSF grant with the approval of the program manager. It was successfully implemented through the concerted efforts of faculty, staff and graduate students to rapidly set up program operations. The goals for the program were met, and the feedback from the students and mentors were very positive.Conclusions: We demonstrated it is possible to rapidly build a virtual internship program to meet student needs, and we are working to obtain funding to continue the project next summer. The future goal will be to offer a hybrid model where students can be virtual or a combination of virtual and on-campus

Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study

Objective To examine the association between chronic use of proton pump inhibitors (PPIs) and risk of hip fracture

Tau repeat regions contain conserved histidine residues that modulate microtubule-binding in response to changes in pH.

Tau, a member of the MAP2/tau family of microtubule-associated proteins, stabilizes and organizes axonal microtubules in healthy neurons. In neurodegenerative tauopathies, tau dissociates from microtubules and forms neurotoxic extracellular aggregates. MAP2/tau family proteins are characterized by three to five conserved, intrinsically disordered repeat regions that mediate electrostatic interactions with the microtubule surface. Here, we used molecular dynamics, microtubule-binding experiments, and live-cell microscopy, revealing that highly-conserved histidine residues near the C terminus of each microtubule-binding repeat are pH sensors that can modulate tau-microtubule interaction strength within the physiological intracellular pH range. We observed that at low pH (<7.5), these histidines are positively charged and interact with phenylalanine residues in a hydrophobic cleft between adjacent tubulin dimers. At higher pH (>7.5), tau deprotonation decreased binding to microtubules both in vitro and in cells. Electrostatic and hydrophobic characteristics of histidine were both required for tau-microtubule binding, as substitutions with constitutively and positively charged nonaromatic lysine or uncharged alanine greatly reduced or abolished tau-microtubule binding. Consistent with these findings, tau-microtubule binding was reduced in a cancer cell model with increased intracellular pH but was rapidly restored by decreasing the pH to normal levels. These results add detailed insights into the intracellular regulation of tau activity that may be relevant in both normal and pathological conditions

Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding

Newly generated actin free barbed ends at the front of motile cells provide sites for actin filament assembly driving membrane protrusion. Growth factors induce a rapid biphasic increase in actin free barbed ends, and we found both phases absent in fibroblasts lacking H+ efflux by the Na-H exchanger NHE1. The first phase is restored by expression of mutant cofilin-H133A but not unphosphorylated cofilin-S3A. Constant pH molecular dynamics simulations and nuclear magnetic resonance (NMR) reveal pH-sensitive structural changes in the cofilin C-terminal filamentous actin binding site dependent on His133. However, cofilin-H133A retains pH-sensitive changes in NMR spectra and severing activity in vitro, which suggests that it has a more complex behavior in cells. Cofilin activity is inhibited by phosphoinositide binding, and we found that phosphoinositide binding is pH-dependent for wild-type cofilin, with decreased binding at a higher pH. In contrast, phosphoinositide binding by cofilin-H133A is attenuated and pH insensitive. These data suggest a molecular mechanism whereby cofilin acts as a pH sensor to mediate a pH-dependent actin filament dynamics

The Grizzly, November 4, 1983

Got a Career? • Convocation Set • Visser Conducts Forum • Ursinus Awaits Celebration • Letters to the Editor: Grenada • Forums Finally Finish • Sixteenth-Century Play to Finish • Sports Medicine - It\u27s Where It\u27s At! • College With a Difference? • Reformation Discussed • Creedence Revived • What is Treaty of Paris? • Japanese Exchange Program Offered • Grizzlies Pull Off Stunning Victory • UC Soccer Awaits ECAC Play • X-Country Caps \u2783 Seasonhttps://digitalcommons.ursinus.edu/grizzlynews/1106/thumbnail.jp

Self-Care for the Prevention and Management of Cardiovascular Disease and Stroke: A Scientific Statement for Healthcare Professionals from the American Heart Association

Self‐care is defined as a naturalistic decision‐making process addressing both the prevention and management of chronic illness, with core elements of self‐care maintenance, self‐care monitoring, and self‐care management. In this scientific statement, we describe the importance of self‐care in the American Heart Association mission and vision of building healthier lives, free of cardiovascular diseases and stroke. The evidence supporting specific self‐care behaviors such as diet and exercise, barriers to self‐care, and the effectiveness of self‐care in improving outcomes is reviewed, as is the evidence supporting various individual, family‐based, and community‐based approaches to improving self‐care. Although there are many nuances to the relationships between self‐care and outcomes, there is strong evidence that self‐care is effective in achieving the goals of the treatment plan and cannot be ignored. As such, greater emphasis should be placed on self‐care in evidence‐based guidelines