2'3'-cGAMP interactome identifies 2'3'-cGAMP/Rab18/FosB signaling in cell migration control independent of innate immunity.

c-di-GAMP was first identified in bacteria to promote colonization, while mammalian 2'3'-cGAMP is synthesized by cGAS to activate STING for innate immune stimulation. However, 2'3'-cGAMP function beyond innate immunity remains elusive. Here, we report that 2'3'-cGAMP promotes cell migration independent of innate immunity.

Molecular and Functional Profiling of Gαi as an Intracellular pH Sensor.

Heterotrimeric G proteins (Gα, Gβ and Gγ) act downstream of G-protein-coupled receptors (GPCRs) to mediate signaling pathways that regulate various physiological processes and human disease conditions. Previously, human Gαi and its yeast homolog Gpa1 have been reported to function as intracellular pH sensors, yet the pH sensing capabilities of Gαi and the underlying mechanism remain to be established. Herein, we identify a pH sensing network within Gαi, and evaluate the consequences of pH modulation on the structure and stability of the G-protein.

Understanding the perspectives and needs of multiple stakeholders: Identifying key elements of a digital health intervention to protect against environmental hazards.

AirRater is a free environmental health smartphone app developed and available in Australia that collects individual health data and disseminates environmental hazard information to populations. Following previous evaluations with app users, the aim of this study was to better understand how clinicians, government agency and non-government advocacy group representatives perceive an app designed to reduce the impacts of environmental hazards on individual and public health. Nine government agency and non-government advocacy group representatives, along with 11 clinicians based in Australia participated in a semi-structured interview or focus group to explore perspectives on AirRater.

Molecular basis and cellular functions of vinculin-actin directional catch bonding.

The ability of cells and tissues to respond differentially to mechanical forces applied in distinct directions is mediated by the ability of load-bearing proteins to preferentially maintain physical linkages in certain directions. However, the molecular basis and biological consequences of directional force-sensitive binding remain unclear. Vinculin (Vcn) is a load-bearing linker protein that exhibits directional catch bonding due to interactions between the Vcn tail domain (Vt) and filamentous (F)-actin.

Methods of Assessing Health Care Costs in a Changing Climate: A Case Study of Heatwaves and Ambulance Dispatches in Tasmania, Australia.

Anthropogenic climate change is causing a rise in global temperatures, with this trend projected to increase into the future. Rising temperatures result in an increase in the frequency and severity of heatwave events, with an associated increase in poor health outcomes for vulnerable individuals. This places an increasing strain on health care services.

Catalytic site mutations confer multiple states of G protein activation.

Heterotrimeric guanine nucleotide-binding proteins (G proteins) that function as molecular switches for cellular growth and metabolism are activated by GTP and inactivated by GTP hydrolysis. In uveal melanoma, a conserved glutamine residue critical for GTP hydrolysis in the G protein α subunit is often mutated in Gα or Gα to either leucine or proline. In contrast, other glutamine mutations or mutations in other Gα subtypes are rare.

Elucidation of the Molecular Basis and Cellular Functions of Vinculin-Actin Directional Catch Bonding.

The ability of cells and tissues to differentially resist or adapt to mechanical forces applied in distinct directions is mediated by the ability of load-bearing proteins to preferentially maintain physical linkages in certain directions. However, the molecular basis and biological consequences of directional force-sensitive binding are unclear. Vinculin (Vcn) is a load-bearing linker protein that exhibits directional catch bonding due to interactions between the Vcn tail domain (Vt) and filamentous (F)-actin.

Evaluating User Preferences, Comprehension, and Trust in Apps for Environmental Health Hazards: Qualitative Case Study.

Background: Climate change is projected to increase environmental health hazard risks through fire-related air pollution and increased airborne pollen levels. To protect vulnerable populations, it is imperative that evidence-based and accessible interventions are available. The environmental health app, AirRater, was developed in 2015 in Australia to provide information on multiple atmospheric health hazards in near real time.

Functional and biological heterogeneity of KRAS mutations.

Missense mutations at the three hotspots in the guanosine triphosphatase (GTPase) RAS-Gly, Gly, and Gln (commonly known as G12, G13, and Q61, respectively)-occur differentially among the three RAS isoforms. Q61 mutations in are infrequent and differ markedly in occurrence. Q61H is the predominant mutant (at 57%), followed by Q61R/L/K (collectively 40%), and Q61P and Q61E are the rarest (2 and 1%, respectively).

Oncogenic KRAS G12C: Kinetic and redox characterization of covalent inhibition.

The recent development of mutant-selective inhibitors for the oncogenic KRAS allele has generated considerable excitement. These inhibitors covalently engage the mutant C12 thiol located within the phosphoryl binding loop of RAS, locking the KRAS protein in an inactive state. While clinical trials of these inhibitors have been promising, mechanistic questions regarding the reactivity of this thiol remain.

Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation.

A distinct profile of NRAS mutants is observed in each tumor type. It is unclear whether these profiles are determined by mutagenic events or functional differences between NRAS oncoproteins. Here, we establish functional hallmarks of NRAS mutants enriched in human melanoma.

Post-translational modification of RAS proteins.

Mutations of RAS genes drive cancer more frequently than any other oncogene. RAS proteins integrate signals from a wide array of receptors and initiate downstream signaling through pathways that control cellular growth. RAS proteins are fundamentally binary molecular switches in which the off/on state is determined by the binding of GDP or GTP, respectively.

Divergent Mechanisms Activating RAS and Small GTPases Through Post-translational Modification.

RAS is a founding member of the RAS superfamily of GTPases. These small 21 kDa proteins function as molecular switches to initialize signaling cascades involved in various cellular processes, including gene expression, cell growth, and differentiation. RAS is activated by GTP loading and deactivated upon GTP hydrolysis to GDP.

Ambulance dispatches and heatwaves in Tasmania, Australia: A case-crossover analysis.

Background: Climate change is causing an increase in the frequency and severity of heatwave events, with a corresponding negative impact on human health. Health service utilisation during a heatwave is increased, with a greater risk of poor health outcomes identified for specific population groups. In this study, we examined the impact of heatwave events on ambulance dispatches in Tasmania, Australia from 2008 to 2019 to explore health service utilisation and identify the most vulnerable populations at a local level.

Characterising non-linear associations between airborne pollen counts and respiratory symptoms from the AirRater smartphone app in Tasmania, Australia: A case time series approach.

Pollen is a well-established trigger of asthma and allergic rhinitis, yet concentration-response relationships, lagged effects, and interactions with other environmental factors remain poorly understood. Smartphone technology offers an opportunity to address these challenges using large, multi-year datasets that capture individual symptoms and exposures in real time. We aimed to characterise associations between six pollen types and respiratory symptoms logged by users of the AirRater smartphone app in Tasmania, Australia.

Monoubiquitination of KRAS at Lysine104 and Lysine147 Modulates Its Dynamics and Interaction with Partner Proteins.

KRAS, a 21 kDa guanine nucleotide-binding protein that functions as a molecular switch, plays a key role in regulating cellular growth. Dysregulation of this key signaling node leads to uncontrolled cell growth, a hallmark of cancer cells. KRAS undergoes post-translational modification by monoubiquitination at various locations, including at lysine104 (K104) and lysine147 (K147).

Environmental Hazards and Behavior Change: User Perspectives on the Usability and Effectiveness of the AirRater Smartphone App.

AirRater is a free smartphone app developed in 2015, supporting individuals to protect their health from environmental hazards. It does this by providing (i) location-specific and near real-time air quality, pollen and temperature information and (ii) personal symptom tracking functionality. This research sought to evaluate user perceptions of AirRater's usability and effectiveness.

A universal allosteric mechanism for G protein activation.

G proteins play a central role in signal transduction and pharmacology. Signaling is initiated by cell-surface receptors, which promote guanosine triphosphate (GTP) binding and dissociation of Gα from the Gβγ subunits. Structural studies have revealed the molecular basis of subunit association with receptors, RGS proteins, and downstream effectors.

Biophysical and Structural Characterization of Novel RAS-Binding Domains (RBDs) of PI3Kα and PI3Kγ.

Phosphatidylinositol-3-kinases (PI3Ks) are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate to generate a key lipid second messenger, phosphatidylinositol 3,4,5-bisphosphate. PI3Kα and PI3Kγ require activation by RAS proteins to stimulate signaling pathways that control cellular growth, differentiation, motility and survival. Intriguingly, RAS binding to PI3K isoforms likely differ, as RAS mutations have been identified that discriminate between PI3Kα and PI3Kγ, consistent with low sequence homology (23%) between their RAS binding domains (RBDs).

Public Health Messaging During Extreme Smoke Events: Are We Hitting the Mark?

Emergency services working to protect communities from harm during wildfires aim to provide regular public advisories on the hazards from fire and smoke. However, there are few studies evaluating the success of public health communications regarding the management of smoke exposure. We explored the responses to smoke-related health advisories of people living in a severely smoke-affected region during extensive wildfires in Tasmania, Australia early in 2019.

KRAS Ubiquitination at Lysine 104 Retains Exchange Factor Regulation by Dynamically Modulating the Conformation of the Interface.

RAS proteins function as highly regulated molecular switches that control cellular growth. In addition to regulatory proteins, RAS undergoes a number of posttranslational modifications (PTMs) that regulate its activity. Lysine 104, a hot spot for multiple PTMs, is a highly conserved residue that forms key interactions that stabilize the RAS helix-2(H2)/helix-3(H3) interface.

The molecular basis for immune dysregulation by the hyperactivated E62K mutant of the GTPase RAC2.

The RAS-related C3 botulinum toxin substrate 2 (RAC2) is a member of the RHO subclass of RAS superfamily GTPases required for proper immune function. An activating mutation in a key switch II region of RAC2 (RAC2) involved in recognizing modulatory factors and effectors has been identified in patients with common variable immune deficiency. To better understand how the mutation dysregulates RAC2 function, we evaluated the structure and stability, guanine nucleotide exchange factor (GEF) and GTPase-activating protein (GAP) activity, and effector binding of RAC2 Our findings indicate the E62K mutation does not alter RAC2 structure or stability.

Can smartphone data identify the local environmental drivers of respiratory disease?

Asthma and allergic rhinitis (or hay fever) are ubiquitous, chronic health conditions that seasonally affect a sizeable proportion of the population. Both are commonly triggered or exacerbated by environmental conditions including aeroallergens, air quality and weather. Smartphone technology offers new opportunities to identify environmental drivers by allowing large-scale, real-time collection of day-to-day symptoms.