Drift in Individual Behavioral Phenotype as a Strategy for Unpredictable Worlds.

Unlabelled: Individuals, even with matched genetics and environment, show substantial phenotypic variability. This variability may be part of a bet-hedging strategy, where populations express a range of phenotypes to ensure survival in unpredictable environments. In addition phenotypic variability between individuals ("bet-hedging"), individuals also show variability in their phenotype across time, even absent external cues.

Disruption of Ca/calmodulin:KSR1 interaction lowers ERK activation.

KSR1, a key scaffold protein for the MAPK pathway, facilitates ERK activation upon growth factor stimulation. We recently demonstrated that KSR1 binds the Ca-binding protein calmodulin (CaM), thereby providing an intersection between KSR1-mediated and Ca signaling. In this study, we set out to generate a KSR1 point mutant with reduced Ca/CaM binding in order to unravel the functional implications of their interaction.

Efficacy and specificity of melanopsin reporters for retinal ganglion cells.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) are specialized retinal output neurons that mediate behavioral, neuroendocrine, and developmental responses to environmental light. There are diverse molecular strategies for marking ipRGCs, especially in mice, making them among the best characterized retinal ganglion cells (RGCs). With the development of more sensitive reporters, new subtypes of ipRGCs have emerged.

A high-throughput, 28-day, microfluidic model of gingival tissue inflammation and recovery.

Nearly half of American adults suffer from gum disease, including mild inflammation of gingival tissue, known as gingivitis. Currently, advances in therapeutic treatments are hampered by a lack of mechanistic understanding of disease progression in physiologically relevant vascularized tissues. To address this, we present a high-throughput microfluidic organ-on-chip model of human gingival tissue containing keratinocytes, fibroblast and endothelial cells.

Precise Quantification of Behavioral Individuality From 80 Million Decisions Across 183,000 Flies.

Individual animals behave differently from each other. This variability is a component of personality and arises even when genetics and environment are held constant. Discovering the biological mechanisms underlying behavioral variability depends on efficiently measuring individual behavioral bias, a requirement that is facilitated by automated, high-throughput experiments.

The structural basis of BCR-ABL recruitment of GRB2 in chronic myelogenous leukemia.

BCR-ABL drives chronic myeloid leukemia (CML). BCR binding to GRB2 transduces signaling via the Ras/MAPK pathway. Despite considerable data confirming the binding, molecular-level understanding of exactly how the two proteins interact, and, especially, what are the determinants of the specificity of the SH2 domain-phosphorylated BCR (pBCR) recognition are still open questions.

The mechanism of activation of MEK1 by B-Raf and KSR1.

MEK1 interactions with B-Raf and KSR1 are key steps in Ras/Raf/MEK/ERK signaling. Despite this, vital mechanistic details of how these execute signal transduction are still enigmatic. Among these is why, despite B-Raf and KSR1 kinase domains similarity, the B-Raf/MEK1 and KSR1/MEK1 complexes have distinct contributions to MEK1 activation, and broadly, what is KSR1's role.

Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.

Here, we discuss the principles of allosteric activating mutations, propagation downstream of the signals that they prompt, and allosteric drugs, with examples from the Ras signaling network. We focus on Abl kinase where mutations shift the landscape toward the active, imatinib binding-incompetent conformation, likely resulting in the high affinity ATP outcompeting drug binding. Recent pharmacological innovation extends to allosteric inhibitor (GNF-5)-linked PROTAC, targeting Bcr-Abl1 myristoylation site, and broadly, allosteric heterobifunctional degraders that destroy targets, rather than inhibiting them.

Gastrectomy mortality in Australia.

Background: Despite advances in medical management and endoscopic therapy, gastrectomy remains an important yet high-risk procedure for a range of benign and malignant upper gastrointestinal pathologies. No study has previously analysed Australian gastrectomy perioperative mortality rate (POMR). This retrospective, population-based cohort study was conducted to determine the Australian national gastrectomy POMR, allowing state-based and regional trends and outcomes to be assessed.

The mechanism of Raf activation through dimerization.

Raf, a threonine/serine kinase in the Raf/MEK/ERK pathway, regulates cell proliferation. Raf's full activation requires dimerization. Aberrant activation through dimerization is an important therapeutic target.

Neuromodulation and Individuality.

Within populations, individuals show a variety of behavioral preferences, even in the absence of genetic or environmental variability. Neuromodulators affect these idiosyncratic preferences in a wide range of systems, however, the mechanism(s) by which they do so is unclear. I review the evidence supporting three broad mechanisms by which neuromodulators might affect variability in idiosyncratic behavioral preference: by being a source of variability directly upstream of behavior, by affecting the behavioral output of a circuit in a way that masks or accentuates underlying variability in that circuit, and by driving plasticity in circuits leading to either homeostatic convergence toward a given behavior or divergence from a developmental setpoint.

Mechanism of activation and the rewired network: New drug design concepts.

Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism.

The associations of factors with previous alcohol use in the Northern Territory compared to other states - an observational study.

Background: Data on previous alcohol use in surgical patients who died in the Northern Territory (NT) are lacking and have important public health implications.

Methods: The prevalence of previous alcohol (ab)use among surgical patients who died (n=560) was assessed in patients within the Northern Territory and the remainder of Australia (n=28,245) over nine years.

Results: The likelihood of previous alcohol use (21.

Ras isoform-specific expression, chromatin accessibility, and signaling.

The anchorage of Ras isoforms in the membrane and their nanocluster formations have been studied extensively, including their detailed interactions, sizes, preferred membrane environments, chemistry, and geometry. However, the staggering challenge of their epigenetics and chromatin accessibility in distinct cell states and types, which we propose is a major factor determining their specific expression, still awaits unraveling. Ras isoforms are distinguished by their C-terminal hypervariable region (HVR) which acts in intracellular transport, regulation, and membrane anchorage.

The mechanism of activation of monomeric B-Raf V600E.

Oncogenic mutations in the serine/threonine kinase B-Raf, particularly the V600E mutation, are frequent in cancer, making it a major drug target. Although much is known about B-Raf's active and inactive states, questions remain about the mechanism by which the protein changes between these two states. Here, we utilize molecular dynamics to investigate both wild-type and V600E B-Raf to gain mechanistic insights into the impact of the Val to Glu mutation.

Elective abdominal wall hernia repair surgical mortality-A systematic review of the literature and peer review of mortality in Australia.

Background: This study systematically reviewed the literature regarding perioperative mortality in human adults undergoing elective surgical abdominal wall hernia repair, including an audit of the Royal Australasian College of Surgeons (RACS) Australian and New Zealand Audit of Surgical Mortality (ANZASM) database.

Methods: A systematic review was conducted in accordance with PRISMA guidelines for the reporting of systematic reviews and meta-analysis of observational studies. Cochrane Library, PubMed, MEDLINE and Embase database searches and data extraction were conducted from June 1979 to October 2019.

Decoding Neural Responses to Motion-in-Depth Using EEG.

Two stereoscopic cues that underlie the perception of motion-in-depth (MID) are changes in retinal disparity over time (CD) and interocular velocity differences (IOVD). These cues have independent spatiotemporal sensitivity profiles, depend upon different low-level stimulus properties, and are potentially processed along separate cortical pathways. Here, we ask whether these MID cues code for different motion directions: do they give rise to discriminable patterns of neural signals, and is there evidence for their convergence onto a single "motion-in-depth" pathway? To answer this, we use a decoding algorithm to test whether, and when, patterns of electroencephalogram (EEG) signals measured from across the full scalp, generated in response to CD- and IOVD-isolating stimuli moving toward or away in depth can be distinguished.

Clustering and phase separation in mixtures of dipolar and active particles.

The self-assembly of colloidal particles in dynamic environments has become an important field of study because of potential applications in fabricating out-of-equilibrium materials. We investigate the phase behavior of mixtures of passive dipolar colloids and active soft spheres using Brownian dynamics simulations in two dimensions. The phase behaviors exhibited include dipolar percolated network, dipolar string-fluid, isotropic fluid, and a phase-separated state.

Control of Synaptic Specificity by Establishing a Relative Preference for Synaptic Partners.

The ability of neurons to identify correct synaptic partners is fundamental to the proper assembly and function of neural circuits. Relative to other steps in circuit formation such as axon guidance, our knowledge of how synaptic partner selection is regulated is severely limited. Drosophila Dpr and DIP immunoglobulin superfamily (IgSF) cell-surface proteins bind heterophilically and are expressed in a complementary manner between synaptic partners in the visual system.

Asymmetries between achromatic and chromatic extraction of 3D motion signals.

Motion in depth (MID) can be cued by high-resolution changes in binocular disparity over time (CD), and low-resolution interocular velocity differences (IOVD). Computational differences between these two mechanisms suggest that they may be implemented in visual pathways with different spatial and temporal resolutions. Here, we used fMRI to examine how achromatic and S-cone signals contribute to human MID perception.