Harold Ridley and the Invention of the Intraocular Lens: a Reappraisal: Harold Ridley and the Invention of the Intraocular Lens.

Harold Ridley permanently implanted the first intraocular lens (IOL) in 1950. The widely accepted narrative is that Ridley and his invention received a hostile reception from Stewart Duke-Elder and other ophthalmic thought leaders. Ridley suffered greatly but was eventually vindicated as later IOL designs were widely accepted.

Flexible fluorine-thiol displacement stapled peptides with enhanced membrane penetration for the estrogen receptor/coactivator interaction.

Understanding how natural and engineered peptides enter cells would facilitate the elucidation of biochemical mechanisms underlying cell biology and is pivotal for developing effective intracellular targeting strategies. In this study, we demonstrate that our peptide stapling technique, fluorine-thiol displacement reaction (FTDR), can produce flexibly constrained peptides with significantly improved cellular uptake, particularly into the nucleus. This platform confers enhanced flexibility, which is further amplified by the inclusion of a D-amino acid, while maintaining environment-dependent α helicity, resulting in highly permeable peptides without the need for additional cell-penetrating motifs.

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.

Work Intensity of Postoperative Care Following Implantation of Presbyopia-Correcting versus Monofocal Intraocular Lenses.

Purpose: To compare the work intensity of postoperative care following implantation of presbyopia-correcting intraocular lenses (IOLs) to that of standard monofocal IOLs.

Patients And Methods: This open-label, multicenter, comparative study retrospectively reviewed the case records of cataract surgery patients who underwent bilateral implantation of either presbyopia-correcting IOLs (presby-IOL group; N=177) or standard monofocal IOLs (monofocal group; N=177). Outcome measures included the total time the patient spent in the office, number of visits, mean duration of visits, and the number of procedures and diagnostic tests during the first postoperative year.

Triphenylphosphine oxide promoting visible-light-driven C-C coupling desulfurization.

Triphenylphosphine oxide (TPPO) and triphenylphosphine (TPP) can form a complex in solution, promoting visible light absorption to trigger electron transfer within the complex and generate radicals. Subsequent radical reactions with thiols enable desulfurization to produce carbon radicals that react with aryl alkenes to yield new C-C bonds. Since ambient oxygen can easily oxidize TPP to TPPO, the reported method requires no explicit addition of a photocatalyst.

Fluorine-thiol displacement probes for acetaminophen's hepatotoxicity.

Chemicals possessing reactive electrophiles can denature innate proteins leading to undesired toxicity, and the overdose-induced liver injury by drugs containing electrophiles has been one of the major causes of non-approval and withdraw by the US Food and Drug Administration (FDA). Elucidating the associated proteins could guide the future development of therapeutics to circumvent these drugs' toxicities, but was largely limited by the current probing tools due to the steric hindrance of chemical tags including the common "click chemistry" labels. Taking the widely used non-steroidal anti-inflammatory drug acetaminophen (APAP) as an example, we hereby designed and synthesized an APAP analogue using fluorine as a steric-free label.

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.

An analysis of pharmacists' workplace patient safety perceptions across practice setting and role characteristics.

Background: Lay press investigations have been published that describe pharmacist errors and the workplace environment in the community pharmacy setting. However, recent studies that explore pharmacists' perceptions of patient safety in the workplace are limited.

Objectives: 1) To describe pharmacists' perceptions of workplace patient safety; 2) To compare pharmacists' perceptions of workplace patient safety across practice setting type, pharmacist roles, average hours worked per shift, and average hours worked per week.

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.

Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction.

We report the discovery of a facile peptide macrocyclization and stapling strategy based on a fluorine thiol displacement reaction (FTDR), which renders a class of peptide analogues with enhanced stability, affinity, cellular uptake, and inhibition of cancer cells. This approach enabled selective modification of the orthogonal fluoroacetamide side chains in unprotected peptides in the presence of intrinsic cysteines. The identified benzenedimethanethiol linker greatly promoted the alpha helicity of a variety of peptide substrates, as corroborated by molecular dynamics simulations.

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.