Plasticity of ether lipids promotes ferroptosis susceptibility and evasion.

Ferroptosis-an iron-dependent, non-apoptotic cell death process-is involved in various degenerative diseases and represents a targetable susceptibility in certain cancers1. The ferroptosis-susceptible cell state can either pre-exist in cells that arise from certain lineages or be acquired during cell-state transitions2-5. However, precisely how susceptibility to ferroptosis is dynamically regulated remains poorly understood. Here we use genome-wide CRISPR-Cas9 suppressor screens to identify the oxidative organelles peroxisomes as critical contributors to ferroptosis sensitivity in human renal and ovarian carcinoma cells. Using lipidomic profiling we show that peroxisomes contribute to ferroptosis by synthesizing polyunsaturated ether phospholipids (PUFA-ePLs), which act as substrates for lipid peroxidation that, in turn, results in the induction of ferroptosis. Carcinoma cells that are initially sensitive to ferroptosis can switch to a ferroptosis-resistant state in vivo in mice, which is associated with extensive downregulation of PUFA-ePLs. We further find that the pro-ferroptotic role of PUFA-ePLs can be extended beyond neoplastic cells to other cell types, including neurons and cardiomyocytes. Together, our work reveals roles for the peroxisome-ether-phospholipid axis in driving susceptibility to and evasion from ferroptosis, highlights PUFA-ePL as a distinct functional lipid class that is dynamically regulated during cell-state transitions, and suggests multiple regulatory nodes for therapeutic interventions in diseases that involve ferroptosis.

Rapid cooling via dry ice preserves the genetic and morphological integrity of fish embryos.

Larval fishes provide a valuable metric for assessing and monitoring species, populations, and ecosystem trends and condition. However, taxonomic resolution for this life stage is inherently problematic because of their individual sizes, limited morphological characteristics and high tissue degradation rates. There is little research on methods that rapidly preserve larval tissues for later morphological and molecular identification. The goal of this study was to test methods of rapidly killing fish embryos that maintain both morphological and molecular integrity. Rapid cooling with dry ice successfully maintained morphological and molecular integrity and may offer a simple and cost-effective approach for larval fish identification.

How Should We Respond to Health Sector Emissions That Exacerbate Climate Change and Inequity?

A warming climate poses substantial risk to public health and worsens existing health inequity. As a contributor to greenhouse gas emissions and air pollution, the health sector has obligations and ample opportunities to protect health by decreasing waste and motivating more system-wide sustainable clinical practices. Such efforts will have important ethical implications for health equity.

Intraoperative Sensory Signals Predict Prognosis for Patients with Traumatic Cervical Spinal Cord Injury.

OBJECTIVE: In patients with traumatic cervical spinal cord injury (tCSCI), the potential role of intraoperative neuromonitoring as a prognostic tool has been insufficiently studied. This study aimed to determine if detectable signals during intraoperative neuromonitoring portend a greater likelihood of recovery for patients with tCSCI. METHODS: Patients who underwent decompression and surgical fixation following tCSCI were retrospectively reviewed through previously prospectively collected data from the Surgical Timing in Acute Spinal Cord Injury Study. Improvement in American Spinal Injury Association (ASIA) motor score and ASIA Impairment Scale grade conversion rates at final follow-up were compared between patients with detectable intraoperative neuromonitoring somatosensory evoked potential (SSEP) signals and those without detectable signals. RESULTS: Forty-nine patients had intraoperative neuromonitoring. Patients with incomplete tCSCI had detectable lower extremity SSEPs more often than patients with complete tCSCI (56.3% vs. 23.5%, P = 0.028). There was no difference in detectable upper extremity SSEPs between complete and incomplete tCSCI (65.6% vs. 58.8%, P = 0.638). Of the 17 patients with complete tCSCI, patients with detectable lower extremity SSEPs had ASIA motor scores similar to the nondetectable cohort on admission (21.5 vs. 16.2, P = 0.609) but higher ASIA motor scores at final follow-up (57.5 vs. 27.1, P = 0.041). Of the 32 patients with incomplete spinal cord injury, there was no difference in grade conversion or motor scores between detectable and nondetectable SSEP cohorts. CONCLUSIONS: The presence of upper extremity SSEP signals in patients who present with complete tCSCI portends greater improvement in ASIA motor scores and likelihood of American Spinal Injury Association Impairment Scale grade conversion at final follow-up.

Robot-Assisted Endocrine Surgery: Indications and Drawbacks.

BACKGROUND: Over the last few decades, robotic surgery with the da Vinci system has become increasingly prevalent. Endocrine surgeons are witnessing a rapid growth in enthusiasm for robotic approaches for treating thyroid, parathyroid, and adrenal disease. For carefully selected patients, the robotic system may be the preferred technique, although its use remains controversial and indications are in evolution. The goal of this article is to review current robotic procedures for thyroidectomy, parathyroidectomy, and adrenalectomy, and scrutinize the existing literature for application of these approaches. METHODS: We systematically searched and reviewed relevant articles on PubMed and MEDLINE databases for robotic or robot-assisted thyroidectomy, parathyroidectomy, or adrenalectomy. RESULTS: The safety and feasibility for robotic thyroidectomy, parathyroidectomy, and adrenalectomy have been repeatedly demonstrated. Although robotic thyroid and parathyroid surgery offers better cosmetic results compared to the conventional open operation, remote-access techniques introduce new risks. Similar outcomes have been reported for laparoscopic and robotic adrenalectomy, but robot-assisted techniques may extend the capabilities of minimally invasive surgery, particularly performing subtotal adrenalectomy. CONCLUSIONS: While robotic procedures offer better ergonomics for the endocrine surgeon and improved cosmesis for the patient, the major drawback to the robot system almost universally is the higher cost. With new robotically assisted surgical devices on the way that could drive down costs and speed up innovation, the indications for robotic endocrine surgery may greatly expand.

Complementary Effects of Host Defense Peptides Piscidin 1 and Piscidin 3 on DNA and Lipid Membranes: Biophysical Insights into Contrasting Biological Activities.

Piscidins were the first antimicrobial peptides discovered in the mast cells of vertebrates. While two family members, piscidin 1 (p1) and piscidin 3 (p3), have highly similar sequences and α-helical structures when bound to model membranes, p1 generally exhibits stronger antimicrobial and hemolytic activity than p3 for reasons that remain elusive. In this study, we combine activity assays and biophysical methods to investigate the mechanisms underlying the cellular function and differing biological potencies of these peptides, and report findings spanning three major facets. First, added to Gram-positive (Bacillus megaterium) and Gram-negative (Escherichia coli) bacteria at sublethal concentrations and imaged by confocal microscopy, both p1 and p3 translocate across cell membranes and colocalize with nucleoids. In E. coli, translocation is accompanied by nonlethal permeabilization that features more pronounced leakage for p1. Second, p1 is also more disruptive than p3 to bacterial model membranes, as quantified by a dye-leakage assay and (2)H solid-state NMR-monitored lipid acyl chain order parameters. Oriented CD studies in the same bilayers show that, beyond a critical peptide concentration, both peptides transition from a surface-bound state to a tilted orientation. Third, gel retardation experiments and CD-monitored titrations on isolated DNA demonstrate that both peptides bind DNA but p3 has stronger condensing effects. Notably, solid-state NMR reveals that the peptides are α-helical when bound to DNA. Overall, these studies identify two polyreactive piscidin isoforms that bind phosphate-containing targets in a poised amphipathic α-helical conformation, disrupt bacterial membranes, and access the intracellular constituents of target cells. Remarkably, the two isoforms have complementary effects; p1 is more membrane active, while p3 has stronger DNA-condensing effects. Subtle differences in their physicochemical properties are highlighted to help explain their contrasting activities.