Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape.

Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, but they induce severe inflammation. Here we show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which regulate downstream inflammation.

Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia.

Macrophages often pervade solid tumors, and clusters of macrophages sometimes associate with longer survival of patients. However, clustering mechanisms and impacts on key functions such as phagocytosis remain obscure. Here, under conditions that maximize cancer cell phagocytosis within cohesive tumors, we uncover pathways that favor dynamic clusters and find a colocalization of tumor-intrusive pseudopodia which we term "intrudopodia.

Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia.

Macrophages often pervade solid tumors, but their nearest neighbor organization is understudied and potentially enables key functions such as phagocytosis. Here, we observe dynamic macrophage clusters in tumors under conditions that maximize cancer cell phagocytosis and use reductionist approaches to uncover pathways to cluster formation and roles for tumor-intrusive pseudopodia, which we term 'intrudopodia'. Macrophage clusters form over hours on low- adhesion substrates after M1 polarization with interferons, including T cell-derived cytokines, and yet clusters prove fluid on timescales of minutes.

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects.

Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions.

Differences in cell shape, motility, and growth reflect chromosomal number variations that can be visualized with live-cell ChReporters.

Chromosome numbers often change dynamically in tumors and cultured cells, which complicates therapy as well as understanding genotype-mechanotype relationships. Here we use a live-cell "ChReporter" method to identify cells with a single chromosomal loss in efforts to better understand differences in cell shape, motility, and growth. We focus on a standard cancer line and first show clonal populations that retain the ChReporter exhibit large differences in cell and nuclear morphology as well as motility.

Small lipid droplets are rigid enough to indent a nucleus, dilute the lamina, and cause rupture.

The nucleus in many cell types is a stiff organelle, but fat-filled lipid droplets (FDs) in cytoplasm are seen to indent and displace the nucleus. FDs are phase-separated liquids with a poorly understood interfacial tension γ that determines how FDs interact with other organelles. Here, micron-sized FDs remain spherical as they indent peri-nuclear actomyosin and the nucleus, while causing local dilution of Lamin-B1 independent of Lamin-A,C and sometimes triggering nuclear rupture.

Rare Adult-onset Citrullinemia Type 1 in the Postpartum Period: A Case Report.

Introduction: Citrullinemia type 1 (CTLN1) is a urea cycle disorder caused by defective argininosuccinate synthetase leading to impaired ammonia elimination. Urea cycle disorders are typically diagnosed on neonatal screening but rarely can lie dormant until a metabolic stressor causes initial onset of symptoms in adulthood.

Case Report: A 23-year-old female presented four days postpartum to the emergency department (ED) obtunded and declined to the point of requiring intubation.

CD47-SIRPα Checkpoint Disruption in Metastases Requires Tumor-Targeting Antibody for Molecular and Engineered Macrophage Therapies.

The macrophage checkpoint interaction CD47-SIRPα is an emerging target for cancer therapy, but clinical trials of monoclonal anti-CD47 show efficacy only in liquid tumors when combined with tumor-opsonizing IgG. Here, in challenging metastatic solid tumors, CD47 deletion shows no effect on tumor growth unless combined with otherwise ineffective tumor-opsonization, and we likewise show wild-type metastases are suppressed by SIRPα-blocked macrophages plus tumor-opsonization. Lung tumor nodules of syngeneic B16F10 melanoma cells with CD47 deletion show opsonization drives macrophage phagocytosis of B16F10s, consistent with growth versus phagocytosis calculus for exponential suppression of cancer.

Suppressing or Enhancing Macrophage Engulfment through the Use of CD47 and Related Peptides.

Foreign particles and microbes are rapidly cleared by macrophages , although many key aspects of uptake mechanisms remain unclear. "Self" cells express CD47 which functions as an anti-phagocytic ligand for SIRPα on macrophages, particularly when pro-phagocytic ligands such as antibodies are displayed in parallel. Here, we review CD47 and related "Self" peptides as modulators of macrophage uptake.

Gaussian curvature dilutes the nuclear lamina, favoring nuclear rupture, especially at high strain rate.

Nuclear rupture has long been associated with deficits or defects in lamins, with recent results also indicating a role for actomyosin stress, but key physical determinants of rupture remain unclear. Here, lamin-B filaments stably interact with the nuclear membrane at sites of low Gaussian curvature yet dilute at high curvature to favor rupture, whereas lamin-A depletion requires high strain-rates. Live-cell imaging of lamin-B1 gene-edited cancer cells is complemented by fixed-cell imaging of rupture in: iPS-derived progeria patients cells, cells within beating chick embryo hearts, and cancer cells with multi-site rupture after migration through small pores.

New Versus Old, The i-View Video Laryngoscope Versus the GlideScope: A Prospective, Randomized, Crossover Trial.

Background: A novel video laryngoscope device, the i-view, may extend intubation capability to the lowest echelons of deployed military medicine. The i-view is a one-time use, disposable laryngoscope. We compared time to completion of endotracheal intubation (ETI) between the i-view and GlideScope among military emergency medicine providers in a simulation setting.

Optimal allocation in annual plants with density-dependent fitness.

We study optimal two-sector (vegetative and reproductive) allocation models of annual plants in temporally variable environments that incorporate effects of density-dependent lifetime variability and juvenile mortality in a fitness function whose expected value is maximized. Only special cases of arithmetic and geometric mean maximizers have previously been considered in the literature, and we also allow a wider range of production functions with diminishing returns. The model predicts that the time of maturity is pushed to an earlier date as the correlation between individual lifetimes increases, and while optimal schedules are bang-bang at the extremes, the transition is mediated by schedules where vegetative growth is mixed with reproduction for a wide intermediate range.

The inhibitory impact of ammonia on thermally hydrolyzed sludge fed anaerobic digestion.

This study evaluated the impact of ammonia on mesophilic anaerobic digestion (AD) with thermal hydrolysis pretreatment (THP) treating a mixture of primary sludge and waste activated sludge and operated under constant organic loading rate of 9 kg COD/m /d. Free ammonia concentrations in the digesters were varied between 37 and 966 mg NH -N/L, while maintaining all other operational conditions constant. A decrease in volatile solids reduction from 54 ± 5% (at <554 mg NH -N/L) to 35 ± 6% at the maximum free ammonia concentration of 966 mg NH -N/L was observed at steady-state conditions.

Utility of Nonspecific Laboratory Testing for Psychiatric Patients Undergoing Medical Screening in a Military Emergency Department.

Introduction: Psychiatric complaints account for a sizable and increasing portion of emergency department (ED) visits. Compared with other medical patients, these patients often require substantial resources because of limited specialized resources and prolonged boarding times, which can be detrimental to the safety and satisfaction of other patients. This can prompt early and indiscriminate laboratory testing to expedite early requests for admission consideration.

Starch storage capacity of sapwood is related to dehydration avoidance during drought.

Premise: The xylem tissue of plants performs three principal functions: transport of water, support of the plant body, and nutrient storage. Tradeoffs may arise because different structural requirements are associated with different functions or because suites of traits are under selection that relate to resource acquisition, use, and turnover. The structural and functional basis of xylem storage is not well established.

Unusual Case of Acute Decompensated Maple Syrup Urine Disease in the Emergency Department.

A case report of an army soldier presenting to the emergency department with acute metabolic derangement resulting in encephalopathy, cerebral edema, and death is presented. The patient had no medical diagnoses before entering military service and was triaged in the emergency department with the common complaint of presyncope. However, as encephalopathy worsened, the patient experienced altered mental status, lethargy, emesis, and seizure.

Structural analysis of resting mouse platelets by 3D-EM reveals an unexpected variation in α-granule shape.

Mice and mouse platelets are major experimental models for hemostasis and thrombosis; however, important physiological data from this model has received little to no quantitative, 3D ultrastructural analysis. We used state-of-the-art, serial block imaging scanning electron microscopy (SBF-SEM, nominal Z-step size was 35 nm) to image resting platelets from C57BL/6 mice. α-Granules were identified morphologically and rendered in 3D space.

Canalicular system reorganization during mouse platelet activation as revealed by 3D ultrastructural analysis.

The canalicular system (CS) has been defined as: an inward, invaginated membrane connector that supports entry into and exit from the platelet; a static structure stable during platelet isolation; and the major source of plasma membrane (PM) for surface area expansion during activation. Recent analysis from STEM tomography and serial block face electron microscopy has challenged the relative importance of CS as the route for granule secretion. Here, We used 3D ultrastructural imaging to reexamine the CS in mouse platelets by generating high-resolution 3D reconstructions to test assumptions 2 and 3.

Recuperative thickening for sludge retention time and throughput management in anaerobic digestion with thermal hydrolysis pretreatment.

This study evaluated the application of recuperative thickening (RT) to enhance anaerobic digestion (AD) performance for AD systems with thermal hydrolysis pretreatment (THP). RT was applied for two different reasons: (a) for increasing the sludge retention time (SRT) to degrade slowly hydrolyzable materials more efficiently and (b) for maintaining SRT at decreased hydraulic retention time (HRT) thus showing potential for increased AD throughput rates. A SRT increase from 15 to 30 days by RT application did not improve AD performance or hydrolysis rates significantly as 15-day SRT was already a factor 2 higher than the estimated washout SRT.

A review of genetic factors underlying craniorachischisis and omphalocele: Inspired by a unique trisomy 18 case.

Very few cases of craniorachischisis (CRN) with concomitant omphalocele (OMP) in the setting of trisomy 18 are reported in literature. Solitary midline closure defects are estimated to be more prevalent in trisomy 18 compared to the general population. Neurulation defect comparisons include anencephaly 0-2% versus 0.

SNARE-dependent membrane fusion initiates α-granule matrix decondensation in mouse platelets.

Platelet α-granule cargo release is fundamental to both hemostasis and thrombosis. Granule matrix hydration is a key regulated step in this process, yet its mechanism is poorly understood. In endothelial cells, there is evidence for 2 modes of cargo release: a jack-in-the-box mechanism of hydration-dependent protein phase transitions and an actin-driven granule constriction/extrusion mechanism.