Methylarginine targeting chimeras for lysosomal degradation of intracellular proteins.

A paradigm shift in drug development is the discovery of small molecules that harness the ubiquitin-proteasomal pathway to eliminate pathogenic proteins. Here we provide a modality for targeted protein degradation in lysosomes. We exploit an endogenous lysosomal pathway whereby protein arginine methyltransferases (PRMTs) initiate substrate degradation via arginine methylation.

Human CD99L2 Regulates a Unique Step in Leukocyte Transmigration.

CD99-like 2 (CD99L2 [L2]) is a highly glycosylated 52-kDa type 1 membrane protein that is important for leukocyte transendothelial migration (TEM) in mice. Inhibiting L2 using function-blocking Ab significantly reduces the recruitment of leukocytes to sites of inflammation in vivo. Similarly, L2 knockout mice have an inherent defect in leukocyte transmigration into sites of inflammation.

Optimised polymer trapped-air lenses for ultrasound focusing in water exploiting Fabry-Pérot resonance.

The concept of employing air volumes trapped inside polymer shells to make a lens for ultrasound focusing in water is investigated. The proposed lenses use evenly-spaced concentric rings, each having an air-filled polymer shell construction, defining concentric water-filled channels. Numerical simulations and experiments have shown that a plane wave can be focused, and that the amplification can be boosted by Fabry-Pérot resonances within the water channels with an appropriate choice of the lens thickness.

Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial.

Broad-spectrum antibiotics for suspected early-onset neonatal sepsis (sEONS) may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in the first week of life, during the assembly phase of the neonatal microbiome. Here, 147 infants born at ≥36 weeks of gestational age, requiring broad-spectrum antibiotics for treatment of sEONS in their first week of life were randomized 1:1:1 to receive three commonly prescribed intravenous antibiotic combinations, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime (ZEBRA study, Trial Register NL4882). Average antibiotic treatment duration was 48 hours.

Early-life viral infections are associated with disadvantageous immune and microbiota profiles and recurrent respiratory infections.

The respiratory tract is populated by a specialized microbial ecosystem, which is seeded during and directly following birth. Perturbed development of the respiratory microbial community in early-life has been associated with higher susceptibility to respiratory tract infections (RTIs). Given a consistent gap in time between first signs of aberrant microbial maturation and the observation of the first RTIs, we hypothesized that early-life host-microbe cross-talk plays a role in this process.

Holey-structured tungsten metamaterials for broadband ultrasonic sub-wavelength imaging in water.

Metamaterials exhibiting Fabry-Pérot resonances are shown to achieve ultrasonic imaging of a sub-wavelength aperture in water immersion across a broad bandwidth. Holey-structured metamaterials of different thickness were additively manufactured using a tungsten substrate and selective laser melting, tungsten being chosen so as to create a significant acoustic impedance mismatch with water. Both broadband metamaterial behavior and sub-wavelength imaging in water are demonstrated experimentally and validated with finite element simulations over the 200-300 kHz range.

High Incidence of Barotrauma in Patients With Severe Coronavirus Disease 2019.

Objective.: To report the high incidence of barotrauma in critically ill patients admitted to the intensive care unit (ICU) with coronavirus disease 2019 (COVID-19) and to discuss its implications.

Design.

Trapped air metamaterial concept for ultrasonic sub-wavelength imaging in water.

Acoustic metamaterials constructed from conventional base materials can exhibit exotic phenomena not commonly found in nature, achieved by combining geometrical and resonance effects. However, the use of polymer-based metamaterials that could operate in water is difficult, due to the low acoustic impedance mismatch between water and polymers. Here we introduce the concept of "trapped air" metamaterial, fabricated via vat photopolymerization, which makes ultrasonic sub-wavelength imaging in water using polymeric metamaterials highly effective.

Ultrasonic Propagation in Highly Attenuating Insulation Materials.

Experiments have been performed to demonstrate that ultrasound in the 100-400 kHz frequency range can be used to propagate signals through various types of industrial insulation. This is despite the fact that they are highly attenuating to ultrasonic signals due to scattering and viscoelastic effects. The experiments used a combination of piezocomposite transducers and pulse compression processing.

Author Correction: Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Impact of delivery mode-associated gut microbiota dynamics on health in the first year of life.

The early-life microbiome appears to be affected by mode of delivery, but this effect may depend on intrapartum antibiotic exposure. Here, we assess the effect of delivery mode on gut microbiota, independent of intrapartum antibiotics, by postponing routine antibiotic administration to mothers until after cord clamping in 74 vaginally delivered and 46 caesarean section born infants. The microbiota differs between caesarean section born and vaginally delivered infants over the first year of life, showing enrichment of Bifidobacterium spp.

Lack of improvement in antimicrobial prescribing after a diagnosis of Clostridium difficile and impact on recurrence.

Background: Antimicrobial use is one of the largest modifiable risk factors for development of Clostridium difficile infection (CDI). We sought to determine if a recent diagnosis of CDI affected the appropriateness of subsequent antimicrobial prescribing.

Methods: This study is a retrospective electronic chart review of the Greater Los Angeles Veterans Administration.

Correction to: Nebulization of RNS60, a Physically-Modified Saline, Attenuates the Adoptive Transfer of Experimental Allergic Encephalomyelitis in Mice: Implications for Multiple Sclerosis Therapy.

The original version of this article unfortunately contained a mistake. The Figure 3, 4, 5 legends have been misplaced. The updated legends along with the figures are corrected with this erratum.

Nebulization of RNS60, a Physically-Modified Saline, Attenuates the Adoptive Transfer of Experimental Allergic Encephalomyelitis in Mice: Implications for Multiple Sclerosis Therapy.

Developing a new and effective therapeutic approach against multiple sclerosis (MS) is always an important area of research. RNS60 is a bioactive aqueous solution generated by subjecting normal saline to Taylor-Couette-Poiseuille flow under elevated oxygen pressure. Recently we have demonstrated that RNS60, administered through intraperitoneal injection, ameliorated clinical symptoms and disease progression of experimental allergic encephalomyelitis (EAE), an animal model of MS.

Cellular and humoral immunity in a wild mammal: Variation with age & sex and association with overwinter survival.

Immune defenses are expected to be crucial for survival under the considerable parasite pressures experienced by wild animals. However, our understanding of the association between immunity and fitness in nature remains limited due to both the complexity of the vertebrate immune system and the often-limited availability of immune reagents in nonmodel organisms. Here, we use methods and reagents developed by veterinary researchers for domestic ungulates on blood samples collected from a wild Soay sheep population, to evaluate an unusually broad panel of immune parameters.

Sex differences in leucocyte telomere length in a free-living mammal.

Mounting evidence suggests that average telomere length reflects previous stress and predicts subsequent survival across vertebrate species. In humans, leucocyte telomere length (LTL) is consistently shorter during adulthood in males than in females, although the causes of this sex difference and its generality to other mammals remain unknown. Here, we measured LTL in a cross-sectional sample of free-living Soay sheep and found shorter telomeres in males than in females in later adulthood (>3 years of age), but not in early life.

4D intravital microscopy uncovers critical strain differences for the roles of PECAM and CD99 in leukocyte diapedesis.

Leukocyte transendothelial migration (TEM) is an essential component of the inflammatory response. In vitro studies with human cells have demonstrated that platelet/endothelial cell adhesion molecule (PECAM) functions upstream of CD99 during TEM; however, results in vivo with mice have been apparently contradictory. In this study we use four-dimensional (4D) intravital microscopy to demonstrate that the site and order of function of PECAM and CD99 in vivo are dependent on the strain of mice.

Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell-Mediated Central Nervous System Autoimmune Disease.

Leukocyte trafficking into the CNS is a prominent feature driving the immunopathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Blocking the recruitment of inflammatory leukocytes into the CNS represents an exploitable therapeutic target; however, the adhesion molecules that specifically regulate the step of leukocyte diapedesis into the CNS remain poorly understood. We report that CD99 is critical for lymphocyte transmigration without affecting adhesion in a human blood-brain barrier model.

Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte transendothelial migration.

CD99 is a critical regulator of leukocyte transendothelial migration (TEM). How CD99 signals during this process remains unknown. We show that during TEM, endothelial cell (EC) CD99 activates protein kinase A (PKA) via a signaling complex formed with the lysine-rich juxtamembrane cytoplasmic tail of CD99, the A-kinase anchoring protein ezrin, and soluble adenylyl cyclase (sAC).

Functional food microstructures for macronutrient release and delivery.

There is a need to understand the role of fat, protein and carbohydrate in human health, and also how foods containing and/or structured using these macronutrients can be designed so that they can have a positive impact on health. This may include a reduction in fat, salt or sugar, the protection and targeted release of micronutrients or active ingredients from/to particular parts of the digestive system, improvement of gastrointestinal health or satiety enhancing properties. Such foods can be designed with various macro- and microstructures that will impact on macronutrient release and delivery.

Phospholipids at the interface: current trends and challenges.

Phospholipids are one of the major structural elements of biological membranes. Due to their amphiphilic character, they can adopt various molecular assemblies when dispersed in water, such as bilayer vesicles or micelles, which give them unique interfacial properties and render them very attractive in terms of foam or emulsion stabilization. This article aims at reviewing the properties of phospholipids at the air/water and oil/water interfaces, as well as the recent advances in using these natural components as stabilizers, alone or in combination with other compounds such as proteins.

GSK3beta and beta-catenin modulate radiation cytotoxicity in pancreatic cancer.

Background: Knowledge of factors and mechanisms contributing to the inherent radioresistance of pancreatic cancer may improve cancer treatment. Irradiation inhibits glycogen synthase kinase 3beta (GSK3beta) by phosphorylation at serine 9. In turn, release of cytosolic membrane beta-catenin with subsequent nuclear translocation promotes survival.

Hyperbilirubinemia.

Hyperbilirubinemia is the most common condition requiring evaluation and treatment in newborns. The clinical manifestation of hyperbilirubinemia-jaundice-occurs in 60% of normal newborns and nearly all preterm infants. Compared with conditions that require advanced pharmacologic and technologic treatment strategies, hyperbilirubinemia seems to be overshadowed and may lose the attention it deserves as a condition that has potentially devastating effects.