Central Venopulmonary Extracorporeal Membrane Oxygenation: Background and Standardized Nomenclature.

This review highlights advancements in extracorporeal life support (ECLS), emphasizing the critical role of standardized terminology, particularly for extracorporeal membrane oxygenation (ECMO) in treating right ventricular and respiratory failure. Advocating for the adoption of the Extracorporeal Life Support Organization (ELSO) Maastricht Treaty for ECLS Nomenclature guidelines, it aims to resolve communication barriers in the ECMO field. Focusing on venopulmonary (VP) ECMO utilizing central pulmonary artery (PA) access, this review details surgical approaches and introduces a terminology guide to support effective knowledge exchange and advancements in patient care.

IL-10 constrains sphingolipid metabolism to limit inflammation.

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice-however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2-5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that 'metabolic correction' of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.

Extracorporeal membrane oxygenation in diabetic ketoacidosis-related cardiac and respiratory failure.

INTRODUCTION: Diabetic ketoacidosis (DKA) is a common clinical problem. When patients develop severe shock and/or respiratory failure, extracorporeal membrane oxygenation (ECMO) may be considered. This case series describes the clinical presentation and outcomes of patients with DKA supported with ECMO. METHODS: We conducted a retrospective and anonymized review of 15 patients with DKA who required ECMO at our institution. Demographic and ECMO-specific data were collected. Additional variables include ICU length of stay (LOS), acute kidney injury and use of continuous renal replacement therapy, disposition, and mortality. RESULTS: All ECMO cannulations were performed by an intensivist using peripheral vascular access. The majority of patients were female (73%) with a median age of 27 (IQR = 21.5-45) years. A diagnosis of diabetes mellitus (DM) prior to ECMO was present in 11 (73%) patients. Venoarterial ECMO was the initial mode used in 11 (73%) patients. The median duration of ECMO support was 7 (IQR = 6-14) days. The median ICU LOS was 12 (IQR = 8.5-20.5) days, and the median hospital LOS was 21 (IQR = 11-36.5) days. Eight patients had cardiac arrest and underwent extracorporeal cardiopulmonary resuscitation (ECPR) of which 4 (50%) patients survived to discharge. Overall, 10 (66.7%) patients were successfully weaned from ECMO and survived to discharge. CONCLUSION: This is the largest case series regarding the use of ECMO for patients with refractory shock, cardiac arrest, or respiratory failure related to DKA. The findings suggest that ECMO is a viable support option for managing these patients and has excellent outcomes, including patients with cardiac arrest.

Standardized nomenclature for peripheral percutaneous cannulation of the pulmonary artery in extracorporeal membrane oxygenation: Current uptake and recommendations for improvement.

The rising application of extracorporeal membrane oxygenation (ECMO) has emphasized the need for consistent and standardized terminology, especially concerning peripheral percutaneous cannulation of the pulmonary artery (PPC-PA). The Extracorporeal Life Support Organization (ELSO) Nomenclature Task Force produced the ELSO Maastricht Treaty for extracorporeal life support (ECLS) Nomenclature to address this challenge. However, adherence to nomenclature recommendations has been poor in publications describing PPC-PA. We aim to describe common nomenclature errors and provide a user-guide for abbreviations that can be used by authors, reviewers, and journal staff to ensure properadherence to standardized nomenclature in publications describing PPC-PA.

IL-10 constrains sphingolipid metabolism via fatty acid desaturation to limit inflammation.

Unchecked chronic inflammation is the underlying cause of many diseases, ranging from inflammatory bowel disease to obesity and neurodegeneration. Given the deleterious nature of unregulated inflammation, it is not surprising that cells have acquired a diverse arsenal of tactics to limit inflammation. IL-10 is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types; however, the exact mechanism by which IL-10 signaling subdues inflammation remains unclear. Here, we find that IL-10 signaling constrains sphingolipid metabolism. Specifically, we find increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10-deficient macrophages. Genetic deletion of CerS2, the enzyme responsible for VLC ceramide production, limited exacerbated inflammatory gene expression associated with IL-10 deficiency both in vitro and in vivo , indicating that "metabolic correction" is able to reduce inflammation in the absence of IL-10. Surprisingly, accumulation of saturated VLC ceramides was regulated by flux through the de novo mono-unsaturated fatty acid (MUFA) synthesis pathway, where addition of exogenous MUFAs could limit both saturated VLC ceramide production and inflammatory gene expression in the absence of IL-10 signaling. Together, these studies mechanistically define how IL-10 signaling manipulates fatty acid metabolism as part of its molecular anti-inflammatory strategy and could lead to novel and inexpensive approaches to regulate aberrant inflammation.

Growth and tissue nutrient responses of adults of Sarracenia alata to prey exclusion, nutrient addition, and neighbor reduction.

PREMISE: Carnivorous plants are often associated with nutrient-poor soils and fires. Fire can decrease available soil nitrogen (N) and increase light availability, thus potentially favoring carnivory if prey provide N. Prey can also be a source of phosphorus (P), however, and soil P-availability often increases and competition for prey can decrease following fire. Carnivory thus might be more advantageous before fire when prey and/or soil P are more limiting. METHODS: We examined nutrient limitation of growth in a carnivorous plant, Sarracenia alata, in a wet pine savanna in southeastern Mississippi, USA. We measured growth and N:P tissue concentration responses of adult plants to a factorial arrangement of prey capture, neighbor reduction, and addition of N, P, and ash to the soil. We tested two hypotheses: (1) Prey provide N, and neighbor reduction and ash addition increase light and soil P and thus the benefit of carnivory; and (2) Prey provide P, neighbor reduction increases prey and/or P, and prey exclusion reduces growth the most when neighbors are not reduced. RESULTS: The exclusion of prey reduced growth more when neighbors were not reduced, an effect that was ameliorated slightly by the addition of P to the soil (the P-limitation hypothesis). Prey exclusion caused a decrease in tissue P when N was added to the soil. CONCLUSIONS: The results of this study with adult plants differed from those of a previous study using small juvenile plants, suggesting a shift from light limitation to P and prey limitation with increasing size.

Inflammasome activation in infected macrophages drives COVID-19 pathology.

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA and a sustained interferon (IFN) response, all of which are recapitulated and required for pathology in the SARS-CoV-2-infected MISTRG6-hACE2 humanized mouse model of COVID-19, which has a human immune system1-20. Blocking either viral replication with remdesivir21-23 or the downstream IFN-stimulated cascade with anti-IFNAR2 antibodies in vivo in the chronic stages of disease attenuates the overactive immune inflammatory response, especially inflammatory macrophages. Here we show that SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release interleukin 1 (IL-1) and IL-18, and undergo pyroptosis, thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and the accompanying inflammatory response are necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Notably, this blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 through the production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.

Inflammasome activation in infected macrophages drives COVID-19 pathology.

Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system 1-20 . Blocking either viral replication with Remdesivir 21-23 or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.

SSX2 promotes the formation of a novel type of intranuclear lamin bodies.

SSX proteins are normally restricted to spermatogenic cells, but ectopic expression can be observed in many types of human cancer. We recently demonstrated that SSX family members may contribute to tumorigenesis by modifying chromatin structure and, in specific settings, compromise chromatin stability. Here, we used normal and tumorigenic breast epithelial cell line models to further study the effect of ectopic expression of SSX2 on nuclear organization. We show that SSX2 induces the formation of a novel type of nucleoplasmic lamin bodies. Ectopic expression of SSX2 in various breast epithelial cell lines led to the formation of a previously undescribed type of intranuclear bodies containing both A and B type lamins but no other components of the nuclear lamina. SSX2-expressing cells contained a highly variable number of lamin bodies distributed throughout the nuclear space. SSX2-mediated establishment of intranuclear lamin bodies could not be linked to previous molecular interactions of SSX proteins, including polycomb proteins and the Mediator complex, but was, however, dependent on S-phase progression. These results reveal a novel interaction between SSX2 and lamins in the nucleoplasmic space. They further suggest that SSX2 promotes the formation of chromatin neighborhoods supporting the organization of lamins into nuclear bodies. We speculate that this may have implications for the organization and functional regulation of chromatin in cancer cells. Our study contributes to the further understanding of the biology of SSX proteins in tumorigenesis.

Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: Intranasally administered insulin has shown promise in both rodent and human studies in Alzheimer's disease; however, both effects and mechanisms require elucidation. OBJECTIVE: We assessed the effects of intranasally administered insulin on white matter health and its association with cognition and cerebral spinal fluid biomarker profiles in adults with mild cognitive impairment or Alzheimer's disease in secondary analyses from a prior phase 2 clinical trial (NCT01767909). DESIGN: A randomized (1:1) double-blind clinical trial. SETTING: Twelve sites across the United States. PARTICIPANTS: Adults with mild cognitive impairment or Alzheimer's disease. INTERVENTION: Participants received either twice daily placebo or insulin (20 IU Humulin R U-100 b.i.d.) intranasally for 12 months. Seventy-eight participants were screened, of whom 49 (32 men) were enrolled. MEASUREMENTS: Changes from baseline in global and regional white matter hyperintensity volume and gray matter volume were analyzed and related to changes in cerebral spinal fluid biomarkers, Alzheimer's Disease Assessment Scale-Cognition, Clinical Disease Rating-Sum of Boxes, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale, and a memory composite. RESULTS: The insulin-treated group demonstrated significantly reduced changes in white matter hyperintensity volume in deep and frontal regions after 12 months, with a similar trend for global volume. White matter hyperintensity volume progression correlated with worsened Alzheimer's disease cerebral spinal fluid biomarker profile and cognitive function; however, patterns of correlations differed by treatment group. CONCLUSION: Intranasal insulin treatment for 12 months reduced white matter hyperintensity volume progression and supports insulin's potential as a therapeutic option for Alzheimer's disease.

Use of Formal and Informal Food Resources by Food Insecure Families in Lima, Peru: A Mixed-Methods Analysis.

The goal of this study was to measure food insecurity among families with children in a low-income district of Lima, Peru and to identify the formal and informal food resources available to them that may affect their food security status. In June-July 2019, we collected data from 329 randomly selected households in Villa El Salvador (Lima, Peru). Following a mixed methods approach, we found that the percentage of households using food assistance programs (FAPs) increased with increasing levels of food insecurity, but two FAPs were heavily used by households regardless of food (in)security. The main reasons for using FAPs included financial need, already being signed up in the program, and believing that the food was of nutritional value; the main reasons for non-use were finding the program unnecessary, dislike or poor perceived quality of the food, and not being able to sign up for the program. Similarly, informal food resources, such as buying food on credit or receiving food from someone outside the household, were incrementally used with increased levels of food insecurity. Our study clarifies the relationship between level of household food insecurity and FAP use - FAPs more commonly used by food insecure households were used because of financial need, whereas the FAPs most commonly used by food secure households were those with automatic enrollment. At a programmatic level, our research highlights the need for making nutritious and preferred foods available in FAPs and standardizing the application of enrollment criteria.

Traumatic right atrial rupture bridge to definitive repair with extra-corporeal life support.

Cardiac injury secondary to non-penetrating trauma is more common than thought, albeit, the injury is usually minor and goes undiagnosed without significant sequelae in most cases. Blunt cardiac rupture is much rarer accounting for <0.05% of all trauma cases but lethal in most circumstances. We present a case report of a young trauma victim who presented with both right atrial rupture and traumatic atrial septal disruption (ASD) requiring extra-corporeal life support (ECLS) and surgical repair. Blunt cardiac trauma with chamber rupture and septal disruption is a devastating injury. Stopping the hemorrhage and using ECLS gave our patient time to stabilize before definitive management of her traumatic ASD.

FGF signaling regulates development by processes beyond canonical pathways.

FGFs are key developmental regulators that engage a signal transduction cascade through receptor tyrosine kinases, prominently engaging ERK1/2 but also other pathways. However, it remains unknown whether all FGF activities depend on this canonical signal transduction cascade. To address this question, we generated allelic series of knock-in Fgfr1 and Fgfr2 mouse strains, carrying point mutations that disrupt binding of signaling effectors, and a kinase dead allele of Fgfr2 that broadly phenocopies the null mutant. When interrogated in cranial neural crest cells, we identified discrete functions for signaling pathways in specific craniofacial contexts, but point mutations, even when combined, failed to recapitulate the single or double null mutant phenotypes. Furthermore, the signaling mutations abrogated established FGF-induced signal transduction pathways, yet FGF functions such as cell-matrix and cell-cell adhesion remained unaffected, though these activities did require FGFR kinase activity. Our studies establish combinatorial roles of Fgfr1 and Fgfr2 in development and uncouple novel FGFR kinase-dependent cell adhesion properties from canonical intracellular signaling.

Prey exclusion combined with simulated fire increases subsequent prey-capture potential in the pale pitcher plant, Sarracenia alata.

PREMISE: The association of carnivory (an adaptation to nutrient-poor soils) with fire has been described as a paradox, given increases in nutrient availability that often accompany fire. The nutrients that increase in availability following fire, however, may not be the same as those provided by prey and may not reduce nutrient limitation if accompanied by even greater increases in light. METHODS: Using a factorial experiment in the field, we examined how simulated fire (clipping plus nitrogen-free fertilizer addition) and prey-derived nutrient availability (prey exclusion) interacted to influence carnivorous potential in Sarracenia alata and belowground competition with its neighbors (manipulated via trenching). We hypothesized that simulated fire combined with prey exclusion would (1) increase the potential for prey capture relative to shade avoidance, hereafter, relative prey-capture potential (RPCP), and/or (2) increase belowground competition with neighboring plants. RESULTS: Sarracenia alata increased RPCP in response to the combination of simulated fire and prey exclusion, despite increases in phosphorus and other nutrients associated with the simulated fire treatment, suggesting that prey capture potential increases in response to increased nitrogen limitation resulting from increases in light and/or phosphorus after fire. We found no evidence of belowground competition. CONCLUSIONS: The potential importance of carnivory in Sarracenia alata increases following fire. This result helps to explain the paradoxical association of carnivorous plants with fire by demonstrating the potential for prey-derived nutrient limitation to increase rather than decrease in response to increases in light and nutrients other than nitrogen following fire.

Bio-inspired gas sensing: boosting performance with sensor optimization guided by "machine learning".

The performance of existing gas sensors often degrades in field conditions because of the loss of measurement accuracy in the presence of interferences. Thus, new sensing approaches are required with improved sensor selectivity. We are developing a new generation of gas sensors, known as multivariable sensors, that have several independent responses for multi-gas detection with a single sensor. In this study, we analyze the capabilities of natural and fabricated photonic three-dimensional (3-D) nanostructures as sensors for the detection of different gaseous species, such as vapors and non-condensable gases. We employed bare Morpho butterfly wing scales to control their gas selectivity with different illumination angles. Next, we chemically functionalized Morpho butterfly wing scales with a fluorinated silane to boost the response of these nanostructures to the vapors of interest and to suppress the response to ambient humidity. Further, we followed our previously developed design rules for sensing nanostructures and fabricated bioinspired inorganic 3-D nanostructures to achieve functionality beyond natural Morpho scales. These fabricated nanostructures have embedded catalytically active gold nanoparticles to operate at high temperatures of ≈300 °C for the detection of gases for solid oxide fuel cell (SOFC) applications. Our performance advances in the detection of multiple gaseous species with specific nanostructure designs were achieved by coupling the spectral responses of these nanostructures with machine learning (a.k.a. multivariate analysis, chemometrics) tools. Our newly acquired knowledge from studies of these natural and fabricated inorganic nanostructures coupled with machine learning data analytics allowed us to advance our design rules for sensing nanostructures toward the required gas selectivity for numerous gas monitoring scenarios at room and high temperatures for industrial, environmental, and other applications.

Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche.

The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts1. Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types2,3. However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E2 (PGE2). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE2 drives the expansion οf a population of Sca-1+ reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1+ cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE2 promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1+ cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE2-Ptger4. Analyses of patient-derived organoids established that PGE2-PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE2-Ptger4-Yap signalling axis.

The nanoscopic molecular pathway through human skin.

BACKGROUND: Knowledge regarding the barrier properties of human skin is important for understanding skin pathology, developing of transdermal drug delivery systems and computational skin absorption models; however, the molecular pathways through human skin remains to be fully investigated on a nanoscopic level. In particular the nanoscopic pathway of molecules passing the intercellular lipid bilayers separating the corneocytes in the stratum corneum (SC) is not fully elucidated. METHODS: Using stimulated emission depletion microscopy (STED) and Förster resonance energy transfer (FRET) the molecular pathways through the SC, the main barrier of the skin, are determined for lipophilic and water-soluble molecules at a nanoscopic resolution. RESULTS: Using STED and confocal microscopy, water-soluble dyes, were observed to be present in both the corneocytes and in the intercellular lipid matrix, whereas the lipophilic dyes were predominately in the intercellular lipid bilayers. FRET was observed in the SC between the lipophilic and water-soluble dyes, the existence of a minimum possible distance between acceptor and donor molecules of 4.0 ±â€¯0.1 nm was found. CONCLUSIONS: The results indicate that lipophilic molecules penetrate the stratum corneum via the intercellular lipids bilayers separating the corneocytes in the SC, while the more water-soluble molecules penetrate the stratum corneum via the transcellular route through the corneocytes and intercellular lipid bilayers via the polar head groups of lipid molecules in the bilayers. GENERAL SIGNIFICANCE: Knowledge of the nanoscopic molecular pathways through human skin will help understand the skin barrier function and will be of use for computational skin absorption models and transdermal drug delivery strategies.