Polyamine metabolism in macrophage-adipose tissue function and homeostasis.

Intracellular metabolism is a crucial regulator of macrophage function. Recent evidence revealed that the polyamine pathway and subsequent hypusination of eukaryotic initiation factor 5A (eIF5A) are master regulators of immune cell functions. In brown adipose tissue (BAT), macrophages show an impressive degree of heterogenicity, with specific subsets supporting adaptive thermogenesis during cold exposure. In this review, we discuss the impact of polyamine metabolism on macrophage diversity and function, with a particular focus on their role in adipose tissue homeostasis. Thus, we highlight the exploration of how polyamine metabolism in macrophages contributes to BAT homeostasis as an attractive and exciting new field of research.

Differences in birch tar composition are explained by adhesive function in the central European Iron Age.

Birch bark tar is the most widely documented adhesive in prehistoric Europe. More recent periods attest to a diversification in terms of the materials used as adhesives and their application. Some studies have shown that conifer resins and beeswax were added to produce compound adhesives. For the Iron Age, no comparative large-scale studies have been conducted to provide a wider perspective on adhesive technologies. To address this issue, we identify adhesive substances from the Iron Age in north-eastern France. We applied organic residue analysis to 65 samples from 16 archaeological sites. This included residues adhering to ceramics, from vessel surface coatings, repaired ceramics, vessel contents, and adhesive lumps. Our findings show that, even during the Iron Age in north-eastern France, birch bark tar is one of the best-preserved adhesive substances, used for at least 400 years. To a lesser extent, Pinaceae resin and beeswax were also identified. Through statistical analyses, we show that molecular composition differs in samples, correlating with adhesive function. This has implications for our understanding of birch bark tar production, processing and mode of use during the Iron Age in France and beyond.

Routine Extubation in the Operating Room After Isolated Coronary Artery Bypass.

BACKGROUND: The benefits of fast-track extubation in the intensive care unit (ICU) after cardiac surgery are well established. Although extubation in the operating room (OR) is safe in carefully selected patients, widespread use of this strategy in cardiac surgery remains unproven. This study was designed to evaluate perioperative outcomes with OR vs ICU extubation in patients undergoing nonemergency, isolated coronary artery bypass grafting (CABG). METHODS: The Society of Thoracic Surgeons (STS) data for all single-center patients who underwent nonemergency isolated CABG over a 6-year interval were analyzed. Perioperative morbidity and mortality with ICU vs OR extubation were compared. RESULTS: Between January 1, 2017 and December 31, 2022, 1397 patients underwent nonemergency, isolated CABG; 891 (63.8%) of these patients were extubated in the ICU, and 506 (36.2%) were extubated in the OR. Propensity matching resulted in 414 pairs. In the propensity-matched cohort, there were no differences between the 2 groups in incidence of reintubation, reoperation for bleeding, total operative time, stroke or transient ischemic attack, renal failure, or 30-day mortality. OR-extubated patients had shorter ICU hours (14 hours vs 20 hours; P < .0001), shorter postoperative hospital length of stay (3 days vs 5 days; P < .0001), a greater likelihood of being discharged directly to home (97.3% vs 89.9%; P < .0001), and a lower 30-day readmission rate (1.7% vs 4.1%; P = .04). CONCLUSIONS: Routine extubation in the OR is a feasible and safe strategy for a broad spectrum of patients after nonemergency CABG, with no increase in perioperative morbidity or mortality. Wider adoption of routine OR extubation for nonemergency CABG is indicated.

Renal Ischemia Tolerance Mediated by eIF5A Hypusination Inhibition Is Regulated by a Specific Modulation of the Endoplasmic Reticulum Stress.

Through kidney transplantation, ischemia/reperfusion is known to induce tissular injury due to cell energy shortage, oxidative stress, and endoplasmic reticulum (ER) stress. ER stress stems from an accumulation of unfolded or misfolded proteins in the lumen of ER, resulting in the unfolded protein response (UPR). Adaptive UPR pathways can either restore protein homeostasis or can turn into a stress pathway leading to apoptosis. We have demonstrated that N1-guanyl-1,7-diamineoheptane (GC7), a specific inhibitor of eukaryotic Initiation Factor 5A (eIF5A) hypusination, confers an ischemic protection of kidney cells by tuning their metabolism and decreasing oxidative stress, but its role on ER stress was unknown. To explore this, we used kidney cells pretreated with GC7 and submitted to either warm or cold anoxia. GC7 pretreatment promoted cell survival in an anoxic environment concomitantly to an increase in xbp1 splicing and BiP level while eiF2α phosphorylation and ATF6 nuclear level decreased. These demonstrated a specific modulation of UPR pathways. Interestingly, the pharmacological inhibition of xbp1 splicing reversed the protective effect of GC7 against anoxia. Our results demonstrated that eIF5A hypusination inhibition modulates distinctive UPR pathways, a crucial mechanism for the protection against anoxia/reoxygenation.

New Strategies Protecting from Ischemia/Reperfusion.

This Special Issue aims to highlight new avenues in the management of Ischemia/Reperfusion (I/R) injury [...].

Intracellular pH Control by Membrane Transport in Mammalian Cells. Insights Into the Selective Advantages of Functional Redundancy.

Intracellular pH is a vital parameter that is maintained close to neutrality in all mammalian cells and tissues and acidic in most intracellular compartments. After presenting the main techniques used for intracellular an vesicular pH measurements we will briefly recall the main molecular mechanisms that affect and regulate intracellular pH. Following this we will discuss the large functional redundancy found in the transporters of H+ or acid-base equivalents. For this purpose, we will use mathematical modeling to simulate cellular response to persistent and/or transient acidification, in the presence of different transporters, single or in combination. We will also test the presence or absence of intracellular buffering. This latter section will highlight how modeling can yield fundamental insight into deep biological questions such as the utility of functional redundancy in natural selection.

Total Synthesis of Aqabamycin G, a Nitrophenyl Indolylmaleimide Marine Alkaloid from Vibrio sp. WMBA.

The first total synthesis of the marine alkaloid aqabamycin G is disclosed. The synthetic sequence involved the stepwise addition to maleimide of an indole motif and a substituted diazo-benzenoid unit derived from acetaminophen. An alternative strategy using a protected phenol is also reported.

Native mitral valve staphylococcus endocarditis with a very unusual complication: Ruptured posterior mitral valve leaflet aneurysm.

Infective endocarditis (IE) is a life-threatening disease associated with in-hospital mortality of nearly one in five cases. IE can destroy valvular tissue, which may rarely progress to aneurysm formation, most commonly at the anterior leaflet in instances of mitral valve involvement. We present a remarkable case of a patient with IE and a rare complication of a ruptured aneurysm of the posterior leaflet of the mitral valve. Two- and Three-dimensional transesophageal echocardiography, intra-operative videography, and histopathologic analysis revealed disruption at this unusual location-at the junction of the P2 and P3 scallops, surrounded by an annular abscess.

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles.

Since the demonstration of its involvement in cell proliferation, the eukaryotic initiation factor 5A (eIF5A) has been studied principally in relation to the development and progression of cancers in which the isoform A2 is mainly expressed. However, an increasing number of studies report that the isoform A1, which is ubiquitously expressed in normal cells, exhibits novel molecular features that reveal its new relationships between cellular functions and organ homeostasis. At a first glance, eIF5A can be regarded, among other things, as a factor implicated in the initiation of translation. Nevertheless, at least three specificities: (1) its extreme conservation between species, including plants, throughout evolution, (2) its very special and unique post-translational modification through the activating-hypusination process, and finally (3) its close relationship with the polyamine pathway, suggest that the role of eIF5A in living beings remains to be uncovered. In fact, and beyond its involvement in facilitating the translation of proteins containing polyproline residues, eIF5A is implicated in various physiological processes including ischemic tolerance, metabolic adaptation, aging, development, and immune cell differentiation. These newly discovered physiological properties open up huge opportunities in the clinic for pathologies such as, for example, the ones in which the oxygen supply is disrupted. In this latter case, organ transplantation, myocardial infarction or stroke are concerned, and the current literature defines eIF5A as a new drug target with a high level of potential benefit for patients with these diseases or injuries. Moreover, the recent use of genomic and transcriptomic association along with metadata studies also revealed the implication of eIF5A in genetic diseases. Thus, this review provides an overview of eIF5A from its molecular mechanism of action to its physiological roles and the clinical possibilities that have been recently reported in the literature.

Gfi1 Loss Protects against Two Models of Induced Diabetes.

Background: Although several approaches have revealed much about individual factors that regulate pancreatic development, we have yet to fully understand their complicated interplay during pancreas morphogenesis. Gfi1 is transcription factor specifically expressed in pancreatic acinar cells, whose role in pancreas cells fate identity and specification is still elusive. Methods: In order to gain further insight into the function of this factor in the pancreas, we generated animals deficient for Gfi1 specifically in the pancreas. Gfi1 conditional knockout animals were phenotypically characterized by immunohistochemistry, RT-qPCR, and RNA scope. To assess the role of Gfi1 in the pathogenesis of diabetes, we challenged Gfi1-deficient mice with two models of induced hyperglycemia: long-term high-fat/high-sugar feeding and streptozotocin injections. Results: Interestingly, mutant mice did not show any obvious deleterious phenotype. However, in depth analyses demonstrated a significant decrease in pancreatic amylase expression, leading to a diminution in intestinal carbohydrates processing and thus glucose absorption. In fact, Gfi1-deficient mice were found resistant to diet-induced hyperglycemia, appearing normoglycemic even after long-term high-fat/high-sugar diet. Another feature observed in mutant acinar cells was the misexpression of ghrelin, a hormone previously suggested to exhibit anti-apoptotic effects on ß-cells in vitro. Impressively, Gfi1 mutant mice were found to be resistant to the cytotoxic and diabetogenic effects of high-dose streptozotocin administrations, displaying a negligible loss of ß-cells and an imperturbable normoglycemia. Conclusions: Together, these results demonstrate that Gfi1 could turn to be extremely valuable for the development of new therapies and could thus open new research avenues in the context of diabetes research.

Identification of adipocytes as target cells for Leishmania infantum parasites.

Leishmania infantum is the causative agent of visceral leishmaniasis transmitted by the bite of female sand flies. According to the WHO, the estimated annual incidence of leishmaniasis is one million new cases, resulting in 30,000 deaths per year. The recommended drugs for treating leishmaniasis include Amphotericin B. But over the course of the years, several cases of relapses have been documented. These relapses cast doubt on the efficiency of actual treatments and raise the question of potential persistence sites. Indeed, Leishmania has the ability to persist in humans for long periods of time and even after successful treatment. Several potential persistence sites have already been identified and named as safe targets. As adipose tissue has been proposed as a sanctuary of persistence for several pathogens, we investigated whether Leishmania infantum could be found in this tissue. We demonstrated both in cell cultures and in vivo that Leishmania infantum was able to infect adipocytes. Altogether our results suggest adipocytes as a 'safe target' for Leishmania infantum parasites.

Evolution of the Synthesis of Remdesivir. Classical Approaches and Most Recent Advances.

The broad-spectrum antiviral Remdesivir, a monophosphate nucleoside analogue prodrug (ProTide), was repurposed. In May 2020, it received emergency approval by the FDA, being the first drug approved to fight the new coronavirus (COVID-19) disease which targets the virus directly. The main synthetic strategies toward Remdesivir, and their relevant modifications, are presented and discussed, to provide a panoramic view of the state-of-the-art and the more important advances in this field. Recent progress, proposed improvements, and uses of novel technologies for the synthetic sequence are also detailed.

Impact of thermogenesis induced by chronic ß3-adrenergic receptor agonist treatment on inflammatory and infectious response during bacteremia in mice.

White adipocytes store energy differently than brown and brite adipocytes which dissipate energy under the form of heat. Studies have shown that adipocytes are able to respond to bacteria thanks to the presence of Toll-like receptors at their surface. Despite this, little is known about the involvement of each class of adipocytes in the infectious response. We treated mice for one week with a ß3-adrenergic receptor agonist to induce activation of brown adipose tissue and brite adipocytes within white adipose tissue. Mice were then injected intraperitoneally with E. coli to generate acute infection. The metabolic, infectious and inflammatory parameters of the mice were analysed during 48 hours after infection. Our results shown that in response to bacteria, thermogenic activity promoted a discrete and local anti-inflammatory environment in white adipose tissue characterized by the increase of the IL-1RA secretion. More generally, activation of brown and brite adipocytes did not modify the host response to infection including no additive effect with fever and an equivalent bacteria clearance and inflammatory response. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes in response to acute bacterial infection and open a way to characterize their effect along more chronic infection as septicaemia.

Paternal multigenerational exposure to an obesogenic diet drives epigenetic predisposition to metabolic diseases in mice.

Obesity is a growing societal scourge. Recent studies have uncovered that paternal excessive weight induced by an unbalanced diet affects the metabolic health of offspring. These reports mainly employed single-generation male exposure. However, the consequences of multigenerational unbalanced diet feeding on the metabolic health of progeny remain largely unknown. Here, we show that maintaining paternal Western diet feeding for five consecutive generations in mice induces an enhancement in fat mass and related metabolic diseases over generations. Strikingly, chow-diet-fed progenies from these multigenerational Western-diet-fed males develop a 'healthy' overweight phenotype characterized by normal glucose metabolism and without fatty liver that persists for four subsequent generations. Mechanistically, sperm RNA microinjection experiments into zygotes suggest that sperm RNAs are sufficient for establishment but not for long-term maintenance of epigenetic inheritance of metabolic pathologies. Progressive and permanent metabolic deregulation induced by successive paternal Western-diet-fed generations may contribute to the worldwide epidemic of metabolic diseases.

Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney.

Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.

Fibronectin Extra Domains tune cellular responses and confer topographically distinct features to fibril networks.

Cellular fibronectin (FN; also known as FN1) variants harboring one or two alternatively spliced so-called extra domains (EDB and EDA) play a central bioregulatory role during development, repair processes and fibrosis. Yet, how the extra domains impact fibrillar assembly and function of the molecule remains unclear. Leveraging a unique biological toolset and image analysis pipeline for direct comparison of the variants, we demonstrate that the presence of one or both extra domains impacts FN assembly, function and physical properties of the matrix. When presented to FN-null fibroblasts, extra domain-containing variants differentially regulate pH homeostasis, survival and TGF-ß signaling by tuning the magnitude of cellular responses, rather than triggering independent molecular switches. Numerical analyses of fiber topologies highlight significant differences in variant-specific structural features and provide a first step for the development of a generative model of FN networks to unravel assembly mechanisms and investigate the physical and functional versatility of extracellular matrix landscapes.This article has an associated First Person interview with the first author of the paper.

Advanced experience allows robotic mitral valve repair in the presence of extensive mitral annular calcification.

OBJECTIVE: Mitral annular calcification is underdiagnosed in patients with mitral regurgitation. After excision, it may require reconstruction of the atrioventricular groove and decreases the probability of valve repair. We reviewed the safety and efficacy of totally endoscopic robotic mitral valve repair in the presence of mitral annular calcification, with an emphasis on pathology and repair techniques. METHODS: Between May 2011 and August 2017, the same 2-surgeon team attempted totally endoscopic robotic mitral valve repair in 64 mitral annular calcification cases, accounting for 12.8% of our experience. Mitral annular calcification associated with a calcified posterior leaflet was not considered for totally endoscopic robotic mitral valve repair. When possible, the mitral annular calcification was excised en bloc using electrocautery, the posterior leaflet separated from the mitral annular calcification and spared, the atrioventricular groove was reconstructed, the posterior leaflet was reattached to the neoannulus, and the repair was completed with annuloplasty. RESULTS: The median age of patients was 65 years, with 21 (32.8%) aged less than 60 years, and 34 (53.1%) were women. The etiology was Barlow's disease in 54 patients (84%). Repair was converted to replacement in 2 patients (3.1%). Cryoablation was performed in 8 patients (12.5%), hybrid percutaneous coronary intervention was performed in 5 patients (7.8%), and tricuspid annuloplasty was performed in 2 patients (3.1%). Median aortic occlusion was 122 minutes, excluding cases with concomitant tricuspid repair. Thirty-three patients (52%) were extubated in the operating room. The median length of stay was 4 days. Residual mitral regurgitation on discharge transthoracic echocardiogram was none to mild in all patients. None of the patients had a perioperative stroke or needed a pacemaker. Thirty-day mortality was 2 (3.1%). CONCLUSIONS: Mitral annular calcification is present in a significant percentage of patients with mitral regurgitation, especially in Barlow's disease, including younger patients. By using a variety of repair techniques, totally endoscopic robotic mitral valve repair can be performed safely and effectively in most mitral annular calcification cases with a noncalcified posterior leaflet.