Sex-specific associations of the maturation locus vgll3 with exploratory behavior and boldness in Atlantic salmon juveniles.

Studies linking genetics, behavior and life history in any species are rare. In Atlantic salmon (Salmo salar), age at maturity is a key life-history trait and associates strongly with the vgll3 locus, whereby the vgll3*E allele is linked with younger age at maturity, and higher body condition than the vgll3*L allele. However, the relationship between this genetic variation and behaviors like boldness and exploration which may impact growth and reproductive strategies is poorly understood. The pace-of-life syndrome (POLS) framework provides predictions, whereby heightened exploratory behavior and boldness are predicted in individuals with the early maturation-associated vgll3 genotype (EE). Here, we tested these predictions by investigating the relationship between vgll3 genotypes and exploration and boldness behaviors in 129 juveniles using the novel environment and novel object trials. Our results indicated that contrary to POLS predictions, vgll3*LL fish were bolder and more explorative, suggesting a genotype-level syndrome including several behaviors. Interestingly, clear sex differences were observed in the latency to move in a new environment, with vgll3*EE males, but not females, taking longer to move than their vgll3*LL counterparts. Our results provide further empirical support for recent calls to consider more nuanced explanations than the pace of life theory for integrating behavior into life-history theory.

What is the meta-analytic evidence for life-history trade-offs at the genetic level?

Understanding the evolutionary mechanisms underlying the maintenance of individual differences in behavior and physiology is a fundamental goal in ecology and evolution. The pace-of-life syndrome hypothesis is often invoked to explain the maintenance of such within-population variation. This hypothesis predicts that behavioral traits are part of a suite of correlated traits that collectively determine an individual's propensity to prioritize reproduction or survival. A key assumption of this hypothesis is that these traits are underpinned by genetic trade-offs among life-history traits: genetic variants that increase fertility, reproduction and growth might also reduce lifespan. We performed a systematic literature review and meta-analysis to summarize the evidence for the existence of genetic trade-offs between five key life-history traits: survival, growth rate, body size, maturation rate, and fertility. Counter to our predictions, we found an overall positive genetic correlation between survival and other life-history traits and no evidence for any genetic correlations between the non-survival life-history traits. This finding was generally consistent across pairs of life-history traits, sexes, life stages, lab vs. field studies, and narrow- vs. broad-sense correlation estimates. Our study highlights that genetic trade-offs may not be as common, or at least not as easily quantifiable, in animals as often assumed.

Utilization of anonymization techniques to create an external control arm for clinical trial data.

BACKGROUND: Subject-level real-world data (RWD) collected during daily healthcare practices are increasingly used in medical research to assess questions that cannot be addressed in the context of a randomized controlled trial (RCT). A novel application of RWD arises from the need to create external control arms (ECAs) for single-arm RCTs. In the analysis of ECAs against RCT data, there is an evident need to manage and analyze RCT data and RWD in the same technical environment. In the Nordic countries, legal requirements may require that the original subject-level data be anonymized, i.e., modified so that the risk to identify any individual is minimal. The aim of this study was to conduct initial exploration on how well pseudonymized and anonymized RWD perform in the creation of an ECA for an RCT. METHODS: This was a hybrid observational cohort study using clinical data from the control arm of the completed randomized phase II clinical trial (PACIFIC-AF) and RWD cohort from Finnish healthcare data sources. The initial pseudonymized RWD were anonymized within the (k, ε)-anonymity framework (a model for protecting individuals against identification). Propensity score matching and weighting methods were applied to the anonymized and pseudonymized RWD, to balance potential confounders against the RCT data. Descriptive statistics for the potential confounders and overall survival analyses were conducted prior to and after matching and weighting, using both the pseudonymized and anonymized RWD sets. RESULTS: Anonymization affected the baseline characteristics of potential confounders only marginally. The greatest difference was in the prevalence of chronic obstructive pulmonary disease (4.6% vs. 5.4% in the pseudonymized compared to the anonymized data, respectively). Moreover, the overall survival changed in anonymization by only 8% (95% CI 4-22%). Both the pseudonymized and anonymized RWD were able to produce matched ECAs for the RCT data. Anonymization after matching impacted overall survival analysis by 22% (95% CI -21-87%). CONCLUSIONS: Anonymization may be a viable technique for cases where flexible data transfer and sharing are required. As anonymization necessarily affects some aspects of the original data, further research and careful consideration of anonymization strategies are needed.

Lipoprotein(a) induces caspase-1 activation and IL-1 signaling in human macrophages.

Introduction: Lipoprotein(a) (Lp(a)) is an LDL-like particle with an additional apolipoprotein (apo)(a) covalently attached. Elevated levels of circulating Lp(a) are a risk factor for atherosclerosis. A proinflammatory role for Lp(a) has been proposed, but its molecular details are incompletely defined. Methods and results: To explore the effect of Lp(a) on human macrophages we performed RNA sequencing on THP-1 macrophages treated with Lp(a) or recombinant apo(a), which showed that especially Lp(a) induces potent inflammatory responses. Thus, we stimulated THP-1 macrophages with serum containing various Lp(a) levels to investigate their correlations with cytokines highlighted by the RNAseq, showing significant correlations with caspase-1 activity and secretion of IL-1ß and IL-18. We further isolated both Lp(a) and LDL particles from three donors and then compared their atheroinflammatory potentials together with recombinant apo(a) in primary and THP-1 derived macrophages. Compared with LDL, Lp(a) induced a robust and dose-dependent caspase-1 activation and release of IL-1ß and IL-18 in both macrophage types. Recombinant apo(a) strongly induced caspase-1 activation and IL-1ß release in THP-1 macrophages but yielded weak responses in primary macrophages. Structural analysis of these particles revealed that the Lp(a) proteome was enriched in proteins associated with complement activation and coagulation, and its lipidome was relatively deficient in polyunsaturated fatty acids and had a high n-6/n-3 ratio promoting inflammation. Discussion: Our data show that Lp(a) particles induce the expression of inflammatory genes, and Lp(a) and to a lesser extent apo(a) induce caspase-1 activation and IL-1 signaling. Major differences in the molecular profiles between Lp(a) and LDL contribute to Lp(a) being more atheroinflammatory.

SARS-CoV-2 reinfection: Adding insult to dysfunctional endothelium in patients with atherosclerotic cardiovascular disease.

In this short narrative review, we aim at defining the pathophysiological role endothelial dysfunction in the observed COVID-19-associated rise in risk of cardiovascular disease. Variants of the SARS-CoV-2 virus have caused several epidemic waves of COVID-19, and the emergence and rapid spread of new variants and subvariants are likely. Based on a large cohort study, the incidence rate of SARS-CoV-2 reinfection is about 0.66 per 10 000 person-weeks. Both the first infection and reinfection with SARS-CoV-2 increase cardiac event risk, particularly in vulnerable patients with cardiovascular risk factors and the accompanying systemic endothelial dysfunction. By worsening pre-existing endothelial dysfunction, both the first infection and reinfection with ensuing COVID-19 may turn the endothelium procoagulative and prothrombotic, and ultimately lead to local thrombus formation. When occurring in an epicardial coronary artery, the risk of an acute coronary syndrome increases, and when occurring in intramyocardial microvessels, scattered myocardial injuries will ensue, both predisposing the COVID-19 patients to adverse cardiovascular outcomes. In conclusion, considering weakened protection against the cardiovascular risk-enhancing reinfections with emerging new subvariants of SARS-CoV-2, treatment of COVID-19 patients with statins during the illness and thereafter is recommended, partly because the statins tend to reduce endothelial dysfunction.

Obesity-induced changes in cancer cells and their microenvironment: Mechanisms and therapeutic perspectives to manage dysregulated lipid metabolism.

Obesity has been closely related to cancer progression, recurrence, metastasis, and treatment resistance. We aim to review recent progress in the knowledge on the obese macroenvironment and the generated adipose tumor microenvironment (TME) inducing lipid metabolic dysregulation and their influence on carcinogenic processes. Visceral white adipose tissue expansion during obesity exerts systemic or macroenvironmental effects on tumor initiation, growth, and invasion by promoting inflammation, hyperinsulinemia, growth-factor release, and dyslipidemia. The dynamic relationship between cancer and stromal cells of the obese adipose TME is critical for cancer cell survival and proliferation as well. Experimental evidence shows that secreted paracrine signals from cancer cells can induce lipolysis in cancer-associated adipocytes, causing them to release free fatty acids and acquire a fibroblast-like phenotype. Such adipocyte delipidation and phenotypic change is accompanied by an increased secretion of cytokines by cancer-associated adipocytes and tumor-associated macrophages in the TME. Mechanistically, the availability of adipose TME free fatty acids and tumorigenic cytokines concomitant with the activation of angiogenic processes creates an environment that favors a shift in the cancer cells toward an aggressive phenotype associated with increased invasiveness. We conclude that restoring the aberrant metabolic alterations in the host macroenvironment and in adipose TME of obese subjects would be a therapeutic option to prevent cancer development. Several dietary, lipid-based, and oral antidiabetic pharmacological therapies could potentially prevent tumorigenic processes associated with the dysregulated lipid metabolism closely linked to obesity.

Coronary microcirculatory dysfunction in hypercholesterolemic patients with COVID-19: potential benefit from cholesterol-lowering treatment.

Patients with hypercholesterolemia often have coronary microvascular dysfunction (CMD). Viral infections, such as the SARS-CoV-2 infection, may also result in CMD. Three non-randomized studies have shown significant beneficial effects of statins on CMD in non-infected patients. Similarly, in SARS-CoV-2 - infected patients one beneficial mechanism of action of statins may be the amelioration of endothelial dysfunction, which is a major driver of CMD. Apart from statins, lipoprotein apheresis and PCSK9 inhibitors can also improve or even reverse CMD. The potential reversal of CMD by using effective cholesterol-lowering medications during and after COVID-19 infection, especially in hypercholesterolemic COVID-19 patients, is important.KEY MESSAGESCoronary microvascular dysfunction (CMD) is common in patients hospitalized with SARS-CoV-2 infectionThree nonrandomized studies in non-infected patients are showing the beneficial effects of statin treatment on CMDEffective cholesterol-lowering medication during and after SARS-CoV-2 infection, especially in hypercholesterolemic COVID-19 patients, is of great significance.

Familial hypercholesterolemia: The nexus of endothelial dysfunction and lipoprotein metabolism in COVID-19.

PURPOSE OF REVIEW: Patients with heterozygous familial hypercholesterolemia (HeFH) are at increased risk for COVID-19 cardiovascular complications in the acute phase of the infection. Elevated levels of LDL-C and often lipoprotein(a) are present from birth and lead to endothelial dysfunction, which is aggravated by a direct viral attack of the endothelial cells and their exposure to the toxic levels of circulating proinflammatory and prothrombotic mediators during the hyperinflammatory reaction typical of COVID-19. RECENT FINDINGS: Evidence to date shows the benefit of lipid-lowering therapy in patients with COVID-19. In HeFH patients who are at much higher cardiovascular risk, the focus should, therefore, be on the effective lowering of LDL-C levels, the root cause of the greater cardiovascular vulnerability to COVID-19 infection in these patients. The ongoing use of statins and other lipid-lowering therapies should be encouraged during the ongoing COVID pandemic to mitigate the risk of cardiovascular complications from COVID-19, particularly in HeFH patients. SUMMARY: Epidemiologic registry data show that the incidence of myocardial infarction is increased in SARS-CoV-2-infected HeFH patients. There is a need to study whether the risk for acute cardiovascular events is increased in the long-term and if there are changes in lipid metabolism after SARS-CoV infection(s) in patients with HeFH.

Atlantic salmon (Salmo salar) age at maturity is strongly affected by temperature, population and age-at-maturity genotype.

Age at maturity is a key life history trait involving a trade-off between survival risk and reproductive investment, and is an important factor for population structures. In ectotherms, a warming environment may have a dramatic influence on development and life history, but this influence may differ between populations. While an increasing number of studies have examined population-dependent reactions with temperature, few have investigated this in the context of maturation timing. Atlantic salmon, a species of high conservation relevance, is a good study species for this topic as it displays considerable variation in age at maturity, of which a large proportion has been associated with a genomic region including the strong candidate gene vgll3. Until now, the effect of this gene in the context of different environments and populations has not been studied. Using a large-scale common-garden experiment, we find strong effects of temperature, population-of-origin, and vgll3 genotype on maturation in 2-year-old male Atlantic salmon (Salmo salar). With a temperature difference of 1.8°C, maturation probability was 4.8 times higher in the warm treatment than the cold treatment. This temperature effect was population-specific and was higher in the southern (60.48°N) compared to the northern (65.01°N) population. The early maturation vgll3*E allele was associated with a significantly higher maturation probability, but there was no vgll3 interaction with temperature or population. Both body condition and body mass associated with maturation. The body mass association was only present in the warm treatment. Our findings demonstrate that (i) populations can vary in their response to temperature change in terms of age at maturity, (ii) high intrinsic growth could be associated with higher thermal sensitivity for life history variation and (iii) vgll3 effects on age at maturity might be similar between populations and different thermal environments.

Environment and mate attractiveness in a wild insect.

The role of female choice in sexual selection is well established, including the recognition that females choose their mates based on multiple cues. These cues may include intrinsic aspects of a male's phenotype as well as aspects of the environment associated with the male. The role of the spatial location of a potential mate has been well studied in territorial vertebrates. However, despite their role as laboratory models for studies of sexual selection, the potential for insects to choose their mates on the basis of location has scarcely been studied. We studied a natural population of individually tagged crickets (Gryllus campestris) in a meadow in Northern Spain. Adults typically move between burrows every few days, allowing us to examine how pairing success of males can be predicted by the burrow they occupy, independent of their own characteristics. We observed the entirety of ten independent breeding seasons to provide replication and to determine whether the relative importance of these factors is stable across years. We find that both male ID and the ID his burrow affect the likelihood that he is paired with a female, but the burrow has a consistently greater influence. Furthermore, the two factors interact: the relative attractiveness of an individual male depends on which burrow he occupies. Our finding demonstrates a close interaction between naturally and sexually selected traits. It also demonstrates that mate choice studies may benefit from considering not only obvious secondary sexual traits, but also more cryptic traits such as microhabitat choice.

Maleficent Comrades: War in Ukraine and COVID-19.

Infectious diseases and war are maleficent comrades. This reality applies equally well to the war in Ukraine and the current coronavirus disease 2019 (COVID-19) pandemic. Europe is facing a huge refugee crisis and potentially the conflict could worsen the COVID-19 pandemic. Initially, 2 major countries of concern are Poland, which has taken the majority of refugees, and Moldova, which has taken a very large number of refugees on a per capita basis. However, the concern extends to the rest of Europe because of the mobility of refugees beyond the first country they enter. Vaccinating, infection control, and boosting refugees should be a priority. However, complete prevention of COVID-19 is very complex because of other issues related to the success of prevention.

Lymphatic vessels are present in human saccular intracranial aneurysms.

Saccular intracranial aneurysm (sIA) rupture leads to subarachnoid haemorrhage and is preceded by chronic inflammation and atherosclerotic changes of the sIA wall. Increased lymphangiogenesis has been detected in atherosclerotic extracranial arteries and in abdominal aortic aneurysms, but the presence of lymphatic vessels in sIAs has remained unexplored. Here we studied the presence of lymphatic vessels in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), using immunohistochemical and immunofluorescence stainings for lymphatic endothelial cell (LEC) markers. Of these LEC-markers, both extracellular and intracellular LYVE-1-, podoplanin-, VEGFR-3-, and Prox1-positive stainings were detected in 83%, 94%, 100%, and 72% of the 36 sIA walls, respectively. Lymphatic vessels were identified as ring-shaped structures positive for one or more of the LEC markers. Of the sIAs, 78% contained lymphatic vessels positive for at least one LEC marker. The presence of LECs and lymphatic vessels were associated with the number of CD68+ and CD163+ cells in the sIA walls, and with the expression of inflammation indicators such as serum amyloid A, myeloperoxidase, and cyclo-oxygenase 2, with the presence of a thrombus, and with the sIA wall rupture. Large areas of VEGFR-3 and α-smooth muscle actin (αSMA) double-positive cells were detected in medial parts of the sIA walls. Also, a few podoplanin and αSMA double-positive cells were discovered. In addition, LYVE-1 and CD68 double-positive cells were detected in the sIA walls and in the thrombus revealing that certain CD68+ macrophages are capable of expressing LEC markers. This study demonstrates for the first time the presence of lymphatic vessels in human sIA walls. Further studies are needed to understand the role of lymphatic vessels in the pathogenesis of sIA.

Tankyrase Inhibition Attenuates Cardiac Dilatation and Dysfunction in Ischemic Heart Failure.

Hyperactive poly(ADP-ribose) polymerases (PARP) promote ischemic heart failure (IHF) after myocardial infarction (MI). However, the role of tankyrases (TNKSs), members of the PARP family, in pathogenesis of IHF remains unknown. We investigated the expression and activation of TNKSs in myocardium of IHF patients and MI rats. We explored the cardioprotective effect of TNKS inhibition in an isoproterenol-induced zebrafish HF model. In IHF patients, we observed elevated TNKS2 and DICER and concomitant upregulation of miR-34a-5p and miR-21-5p in non-infarcted myocardium. In a rat MI model, we found augmented TNKS2 and DICER in the border and infarct areas at the early stage of post-MI. We also observed consistently increased TNKS1 in the border and infarct areas and destabilized AXIN in the infarct area from 4 weeks onward, which in turn triggered Wnt/ß-catenin signaling. In an isoproterenol-induced HF zebrafish model, inhibition of TNKS activity with XAV939, a TNKSs-specific inhibitor, protected against ventricular dilatation and cardiac dysfunction and abrogated overactivation of Wnt/ß-catenin signaling and dysregulation of miR-34a-5p induced by isoproterenol. Our study unravels a potential role of TNKSs in the pathogenesis of IHF by regulating Wnt/ß-catenin signaling and possibly modulating miRNAs and highlights the pharmacotherapeutic potential of TNKS inhibition for prevention of IHF.