Experimental Myocardial Infarction Induces Altered Regulatory T Cell Hemostasis,and Adoptive Transfer Attenuates Subsequent Remodeling

Background

Ischemic cardiac damage is associated with upregulation of cardiac pro-inflammatory cytokines, as well as invasion of lymphocytes into the heart. Regulatory T cells (Tregs) are known to exert a suppressive effect on several immune cell types. We sought to determine whether the Treg pool is influenced by myocardial damage and whether Tregs transfer and deletion affect cardiac remodeling.

Methods and Results

The number and functional suppressive activity of Tregs were assayed in mice subjected to experimental myocardial infarction. The numbers of splenocyte-derived Tregs in the ischemic mice were significantly higher after the injury than in the controls, and their suppressive properties were significantly compromised. Compared with PBS, adoptive Treg transfer to mice with experimental infarction reduced infarct size and improved LV remodeling and functional performance by echocardiography. Treg deletion with blocking anti-CD25 antibodies did not influence infarct size or echocardiographic features of cardiac remodeling.

Conclusion

Treg numbers are increased whereas their function is compromised in mice with that underwent experimental infarction. Transfer of exogeneous Tregs results in attenuation of myocardial remodeling whereas their ablation has no effect. Thus, Tregs may serve as interesting potential interventional targets for attenuating left ventricular remodeling.     

Optimal control of the spatial allocation of COVID-19 vaccines: Italy as a case study

While campaigns of vaccination against SARS-CoV-2 are underway across the world, communities face the challenge of a fair and effective distribution of a limited supply of doses. Current vaccine allocation strategies are based on criteria such as age or risk. In the light of strong spatial heterogeneities in disease history and transmission, we explore spatial allocation strategies as a complement to existing approaches. Given the practical constraints and complex epidemiological dynamics, designing effective vaccination strategies at a country scale is an intricate task. We propose a novel optimal control framework to derive the best possible vaccine allocation for given disease transmission projections and constraints on vaccine supply and distribution logistics. As a proof-of-concept, we couple our framework with an existing spatially explicit compartmental COVID-19 model tailored to the Italian geographic and epidemiological context. We optimize the vaccine allocation on scenarios of unfolding disease transmission across the 107 provinces of Italy, from January to April 2021. For each scenario, the optimal solution significantly outperforms alternative strategies that prioritize provinces based on incidence, population distribution, or prevalence of susceptibles. Our results suggest that the complex interplay between the mobility network and the spatial heterogeneities implies highly non-trivial prioritization strategies for effective vaccination campaigns. Our work demonstrates the potential of optimal control for complex and heterogeneous epidemiological landscapes at country, and possibly global, scales.     

Activation of Plasmin in Mastitic Milk

Milk and whey samples from healthy and inflamed udder quarters of 10 Ayrshire cows were analyzed for proteolytic activity using radial caseolysis procedures, a fluorogenic coumaryl peptide substrate, and casein agarose zymography. Free lysosomal enzyme activity (N–acetyl–beta–D–glucosaminidase) was used as the criterion for inflammation. All mastitic milk samples had proteolytic activity, tentatively identified as plasmin (comigration at Mr 83 000 and characteristic fragmentation). The plasmin activities in mastitic milk were on average 2.9 μg/ml (range 0.5–12.5) as measured by radial caseolysis. Milk or whey specimens from healthy quarters were all negative except 1 in which an activity of 0.1 μg/ml was found in both specimens. The caseolytic activities were totally inhibited by 50 KITJ/ml of aprotinin, a serine proteinase inhibitor from bovine lung. No free plasminogen activator (PA) activity was found in any of the samples. Howewer, according to zymographic analyses PA molecules corresponding to urokinase were found in healthy and especially in mastitic specimens. Analysis of plasmin may provide an alternative means of screening for mastitic milk samples.     

Social stress shortens lifespan in mice

Stress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age‐related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early‐stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon.     

Redescription of Dekeyseria picta (Siluriformes; Loricariidae), a poorly known ancistrin from the Amazon and Orinoco Basins

A re‐evaluation of Dekeyseria brachyura and D. pulchra found them to be junior synonyms of D. picta, the oldest species among these congeners, based on continuous intraspecific variation in morphometrics and colour pattern. Examination of material deposited at Brazilian and Venezuelan collections, including the original type specimens of Ancistrus brachyurus and A. pictus, plus samples recently collected in the Rio Negro, Amazonas, Brazil, allowed re‐evaluation of the taxonomic status of D. picta and provides additional information on its distribution, habitats and reproductive strategies.     

Phylogeny of the genus Tordylium (Tordylineae,Apioideae, Apiaceae) inferred from morphological data

Tordylium is a medium‐sized genus characterized by an annual habit, 1–3‐pinnate leaves, dorsally compressed mericarps, and thickened mericarp margins. Eighteen Tordylium species occur in Turkey, of which seven are endemic. Although the morphology of the genus is well known, evolutionary relationships among its species have never been evaluated. In this study, phylogenetic relationships within Tordylium are investigated using parsimony analysis based on morphological data from 17 ingroup and 15 outgroup taxa from Turkey. The results indicate that Tordylium is paraphyletic due to the inclusion of Ormosciadium. Further, it suggests that Hasselquistia, Condylocarpus and Ainsworthia are nested within Tordylium, confirming their current taxonomic treatment as synonyms. Within the paraphyletic Tordylium, two major clades are apparent, but these clades are not compatible with the current sub‐generic classification. Tordylium lanatum, T. aegyptiacum and T. elegans, which have dimorphic mericarps, form a monophyletic subclade. In addition, it is suggested that T. aegaeum should be accepted as a distinct species rather than as a synonym of T. pestalozzae.     

Chronic kidney disease induced by an adenine rich diet upregulates integrin linked kinase (ILK) and its depletion prevents the disease progression

Kidney fibrosis is one of the main pathological findings of progressive chronic kidney disease (CKD) although the pathogenesis of renal scar formation remains incompletely explained. Integrin-linked kinase (ILK), a major scaffold protein between the extracellular matrix (ECM) and intracellular signaling pathways, is involved in several pathophysiological processes during renal damage. However, ILK contribution in the CKD progress remains to be fully elucidated. In the present work, we studied 1) the renal functional and structural consequences of CKD genesis and progression when ILK is depleted and 2) the potential of ILK depletion as a therapeutic approach to delay CKD progression. We induced an experimental CKD model, based on an adenine-supplemented diet on adult wild-type (WT) and ILK-depleted mice, with a tubulointerstitial damage profile resembling that is observed in human CKD. The adenine diet induced in WT mice a progressive increase in plasma creatinine and urea concentrations. In the renal cortex it was also observed tubular damage, interstitial fibrosis and progressive increased ECM components, pro-inflammatory and chemo-attractant cytokines, EMT markers and TGF-β1 expressions. These observations were highly correlated to a simultaneous increase of ILK expression and activity. In adenine-fed transgenic ILK-depleted mice, all these changes were prevented. Additionally, we evaluated the potential role of ILK depletion to be applied after the disease induction, as an effective approach to interventions in human CKD subjects. In this scenario, two weeks after the establishment of adenine-induced CKD, ILK was abrogated in WT mice and stabilized renal damage, avoiding CKD progression. We propose ILK to be a potential target to delay renal disease progression.     

Construction of a medium-density horse gene map

A medium-density map of the horse genome (Equus caballus) was constructed using genes evenly distributed over the human genome. Three hundred and twenty-three exonic primer pairs were used to screen the INRA and the CHORI-241 equine BAC libraries by polymerase chain reaction and by filter hybridization respectively. Two hundred and thirty-seven BACs containing equine gene orthologues, confirmed by sequencing, were isolated. The BACs were localized to horse chromosomes by fluorescent in situ hybridization (FISH). Overall, 165 genes were assigned to the equine genomic map by radiation hybrid (RH) (using an equine RH(5000) panel) and/or by FISH mapping. A comparison of localizations of 713 genes mapped on the horse genome and on the human genome revealed 59 homologous segments and 131 conserved segments. Two of these homologies (ECA27/HSA8 and ECA12p/HSA11p) had not been previously identified. An enhanced resolution of conserved and rearranged chromosomal segments presented in this study provides clarification of chromosome evolution history.