Venous and arterial cerebral thrombosis: a COVID-19 dual pathology and single possible etiology—a case report

Background Corona virus disease of the year 2019 (COVID-19) is still devastating the world for more than 19 months since its declaration as a pandemic by world health organization. Its manifestations does not stand at respiratory system but involves other body systems including central nervous system and its vasculature. In the following case report, cerebral venous and arterial thrombosis is detected in a case just in convalescence from COVID-19 with still detected positive IgM. Case presentation A 68-year-old female presenting with disturbed conscious level, bilateral convergent squint, single attack of generalized seizures, left sided dense weakness within a short time from catching COVID-19 and while still in quarantine hospital in recovery phase from infection. Magnetic resonance studies revealed bilateral cortical border zone infarcts as well as left lateral dural sinus and deep venous thrombosis. Conclusion Along the forth wave, COVID-19 is still hitting hardly the central nervous system vasculature.

Co-transplantation of Mesenchymal Stromal Cells and Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improves Cardiac Function After Myocardial Damage

Induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) represent an attractive resource for cardiac regeneration. However, survival and functional integration of transplanted iPS-CM is poor and remains a major challenge for the development of effective therapies. We hypothesized that paracrine effects of co-transplanted mesenchymal stromal cells (MSCs) augment the retention and therapeutic efficacy of iPS-CM in a mouse model of myocardial infarction (MI). To test this, either iPS-CM, MSC, or both cell types were transplanted into the cryoinfarction border zone of syngeneic mice immediately after injury. Bioluminescence imaging (BLI) of iPS-CM did not confirm enhanced retention by co-application of MSC during the 28-day follow-up period. However, histological analyses of hearts 28 days after cell transplantation showed that MSC increased the fraction of animals with detectable iPS-CM by 2-fold. Cardiac MRI analyses showed that from day 14 after transplantation on, the animals that have received cells had a significantly higher left ventricular ejection fraction (LVEF) compared to the placebo group. There was no statistically significant difference in LVEF between animals transplanted only with iPS-CM or only with MSC. However, combined iPS-CM and MSC transplantation resulted in higher LVEF compared to transplantation of single-cell populations during the whole observation period. Histological analyses revealed that MSC increased the capillarization in the myocardium when transplanted alone or with iPS-CM and decreased the infarct scar area only when transplanted in combination with iPS-CM. These results indicate that co-transplantation of iPS-CM and MSC improves cardiac regeneration after cardiac damage, demonstrating the potential of combining multiple cell types for increasing the efficacy of future cardiac cell therapies.

Disassembly and Mislocalization of AQP4 in Incipient Scar Formation After Experimental Stroke

There is an urgent need to better understand the mechanisms involved in scar formation in brain. It is well known that astrocytes are critically engaged in this process. Here we analyze in-cipient scar formation one week after a discrete ischemic insult to the cerebral cortex. We show that the infarct border zone is characterized by pronounced changes in the organization and subcellular localization of the major astrocytic protein AQP4. Specifically there is a loss of AQP4 from astrocytic endfoot membranes that anchor astrocytes to pericapillary basal laminae and a disassembly of the supramolecular AQP4 complexes that normally abound in these membranes. This disassembly may be mechanistically coupled to a downregulation of the newly discovered AQP4 isoform AQP4ex. AQP4 has adhesive properties and is assumed to facilitate astrocyte mo-bility by permitting rapid volume changes at the leading edges of migrating astrocytes. Thus, the present findings provide new insight in the molecular basis of incipient scar formation.

Haemagogus leucocelaenus (Diptera: Culicidae), the potential wild vector of yellow fever in the border zone of northern Misiones, Argentina

Haemagogus leucocelaenus (Diptera: Culicidae) is considered the primary vector of yellow fever virus (Flaviviridae) in wild environments in South America. Previous research has defined Hg. leucocelaenus as a wild species with phytotelmata-type breeding sites. The objective of this study was to report the temporal and space occurrence of Hg. leucocelaenus at the microscale in the wild-periurban fringe through a systematic and spatially stratified sampling using 81 ovitraps between April 2019 and February 2 020 in the locality of Puerto Iguazú, Argentina. Of the total ovitraps, eight were positive for Hg. leucocelaenus, six in the wild environment and two in the periurban environment. Regarding the time distribution, 98.5% of the occurrence was concentrated in November and December 2019 towards the beginning of the rainy season. The results confirm the habitat plasticity of Hg. leucocelaenus and establish the aptitude of artificial containers as a methodology in monitoring studies, since they illustrate the potential of wild populations to deposit fertile eggs in them at least up to 300 m from the wild-periurban fringe. This work is a contribution to determine the temporal and space risk of yellow fever virus transmission in the region, based on the distribution patterns of this species as a function to the ecotone associated with forest borders and climatic variables.

Myofibroblast Senescence Promotes Arrhythmogenic Remodeling in the Aged Infarcted Rabbit Heart

Progressive tissue remodeling after myocardial infarction (MI) promotes cardiac arrhythmias. This process is well studied in young animals, but little is known about pro-arrhythmic changes in aged animals. Senescent cells accumulate with age and accelerate age-associated diseases. Senescent cells interfere with cardiac function and outcome post-MI with age, but studies have not been performed in large animals, and the mechanisms are unknown. Here, we investigated the role of senescence in regulating inflammation, fibrosis, and arrhythmogenesis in young and aged infarcted rabbits. Aged rabbits exhibited increased peri-procedural mortality and arrhythmogenic electrophysiological remodeling at the infarct border zone (IBZ) compared to young rabbits. Studies of the aged infarct zone revealed persistent myofibroblast senescence and increased inflammatory signaling over a twelve-week timecourse. Senescent IBZ myofibroblasts in aged rabbits appear to be coupled to myocytes, and our computational modeling showed that senescent myofibroblast-cardiomyocyte coupling prolongs action potential duration (APD) and facilitates conduction block permissive of arrhythmias. Aged infarcted human ventricles show levels of senescence consistent with aged rabbits, and senescent myofibroblasts also couple to IBZ myocytes. Our findings suggest that senolytic drugs may mitigate arrhythmias post-MI.

Characterizing Neonatal Heart Maturation, Regeneration, and Scar Resolution Using Spatial Transcriptomics

The neonatal mammalian heart exhibits a remarkable regenerative potential, which includes fibrotic scar resolution and the generation of new cardiomyocytes. To investigate the mechanisms facilitating heart repair after apical resection in neonatal mice, we conducted bulk and spatial transcriptomic analyses at regenerative and non-regenerative timepoints. Importantly, spatial transcriptomics provided near single-cell resolution, revealing distinct domains of atrial and ventricular myocardium that exhibit dynamic phenotypic alterations during postnatal heart maturation. Spatial transcriptomics also defined the cardiac scar, which transitions from a proliferative to secretory phenotype as the heart loses regenerative potential. The resolving scar is characterized by spatially and temporally restricted programs of inflammation, epicardium expansion and extracellular matrix production, metabolic reprogramming, lipogenic scar extrusion, and cardiomyocyte restoration. Finally, this study revealed the emergence of a regenerative border zone defined by immature cardiomyocyte markers and the robust expression of Sprr1a. Taken together, our study defines the spatially and temporally restricted gene programs that underlie neonatal heart regeneration and provides insight into cardio-restorative mechanisms supporting scar resolution.

Interpretable surface-based detection of focal cortical dysplasias: a MELD study

Introduction: One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualise on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. Methods: The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonised a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Results: Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. Overall, after including a border-zone around lesions, the developed MELD FCD surface-based algorithm had a sensitivity of 67% and a specificity of 54% on the withheld test cohort, and a sensitivity of 85% on a restricted subcohort of seizure free patients with FCD type IIB who had T1 and FLAIR MRI data. Conclusions: This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions.

Spatiotemporal transcriptomics reveals pathogenesis of viral myocarditis

A significant fraction of sudden death in children and young adults is due to myocarditis, an inflammatory disease of the heart, most often caused by viral infection. Here we used integrated single-cell and spatial transcriptomics to create a high-resolution, spatially resolved map of reovirus-induced myocarditis in neonatal murine hearts. We assayed hearts collected at three timepoints after reovirus infection and studied the temporal, spatial, and cellular heterogeneity of host-virus interactions. We further assayed the intestine, the primary site of reovirus infection to establish a full chronology of molecular events that ultimately lead to myocarditis. We implemented targeted enrichment of viral transcripts to establish the cellular targets of the virus in the intestine and the heart. Our data give insight into the cell-type specificity of innate immune responses, and into the transcriptional states of inflamed cardiac cells that recruit circulating immune cells, including cytotoxic T cells which induce pyroptosis in the myocarditic tissue. Analyses of spatially restricted gene expression in myocarditic regions and the border zone around those regions identified immune-mediated cell-type specific injury and stress responses. Overall, we observe a dynamic and complex network of cellular phenotypes and cell-cell interactions associated with viral myocarditis.