A placental model of SARS-CoV-2 infection reveals ACE2-dependent susceptibility and differentiation impairment in syncytiotrophoblasts.

SARS-CoV-2 infection causes COVID-19. Several clinical reports have linked COVID-19 during pregnancy to negative birth outcomes and placentitis. However, the pathophysiological mechanisms underpinning SARS-CoV-2 infection during placentation and early pregnancy are not clear. Here, to shed light on this, we used induced trophoblast stem cells to generate an in vitro early placenta infection model. We identified that syncytiotrophoblasts could be infected through angiotensin-converting enzyme 2 (ACE2). Using a co-culture model of vertical transmission, we confirmed the ability of the virus to infect syncytiotrophoblasts through a previous endometrial cell infection. We further demonstrated transcriptional changes in infected syncytiotrophoblasts that led to impairment of cellular processes, reduced secretion of HCG hormone and morphological changes vital for syncytiotrophoblast function. Furthermore, different antibody strategies and antiviral drugs restore these impairments. In summary, we have established a scalable and tractable platform to study early placental cell types and highlighted its use in studying strategies to protect the placenta.

FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy.

The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG's glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.

PUMA promotes apoptosis of hematopoietic progenitors driving leukemic progression in a mouse model of myelodysplasia.

Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis with resultant cytopenias. Increased apoptosis and aberrantly functioning progenitors are thought to contribute to this phenotype. As is the case for other malignancies, overcoming apoptosis is believed to be important in progression toward acute myeloid leukemia (AML). Using the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, we previously reported that overexpression of the anti-apoptotic protein BCL2, blocked apoptosis and improved cytopenias, paradoxically, delaying leukemic progression. To further understand this surprising result, we examined the role of p53 and its pro-apoptotic effectors, PUMA and NOXA in NHD13 mice. The absence of p53 or PUMA but not NOXA reduced apoptosis and expanded the numbers of MDS-repopulating cells. Despite a similar effect on apoptosis and cell numbers, the absence of p53 and PUMA had diametrically opposed effects on progression to AML: absence of p53 accelerated leukemic progression, while absence of PUMA significantly delayed progression. This may be explained in part by differences in cellular responses to DNA damage. The absence of p53 led to higher levels of γ-H2AX (indicative of persistent DNA lesions) while PUMA-deficient NHD13 progenitors resolved DNA lesions in a manner comparable to wild-type cells. These results suggest that targeting PUMA may improve the cytopenias of MDS without a detrimental effect on leukemic progression thus warranting further investigation.

The emotional impact of European tobacco-warning images.

OBJECTIVE: The emotional impact of the tobacco-warning images proposed by the European Commission to reduce tobacco consumption is evaluated in the context of the International Affective Picture System, a well-established procedure for investigating appetitive (approach) and defensive (avoidance) motivational tendencies evoked by images. METHODS: In a cross-sectional study, 597 healthy male and female volunteers (from the University of Granada, the University of Balearic Islands and four different schools of Valencia and Balearic Islands) distributed in six age groups (13-14, 15-16, 17-18, 19-20, 21-22 and over 23 years old) and four smoking status groups (non-smokers, one-time smokers, occasional smokers and heavy smokers) rated their emotional responses to 35 European tobacco-warning images together with 42 pleasant and 42 unpleasant International Affective Picture System pictures using the valence and arousal scales of the Self-Assessment Manikin. FINDINGS: The results of the study indicate that the majority of the tobacco-warning images (83%) were distributed within the unpleasant space and ranged from moderately unpleasant to very unpleasant. However, a small but significant number of images (17%) were also distributed within the pleasant space, ranging from moderately pleasant to very pleasant. Only four unpleasant pictures were rated as highly arousing (11.4%). Women, the older age groups (over 17 years old), and occasional smokers evaluated these images as significantly more arousing than the other groups. CONCLUSION: Findings suggest that the capability of the European tobacco-warning images to prompt negative attitudes to reduce tobacco consumption might not extend to the general population but would be limited to specific target groups.

A new family of metrics for biopolymer contact structures.

Contact structures are simplified representations of biopolymers' three-dimensional structures. In this paper we introduce a new family of metrics (dm)m >/=3 for contact structures of a fixed length, based on their representation by means of edge ideals of a polynomial ring, that generalize Reidys and Stadler's subgroup metric for RNA secondary structures. We study some abstract properties of these metrics, and we obtain explicit descriptions of them for some values of m.