In December 2019, an outbreak of pneumonia of unknown origin was reported in Wuhan, Hubei Province, China. Pneumonia cases were epidemiologically linked to the Huanan Seafood Wholesale Market. Inoculation of respiratory samples into human airway epithelial cells, Vero E6 and Huh7 cell lines, led to the isolation of a novel respiratory virus whose genome analysis showed it to be a novel coronavirus related to SARS-CoV, and therefore named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a betacoronavirus belonging to the subgenus Sarbecovirus. The global spread of SARS-CoV-2 and the thousands of deaths caused by coronavirus disease (COVID-19) led the World Health Organization to declare a pandemic on 12 March 2020. To date, the world has paid a high toll in this pandemic in terms of human lives lost, economic repercussions and increased poverty. In this review, we provide information regarding the epidemiology, serological and molecular diagnosis, origin of SARS-CoV-2 and its ability to infect human cells, and safety issues. Then we focus on the available therapies to fight COVID-19, the development of vaccines, the role of artificial intelligence in the management of the pandemic and limiting the spread of the virus, the impact of the COVID-19 epidemic on our lifestyle, and preparation for a possible second wave.

Summaryp73 has been recently identified as a new structural and functional homologue of the transcription factor p53. It is expressed in either a full-length form, ␣ , or a shorter ␤ mRNA variant, with exon 13 spliced out. Here we report the identification and functional characterization of two new p73 splicing variants, ␥ (splicing out exon 11) and ␦ (splicing out exons 11, 12, and 13). Both ␥ and ␦ p73 variants are expressed in human peripheral blood lymphocytes, primary keratinocytes, and different tumor cell lines, including neuroblastoma, glioblastoma, melanoma, hepatoma, and leukemia. The expression pattern of the four p73 splicing variants differs in both primary cells of different lineage and established cell lines even within the same type of tumor. A two-hybrid assay was used to characterize the homodimeric and heterodimeric interactions between the p73 variants, and showed that neither p73 ␥ nor p73 ␦ interact with p53, whereas p73 ␥ showed strong interactions with all p73 isoforms, and p73 ␦ binds efficiently p73 ␣ and p73 ␥ but only weakly p73 ␤ . At the functional level, p73 ␥ is significantly less efficient in activating transcription of the p21 Waf1/Cip1 promoter than p53 or p73 ␤ , whereas the effect of p73 ␦ is intermediate and comparable to that of p73 ␣ . The ability of the different p73 variants to affect cell growth in p53 null osteosarcoma SAOS-2 cells correlates with their transcriptional activity on the p21 Waf1/Cip1 promoter: p73 ␤ is the most efficient in inhibiting colony formation, whereas p73 ␥ is almost ineffective. Our results suggest that p73 isoforms may be differentially regulated, with four different isoforms capable of interacting among themselves and with p53. The relative expression level of each splice variant may modulate p73 transcriptional and growth suppression activities by affecting heterodimer formation.

Background-Aging is a major risk factor for the development of atherosclerosis and coronary artery disease. Through a microarray approach, we have identified a microRNA (miR-217) that is progressively expressed in endothelial cells with aging. miR-217 regulates the expression of silent information regulator 1 (SirT1), a major regulator of longevity and metabolic disorders that is progressively reduced in multiple tissues during aging. Methods and Results-miR-217 inhibits SirT1 expression through a miR-217-

TP63, an important epithelial developmental gene, has significant homology to p53. Unlike p53, the expression of p63 is regulated by two different promoters resulting in proteins with opposite functions: the full-length transcriptionally active TAp63 and the dominant-negative DNp63. We investigated the downstream mechanisms by which TAp63a elicits apoptosis. TAp63a directly transactivates the CD95 gene via the p53 binding site in the first intron resulting in upregulation of a functional CD95 death receptor. Stimulation and blocking experiments of the CD95, TNF-R and TRAIL-R death receptor systems revealed that TAp63a can trigger expression of each of these death receptors. Furthermore, our findings demonstrate a link between TAp63a and the mitochondrial apoptosis pathway. TAp63a upregulates expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of RAD9, DAP3 and APAF1. Of clinical relevance is the fact that TAp63a is induced by many chemotherapeutic drugs and that inhibiting TAp63 function leads to chemoresistance. Thus, beyond its importance in development and differentiation, we describe an important role for TAp63a in the induction of apoptosis and chemosensitivity.

p63 inhibits metastasis. Here, we show that p63 (both TAp63 and ΔNp63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial-mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti-miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing endogenous mutated p53, can be abrogated by pre-miR-205 or silencing of mutated p53. In accordance with this in vitro data, ΔNp63 or miR-205 significantly inhibits the incidence of lung metastasis in vivo in a mouse tail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in a set of 218 human prostate cancer samples. This was confirmed in an independent clinical data set of 281 patients. Loss of this axis was associated with higher Gleason scores, an increased likelihood of metastatic and infiltration events, and worse prognosis. These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer

Epidermal development requires the transcription factor p63, as p63À/À mice are born dead, without skin. The gene expresses two proteins, one with an amino-terminal transactivation domain (TAp63) and one without (DNp63), although their relative contribution to epidermal development is unknown. To address this issue, we reintroduced TAp63a and/or DNp63a under the K5 promoter into p63À/À mice by in vivo genetic complementation. Whereas p63À/À and p63À/À;TA mice showed extremely rare patches of poorly differentiated keratinocytes, p63À/À;DN mice showed significant epidermal basal layer formation. Double TAp63a/ DNp63a complementation showed greater patches of differentiated skin; at the ultrastructural level, there was clear reformation of a distinct basal membrane and hemidesmosomes. At the molecular level, DNp63 regulated expression of genes characteristic of the basal layer (K14), interacting (by Chip, luc assay) with the third p53 consensus site. Conversely, TAp63 transcribed the upper layer's genes (Ets-1, K1, transglutaminases, involucrin). Therefore, the two p63 isoforms appear to play distinct cooperative roles in epidermal formation.

Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant form of genetic hair loss. In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5' UTR of the gene encoding the human hairless homolog (HR). U2HR is predicted to encode a 34-amino acid peptide that is highly conserved among mammals. In 18 more families from different ancestral groups, we identified a range of defects in U2HR, including loss of initiation, delayed termination codon and nonsense and missense mutations. Functional analysis showed that these classes of mutations all resulted in increased translation of the main HR physiological ORF. Our results establish the link between MUHH and U2HR, show that fine-tuning of HR protein levels is important in control of hair growth, and identify a potential mechanism for preventing hair loss or promoting hair removal.

3). In particular, the U7 small nuclear ribonucleoproteins and other factors involved in histone precursor mRNA processing are known to accumulate within CBs (1, 4). Notably, CBs also associate with the major histone gene clusters in a variety of organisms, including mammals, amphibians, and dipterans (5, 6). In addition to participating in various RNA-processing activities, CBs have also been implicated in transcriptional regulation of the cell-cycledependent histone genes. Phosphorylation of a CB component p220͞nuclear protein, ataxia-telangiectasia (NPAT) by cyclin E͞Cdk2 is required for activation of histone transcription, exit from G 1 , and progression through S phase (7-12). Taken together, these observations suggest that CBs are intimately involved in histone gene expression.In this study, we identify FADD-like IL-1␤-converting enzyme (FLICE) associated huge protein (FLASH) (13) as a component of the histone gene expression machinery. Although FLASH was originally identified as a component of the apoptotic signaling complex known as the death-inducing signaling complex (DISC) that is assembled in response to Fas ligand binding (13, 14), we have recently shown that FLASH is an essential component of CBs and is required for maintenance of their structure (15). We show that FLASH colocalizes with the histone transcriptional activator, NPAT, in CBs and is required for efficient expression of histone genes. Results FLASH Down-Regulation Results in S-Phase Block.One of the hallmarks of proteins that are involved in expression of the cell-cycle-dependent histone genes is that perturbation of their function results in an accumulation of cells in S phase. Accordingly, we found that treatment of cells with short hairpin RNAs (shRNAs) targeting FLASH (shFLASH) resulted in a dramatic block of cells within S-phase of the cell cycle (Fig. 1a). Such a block was observed in all cell lines tested (HEK293, HeLa, MCF-7, SAOS2, 3T3 and MEFs) reaching up to 70% after 72 h (see Fig. 5, which is published as supporting information on the PNAS web site). These findings were confirmed through use of a colony-forming assay, revealing that down-regulation of FLASH resulted in a remarkable reduction in growth of the shFLASH-treated cells (Fig. 1b). Western blot in Fig. 1c confirms FLASH protein levels downregulation after shRNA treatment.Another hallmark of genes involved in histone gene expression is that their protein levels are up-regulated during S phase. Endogenous FLASH expression showed a clear cell-cycledependence, peaking during S-phase, when cells were synchronized by thymidine block and deoxycytidine release (Fig. 1d). Consistent with these observations, we found that the number of FLASH-positive bodies was correlated with the cell cycle. Primary (IMR90) cells were used for this analysis, as they are diploid. As shown in Fig. 1e, the number of FLASH bodies in BrdU-positive (S-phase cells) was typically four, whereas in BrdU-negative cells, the number was typically two. FLASH Interacts with NPAT and Is Bound to Histone Ge...