The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Caractérisation moléculaire de la laforine impliquée dans la maladie de Lafora (une protéine phosphatase humaine à double spécificité associée à un domaine de fixation à l'amidon)

Certaines mutations dans le gène EPM2A provoquent la maladie de Lafora, une épilepsie myoclonique progressive dont l'issue est fatale, caractérisée par la présence de corps d'inclusion de polyglucosan dans les tissus nerveux. L'analyse de la séquence du produit du gène (laforine) suggère la présence de deux domaines : un site de liaison à l'amidon (CBM20) en N-terminal, identifié pour la première fois dans une protéine humaine et un site catalytique de phosphatase à double spécificité (DSPc) en C-terminal. La partie codante du gène a été clonée a partir d'une banque de cDNA humain. Différentes constructions ont été réalisées et ont permis d'obtenir la laforine pure et soluble. Une première caractérisation a montré que la laforine se liait à l'amidon, conformément aux prédictions, mais également au glycogène. Des expériences de compétition entre ces deux polysaccharides mettent en évidence que la fixation aux sucres est spécifique. L'activité catalytique phosphatase a été mesurée pour deux substrats : le p-nitrophényl phosphate et l'O-méthylfluorescéinyl phosphate (OMFP). Les paramètres cinétiques montrent une meilleure efficacité catalytique vis-à-vis de l'OMFP, indiquant que la laforine porte une fonction de DSP. Ni le glycogène ni de petits saccharides n'affectent la fonction catalytique. Ceci est à comparer aux données sur les MAP kinases phosphatases (MKP) dont le site catalytique est homologue à celui de la laforine mais dont l'activité est régulée par la fixation au substrat. Par conséquent, il apparaît que le rôle du domaine CBM20 de la laforine soit de localiser la protéine au glycogène où elle pourrait jouer un rôle, qui reste à élucider, dans son métabolisme.Mutations in the EPM2A gene cause Lafora disease, a fatal progressive myoclonus epilepsy characterized by the presence of polyglucosan inclusion bodies in nervous tissues. Sequence analysis of the gene product (laforin), suggested two domains: an N-terminal starch-binding domain (CBM20), found for the first time in a human protein, and a C-terminal dual specificity phosphatase catalytic domain (DSPc). The gene was cloned from human muscle cDNA. Different constructs were assayed to express and purify the laforin which aggregated easily. Adsorption experiments demonstrate that laforin binds granular starch as predicted, and ultracentrifugation studies showed the protein also binds to glycogen. Competition experiments between granular starch with either glycogen or beta-cyclodextrin indicated the binding to be specific. To demonstrate the second predicted function, the catalytic activity was tested with p-nitrophenyl phosphate and O-methylfluorescein phosphate (OMFP), two non physiological substrates. Laforin exhibited a better efficiency toward OMFP, indicating that laforin bears a DSP function. Further experiments showed that neither glycogen nor smaller sugars affected the laforin catalytic activity. This is in contrast with MAP kinases phosphatases (MKP). Indeed, the laforin catalytic domain is homologous to that of MKPs but CBM20 is different from their regulatory domain. For MKPs, the catalytic activity is increased when the regulatory domain binds to their substrates. Thus it appears that the role of the laforin CBM20 domain is to target the protein to glycogen in the cells. In conclusion laforin may play a role in glycogen metabolism which has to be elucidated.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Due anni di riforme pensionistiche: gli effetti sulla spesa e le questioni ancora aperte

Nel nostro lavoro presentiamo le innovazioni normative introdotte negli ultimi due anni e utilizziamo il modello Cer di simulazione della spesa pensionistica di lungo periodo per valutare gli impatti economici delle principali innovazioni normative introdotte dalla riforma Fornero. Le comparazione dei risultati delle nostre simulazioni con le stime degli impatti di fonte governativa mostra delle differenze spesso notevoli nel breve periodo. Il profilo di lungo periodo in rapporto al Pil, tuttavia, è simile, e indica una spesa che, dopo un periodo di sensibile riduzione, ritorna ai valori previsti nello scenario pre-riforma e addirittura li supera. La decomposizione della spesa pensionistica fra numero dei trattamenti e loro importo medio ci permette di identificare l’origine di questo andamento temporale degli effetti economici della riforma Fornero. Il posponimento dell’anno di pensionamento, infatti, riduce il numero dei pensionati, ma aumenta in modo rilevante l’importo delle pensioni. Ciò perché i lavoratori accumulano un maggiore ammontare di contributi, ma soprattutto perché si pensionano ad una età molto più avanzata e quindi a loro si applicano modalità di calcolo della pensione più favorevoli. Nel testo viene fornita una stima dell’incremento dell’età di pensionamento prevedibile per i lavoratori del settore privato in seguito alla riforma Fornero

Assignment of TCRA/TCRD locus to sheep chromosome bands 7q1.4->7q2.2 by fluorescence in situ hybridization

Two genomic clones for the TCRA/TCRD locus have been isolated and characterized in sheep. The first clone corresponds to a new sheep Valpha element, the other to the entire Cdelta gene. Chromosomal mapping by fluorescence in situ hybridization (FISH) of Valpha and Cdelta clones localized the TCRA/TCRD locus on sheep chromosome region 7q14-->q22. This is the first physical assignment for genomic clones on sheep chromosome 7 by FISH. Moreover, the present data put the ovine 7q14-->q22 and the human 14q11.2 regions in the same syntenic group

The clinical use of regenerative therapy in COPD

Roberto Lipsi,1 Paola Rogliani,1 Luigino Calzetta,2 Andrea Segreti,1 Mario Cazzola1 1Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; 2Department of Pulmonary Rehabilitation, San Raffaele Pisana Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, Rome, Italy Abstract: Regenerative or stem cell therapy is an emerging field of treatment based on stimulation of endogenous resident stem cells or administration of exogenous stem cells to treat diseases or injury and to replace malfunctioning or damaged tissues. Current evidence suggests that in the lung, these cells may participate in tissue homeostasis and regeneration after injury. Animal and human studies have demonstrated that tissue-specific stem cells and bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells or humoral factors responsible for the activation of endogenous stem/progenitor cells may be a potent next-generation therapy for chronic obstructive pulmonary disease. The use of bone marrow-derived stem cells could allow repairing and regenerate the damaged tissue present in chronic obstructive pulmonary disease by means of their engraftment into the lung. Another approach could be the stimulation of resident stem cells by means of humoral factors or photobiostimulation. Keywords: chronic obstructive pulmonary disease, stem cells, regenerative therapy, all-trans retinoic acid, photobiostimulatio