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

In-depth Characterization of Human iPSC-Cardiomyocytes Models of Long QT-3 and Brugada Syndromes during in vitro Maturation

Cardiovascular diseases can be congenital or acquired and represent the main cause of mortality worldwide. Long QT Syndrome 3 (LQTS3) and Brugada Syndrome (BrS) are congenital channelopathies mostly caused by SCN5A mutation. Both diseases have been associated with gain- and loss-of-function of the channel respectively. However, some mutations display an overlapping phenotype between the two diseases, rendering the diagnostic as well as the therapy of the diseases challenging. The use of disease-specific pluripotent stem cells to develop disease models has enabled the research of pathogenic pathways related to diseases and the search for new treatments. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a platform that has allowed advancement in personalized therapy circumventing the problem of genotype-phenotype differences existing between individuals. This study aimed to characterize both disease phenotypes at a cellular, molecular, and functional level. For this purpose, we used different stages of cardiomyocytes maturation to perform our experiments. The use of cardiomyocytes at distinct time points of maturation revealed that a certain threshold of CMs maturity is necessary for the evaluation of disease phenotypes during in-vitro experiments. At the cellular level, we observed that Cx43 distribution within the intercalated discs is not disturbed in disease models compared to the control. However, numerous genes coding for proteins involved in the mechanisms of ECC and cardiomyocytes' contractility were dysregulated. The molecular data as well as the patch-clamp analysis allow us to hypothesize that V240M mutation could be associated with a mixed phenotype between LQTS3 and BrS, and that the Q646Rfs*5 mutation is associated with BrS as described by prior studies. The calcium imaging showed that in the two disease models, the Ca2+ transient is impaired, and the time corresponding to 50% of Ca2+ extrusion is prolonged

The More, the Merrier? Multiple Myoglobin Genes in Fish Species, Especially in Gray Bichir (Polypterus senegalus) and Reedfish (Erpetoichthys calabaricus)

The members of the globin superfamily are a classical model system to investigate gene evolution and their fates as well as the diversity of protein function. One of the best-known globins is myoglobin (Mb), which is mainly expressed in heart muscle and transports oxygen from the sarcolemma to the mitochondria. Most vertebrates harbor a single copy of the myoglobin gene, but some fish species have multiple myoglobin genes. Phylogenetic analyses indicate an independent emergence of multiple myoglobin genes, whereby the origin is mostly the last common ancestor of each order. By analyzing different transcriptome data sets, we found at least 15 multiple myoglobin genes in the polypterid gray bichir (Polypterus senegalus) and reedfish (Erpetoichthys calabaricus). In reedfish, the myoglobin genes are expressed in a broad range of tissues but show very different expression values. In contrast, the Mb genes of the gray bichir show a rather scattered expression pattern; only a few Mb genes were found expressed in the analyzed tissues. Both, gray bichir and reedfish possess lungs which enable them to inhabit shallow and swampy waters throughout tropical Africa with frequently fluctuating and low oxygen concentrations. The myoglobin repertoire probably reflects the molecular adaptation to these conditions. The sequence divergence, the substitution rate, and the different expression pattern of multiple myoglobin genes in gray bichir and reedfish imply different functions, probably through sub- and neofunctionalization during evolution

Modeling genetic cardiac channelopathies using induced pluripotent stem cells - Status quo from an electrophysiological perspective

Long QT syndrome (LQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT) are genetic diseases of the heart caused by mutations in specific cardiac ion channels and are characterized by paroxysmal arrhythmias, which can deteriorate into ventricular fibrillation. In LQTS3 and BrS different mutations in the SCN5A gene lead to a gain-or a loss-of-function of the voltage-gated sodium channel Nav1.5, respectively. Although sharing the same gene mutation, these syndromes are characterized by different clinical manifestations and functional perturbations and in some cases even present an overlapping clinical phenotype. Several studies have shown that Na(+ )current abnormalities in LQTS3 and BrS can also cause Ca2+-signaling aberrancies in cardiomyocytes (CMs). Abnormal Ca2+ homeostasis is also the main feature of CPVT which is mostly caused by heterozygous mutations in the RyR2 gene. Large numbers of disease-causing mutations were identified in RyR2 and SCN5A but it is not clear how different variants in the SCN5A gene produce different clinical syndromes and if in CPVT Ca2+ abnormalities and drug sensitivities vary depending on the mutation site in the RyR2. These questions can now be addressed by using patient-specific in vitro models of these diseases based on induced pluripotent stem cells (iPSCs). In this review, we summarize different insights gained from these models with a focus on electrophysiological perturbations caused by different ion channel mutations and discuss how will this knowledge help develop better stratification and more efficient personalized therapies for these patients

QuinoMit Q10-Fluid attenuates hydrogen peroxide-induced irregular beating in mouse pluripotent stem cell-derived cardiomyocytes

Background: Coenzyme Q10 (CoQ10) is a crucial component of the mitochondrial structure which is involved in producing more than 90% of cellular ATP. This study aimed to investigate the protective effects and underlying mechanisms of QuinoMit Q10-Fluid against hydrogen peroxide (H2O2)-induced arrhythmias on cardiomyocytes (CMs). Methods: Undifferentiated stem cell-derived CMs were cultured in the presence of different concentrations of QuinoMit Q10-Fluid. To investigate if CoQ10 has anti-apoptotic activity, CMs were exposed to H2O2 for up to 100 h with or without CoQ10. The expression levels of cardiac reference genes were determined by RT-PCR. The structural and functional properties of CMs were examined by immunofluorescence and the xCELLigence system. Caspase 3/7 assay was also performed for cell apoptosis study. Results: The study showed that QuinoMit Q10-Fluid inhibits the proliferation of pluripotent stem cells at high concentrations and had less effect on cardiomyogenesis. However, the beating rate of clusters containing CMs generated under QuinoMit Q10-Fluid (1:100) was significantly increased. This increase was accompanied by the up-regulated expression level of some important cardiac markers during differentiation. Treatment of CMs with H2O2 notably induced irregular beating and decreased the amplitude of the beating signal of CMs, concomitantly with increased caspase-3/7 activity. However, CMs pretreated with QuinoMit exhibited a protective effect against H2O2 -induced arrhythmia. Conclusion: Our results reveal that QuinoMit Q10-Fluid attenuates H2O2-induced irregular beating in mouse pluripotent stem cell-derived CMs, at least partly by reducing the generation of ROS, suggesting a protective effect against CM dysfunctions

Effects of plant extracts and derivatives on cardiac K⁺, Nav, and Ca_v channels: a review

Natural products (NPs) are endless sources of compounds for fighting against several pathologies. Many dysfunctions, including cardiovascular disorders, such as cardiac arrhythmias have their modes of action regulation of the concentration of electrolytes inside and outside the cell targeting ion channels. Here, we highlight plant extracts and secondary metabolites’ effects on the treatment of related cardiac pathologies on hERG, Nav, and Cav of cardiomyocytes. The natural product’s pharmacology of expressed receptors like alpha-adrenergic receptors causes an influx of Ca2+ ions through receptor-operated Ca2+ ion channels. We also examine the NPs associated with cardiac contractions such as myocardial contractility by reducing the L-type calcium current and decreasing the intracellular calcium transient, inhibiting the K+ induced contractions, decreasing amplitude of myocyte shortening and showed negative ionotropic and chronotropic effects due to decreasing cytosolic Ca2+. We examine whether the NPs block potassium channels, particular the hERG channel and regulatory effects on Nav1.7.</p

Sea Level Variability and Change

Land surface albedo represents the fraction of solar radiation scattered backward by land surfaces. In the presence of vegetation, surface albedo results from complex nonlinear radiation transfer processes determining the amount of radiation that is scattered by the vegetation and its background, transmitted through the vegetation layer, or absorbed by the vegetation layer and its background. Anomalies in mid- and high latitude regions of the Northern Hemisphere result mainly from interannual variations in snow cover extent and duration in winter and spring. The large negative anomalies over the United States reflect the lack of snowfall and snowpack over the Rockies, the Midwest, and much of the eastern half of the country.JRC.H.7-Climate Risk Managemen

State of the Climate in 2012

For the first time in serveral years, the El Nino-Southern Oscillation did not dominate regional climate conditions around the globe. A weak La Ni a dissipated to ENSOneutral conditions by spring, and while El Nino appeared to be emerging during summer, this phase never fully developed as sea surface temperatures in the eastern conditions. Nevertheless, other large-scale climate patterns and extreme weather events impacted various regions during the year. A negative phase of the Arctic Oscillation from mid-January to early February contributed to frigid conditions in parts of northern Africa, eastern Europe, and western Asia. A lack of rain during the 2012 wet season led to the worst drought in at least the past three decades for northeastern Brazil. Central North America also experienced one of its most severe droughts on record. The Caribbean observed a very wet dry season and it was the Sahel's wettest rainy season in 50 years. Overall, the 2012 average temperature across global land and ocean surfaces ranked among the 10 warmest years on record. The global land surface temperature alone was also among the 10 warmest on record. In the upper atmosphere, the average stratospheric temperature was record or near-record cold, depending on the dataset. After a 30-year warming trend from 1970 to 1999 for global sea surface temperatures, the period 2000-12 had little further trend. This may be linked to the prevalence of La Ni a-like conditions during the 21st century. Heat content in the upper 700 m of the ocean remained near record high levels in 2012. Net increases from 2011 to 2012 were observed at 700-m to 2000-m depth and even in the abyssal ocean below. Following sharp decreases in to the effects of La Ni a, sea levels rebounded to reach records highs in 2012. The increased hydrological cycle seen in recent years continued, with more evaporation in drier locations and more precipitation in rainy areas. In a pattern that has held since 2004, salty areas of the ocean surfaces and subsurfaces were anomalously salty on average, while fresher areas were anomalously fresh. Global tropical cyclone activity during 2012 was near average, with a total of 84 storms compared with the 1981-2010 average of 89. Similar to 2010 and 2011, the North Atlantic was the only hurricane basin that experienced above-normal activity. In this basin, Sandy brought devastation to Cuba and parts of the eastern North American seaboard. All other basins experienced either near-or below-normal tropical cyclone activity. Only three tropical cyclones reached Category 5 intensity-all in Bopha became the only storm in the historical record to produce winds greater than 130 kt south of 7 N. It was also the costliest storm to affect the Philippines and killed more than 1000 residents. Minimum Arctic sea ice extent in September and Northern Hemisphere snow cover extent in June both reached new record lows. June snow cover extent is now declining at a faster rate (-17.6% per decade) than September sea ice extent (-13.0% per decade). Permafrost temperatures reached record high values in northernmost Alaska. A new melt extent record occurred on 11-12 July on the Greenland ice sheet; 97% of the ice sheet showed some form of melt, four times greater than the average melt for this time of year. The climate in Antarctica was relatively stable overall. The largest maximum sea ice extent since records begain in 1978 was observed in September 2012. In the stratosphere, warm air led to the second smallest ozone hole in the past two decades. Even so, the springtime ozone layer above Antarctica likely will not return to its early 1980s state until about 2060. Following a slight decline associated with the global 2 emissions from fossil fuel combustion and cement production reached a record 9.5 +/- 0.5 Pg C in 2011 and a new record of 9.7 +/- 0.5 Pg C is estimated for 2012. Atmospheric CO2 concentrations increased by 2.1 ppm in 2012, to 392.6 ppm. In spring 2012, 2 concentration exceeded 400 ppm at 7 of the 13 Arctic observation sites. Globally, other greenhouse gases including methane and nitrous oxide also continued to rise in concentration and the combined effect now represents a 32% increase in radiative forcing over a 1990 baseline. Concentrations of most ozone depleting substances continued to fall