Optogenetic acidification of synaptic vesicles and lysosomes

Acidification is required for the function of many intracellular organelles, but methods to acutely manipulate their intraluminal pH have not been available. Here we present a targeting strategy to selectively express the light-driven proton pump Arch3 on synaptic vesicles. Our new tool, pHoenix, can functionally replace endogenous proton pumps, enabling optogenetic control of vesicular acidification and neurotransmitter accumulation. Under physiological conditions, glutamatergic vesicles are nearly full, as additional vesicle acidification with pHoenix only slightly increased the quantal size. By contrast, we found that incompletely filled vesicles exhibited a lower release probability than full vesicles, suggesting preferential exocytosis of vesicles with high transmitter content. Our subcellular targeting approach can be transferred to other organelles, as demonstrated for a pHoenix variant that allows light-activated acidification of lysosomes

Design science : why, what and how – revisited

Design Science is the discipline that studies the creation of artifacts – products, services, and systems and their embedding in our physical, virtual, psychological, economic, and social environments. This editorial is a collective effort of the Design Science Journal’s editorial board members, past and present. The journal’s inaugural 2015 editorial, “Design Science: Why, What and How,” reflected the thoughts and vision of that first editorial board for the new journal and the discipline it represented. The present contribution offers the reflections of editors who served the journal in the past 10 years. The individual contributions were not primed and are presented here unedited for conformity or consistency. Differently from the 2015 editorial, there is no effort to synthesize the individual contributions, leaving the task to our readers, who can draw their own conclusions about the Design Science Journal and community accomplishments to date, and the challenges ahead

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

Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

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

A direct comparison of single-grain and multi-grain aliquot luminescence dating of feldspars from colluvial deposits in KwaZulu-Natal, South Africa

International audienceThe erosional landscape of the Jojosi dongas in KwaZulu-Natal, South Africa, exposes accretionary slope deposits that preserve important geological and archaeological information. This landscape was occupied by modern humans during the Stone Age for many thousands of years, as evidenced by the presence of numerous stone artefacts on the surface and interbedded within at least three phases of gully cut-and-fill deposits. A contextualisation of the artefacts and their role for human evolution in southern Africa, along with developing an understanding of the environmental conditions that shaped this inhabited landscape, is only made possible by establishing a robust chronological framework. Here, we use luminescence dating of feldspars to constrain the geochronological framework for the sequence of accretionary hillslope deposition at Jojosi at three sampling locations. Measurements of feldspar single grains show low luminescence sensitivity of the individual grains and a variable proportion of grains in saturation. Summing the luminescence signal of individual grains and creating synthetic aliquots enables us to study the effect of signal averaging on the luminescence sensitivity, signal saturation, and dose distributions. We then compare the results from individual grain measurements and synthetic aliquots to true multi-grain aliquots. To allow a quantification of the results, we apply four different dose models, including the Central Age Model (CAM), the Average Dose Model (ADM), BayLum, and a standardised growth curve (SGC) approach, using an averaged Ln/Tn value interpolated onto the SGC. Doses calculated for the different samples range from ∼ 80 to ∼ 800 Gy and contain 6 % to 67 % saturated grains. We evaluate the performance of the different dose models over this range in equivalent doses and relative number of saturated grains. On average, we find good agreement between the results obtained using the different dose models but observe that samples with a large number of saturated grains impact the consistency of the result. Overall, all dose models and data sets give consistent results below a saturated grain threshold of ∼ 15 %, corresponding to a dose of ∼ 120 Gy in this study. Finally, we favour BayLum for age calculations of the single-grain and multi-grain aliquot data sets, representing the opportunity to refine the chronology by including stratigraphic information in the age calculations. We are able to establish a chronology for the three sampled sections within the Jojosi dongas, constraining erosional and depositional processes from ∼ 100 to ∼ 700 ka, and human occupation of the area spanning from early marine isotope stage (MIS) 5 to late MIS 6

A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model

Alzheimer disease (AD) is characterized by excessive deposition of amyloid beta-peptides (A beta peptides) in the brain. In the nonamyloidogenic pathway, the amyloid precursor protein (APP) is cleaved by the alpha-secretase within the A beta peptide sequence. Proteinases of the ADAM family (adisintegrin and metalloproteinase) are the main candidates as physiologically relevant alpha-secretases, but early lethality of knockout animals prevented a detailed analysis in neuronal cells. To overcome this restriction, we have generated transgenic mice that overexpress either ADAM10 or a catalytically inactive ADAM10 mutant. In this report we show that a moderate neuronal overexpression of ADAM10 in mice transgenic for human APP([V717I]) increased the secretion of the neurotrophic soluble alpha-secretase-released N-terminal APP domain (APPs alpha), reduced the formation of A beta peptides, and prevented their deposition in plaques. Functionally, impaired long-term potentiation and cognitive deficits were alleviated. Expression of mutant catalytically inactive ADAM10 led to an enhancement of the number and size of amyloid plaques in the brains of double-transgenic mice. The results provide the first in vivo evidence for a proteinase of the ADAM family as an alpha-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in alpha-secretase activity contributes to the development of AD.The authors thank C. Haass and S. Sinha for antibodies, L. Zhang for technical assistance in behavioral studies, and M. Protschka for microinjection. Parts of this work have been supported by the Deutsche Forschungsgemeinschaft (to F. Fahrenholz and R. Postina), the Fritz Thyssen Foundation (to F. Fahrenholz and E. Kojro), and the Boehringer-Ingelheim Foundation (to M. Blessing). I. Dewachter and F. van Leuven were supported by the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWOVlaanderen) and the Katholieke Universiteit Leuven Research Fund. E. Godaux was supported by the Queen Elisabeth Fund for Medical Research, Belgium