Plk4 and Aurora A cooperate in the initiation of acentriolar spindle assembly in mammalian oocytes

Establishing the bipolar spindle in mammalian oocytes after their prolonged arrest is crucial for meiotic fidelity and subsequent development. In contrast to somatic cells, the first meiotic spindle assembles in the absence of centriole-containing centrosomes. Ran-GTP can promote microtubule nucleation near chromatin, but additional unidentified factors are postulated for the activity of multiple acentriolar microtubule organizing centers in the oocyte. We now demonstrate that partially overlapping, nonredundant functions of Aurora A and Plk4 kinases contribute to initiate acentriolar meiosis I spindle formation. Loss of microtubule nucleation after simultaneous chemical inhibition of both kinases can be significantly rescued by drug-resistant Aurora A alone. Drug-resistant Plk4 can enhance Aurora A–mediated rescue, and, accordingly, Plk4 can phosphorylate and potentiate the activity of Aurora A in vitro. Both kinases function distinctly from Ran, which amplifies microtubule growth. We conclude that Aurora A and Plk4 are rate-limiting factors contributing to microtubule growth as the acentriolar oocyte resumes meiosis.L. Bury was the recipient of a Cancer Research UK research studentship from Cambridge Cancer Centre. P.A. Coelho is supported by Cancer Research UK program grant C3/A18795 to D.M. Glover. M. Zernicka-Goetz is a Wellcome Trust Senior Fellow. P.A. Eyers acknowledges North West Cancer Research for additional support (grants CR1037 and CR1088)

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

Clinical Observations Associated with Phenobarbital Serum Monitoring to Manage Epilepsy in a California Sea Lion with Domoic Acid Toxicosis

The marine algal toxin domoic acid is an important threat to marine mammal health, and exposure can lead to both acute neurologic signs and a chronic epileptic syndrome in California sea lions (Zalophus californianus). Phenobarbital has been used for several decades to manage seizures, although reports are limited correlating dosing, serum monitoring and clinical efficacy in this species. This report details serum monitoring over 33 months in an 8-year-old male sea lion. Seizure control was achieved when phenobarbital concentrations were above 18 μg/mL, and sedation and ataxia were noted when concentrations were above 35 μg/mL. There was no clinically significant difference between phenobarbital concentrations resulting from once-daily versus twice-daily dosing. Serum levels remained detectable as far as 101 days after administration, and remained stable during periods of prolonged anorexia, although dramatic decreases in serum concentrations were noted immediately after normal eating resumed. For this animal, a serum phenobarbital target range of 20–30 μg/mL was achievable with a dose of 1.5 mg/kg once daily followed by therapeutic monitoring, and this is a reasonable recommended concentration and initial dose for clinicians treating this species. Long-term seizure control may be difficult to achieve with anti-epileptic drugs such as phenobarbital alone, and further research is needed to make novel options useful for clinical management of biotoxin-related neurologic disease in this aquatic species

Clinical Observations Associated with Phenobarbital Serum Monitoring to Manage Epilepsy in a California Sea Lion with Domoic Acid Toxicosis

The marine algal toxin domoic acid is an important threat to marine mammal health, and exposure can lead to both acute neurologic signs and a chronic epileptic syndrome in California sea lions (Zalophus californianus). Phenobarbital has been used for several decades to manage seizures, although reports are limited correlating dosing, serum monitoring and clinical efficacy in this species. This report details serum monitoring over 33 months in an 8-year-old male sea lion. Seizure control was achieved when phenobarbital concentrations were above 18 μg/mL, and sedation and ataxia were noted when concentrations were above 35 μg/mL. There was no clinically significant difference between phenobarbital concentrations resulting from once-daily versus twice-daily dosing. Serum levels remained detectable as far as 101 days after administration, and remained stable during periods of prolonged anorexia, although dramatic decreases in serum concentrations were noted immediately after normal eating resumed. For this animal, a serum phenobarbital target range of 20–30 μg/mL was achievable with a dose of 1.5 mg/kg once daily followed by therapeutic monitoring, and this is a reasonable recommended concentration and initial dose for clinicians treating this species. Long-term seizure control may be difficult to achieve with anti-epileptic drugs such as phenobarbital alone, and further research is needed to make novel options useful for clinical management of biotoxin-related neurologic disease in this aquatic species

A Systematic Review of Changes in Marine Mammal Health in North America, 1972-2012: The Need for a Novel Integrated Approach

<div><p>Marine mammals are often cited as “sentinels of ocean health” yet accessible, synthesized data on their health changes that could effectively warn of ocean health changes are rare. The objectives of this study were to 1) perform a systematic review of published cases of marine mammal disease to determine spatial and temporal trends in disease from 1972–2012, including changes in regions and taxa affected and specific causes; and 2) compare numbers of published cases of neoplasia with known, hospital-based neoplasia records to explore the causes of discrepancy between numbers of published cases and true disease trends. Peer-reviewed literature was compiled, and data were collected from The Marine Mammal Center database in Sausalito, California for comparison of numbers of neoplasia cases. Toxicoses from harmful algal blooms appear to be increasing. Viral epidemics are most common along the Atlantic U.S. coastline, while bacterial epidemics, especially leptospirosis, are most common along the Pacific coast. Certain protozoal and fungal zoonoses appear to be emerging, such as <i>Toxoplasma gondii</i> in southern sea otters in California, and <i>Cryptococcus gattii</i> in cetaceans in the Pacific Northwest. Disease reports were most common from California where pinniped populations are large, but increased effort also occurs. Anthropogenic trauma remains a large threat to marine mammal health, through direct mortality and indirect chronic disease. Neoplasia cases were under-reported from 2003–2012 when compared to true number of cases, and over-reported in several years due to case duplication. Peer-reviewed literature greatly underestimates the true magnitude of disease in marine mammals as it focuses on novel findings, fails to reflect etiology of multifactorial diseases, rarely reports prevalence rather than simple numbers of cases, and is typically presented years after a disease first occurs. Thus literature cannot guide management actions adequately, nor inform indices of ocean health. A real-time, nationally centralized system for reporting marine mammal disease data is needed to be able to understand how marine mammal diseases are changing with ecosystem changes, and before these animals can truly be considered ‘sentinels of ocean health’.</p></div

Annual number of calculated cases of trauma extracted from published reports on marine mammal disease.

<p>Source of trauma was designated as anthropogenic or non-anthropogenic/unknown.</p

Calculated cases divided into those describing clinical disease (“disease”) and those with only the disease-causing agent isolated (“isolation”) for the infectious disease and biotoxicosis categories, 1972–2012.

<p>Calculated cases divided into those describing clinical disease (“disease”) and those with only the disease-causing agent isolated (“isolation”) for the infectious disease and biotoxicosis categories, 1972–2012.</p

Annual number of calculated cases by disease category and region extracted from published reports on marine mammal disease.

<p>For each disease category, regions representing less than 10% of the cumulative number of calculated cases were grouped (other). CA = California, GoM = Gulf of Mexico, NW = Pacific Northwest, AK = Alaska, NE = Northeast U.S., and SE = Southeast U.S.</p