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BackgroundThe identification of the molecular basis of mitochondrial disorders continues to be challenging and expensive. The increasing usage of next-generation sequencing is facilitating the discovery of the genetic aetiology of heterogeneous phenotypes associated with these conditions. Coenzyme Q10 (CoQ10) is an essential cofactor for mitochondrial respiratory chain complexes and other biochemical pathways. Mutations in genes involved in CoQ10 biosynthesis cause primary CoQ10 deficiency syndromes that can be treated with oral supplementation of ubiquinone.MethodsWe used whole exome sequencing to evaluate six probands from four unrelated families with clinical findings suggestive of a mitochondrial disorder. Clinical data were obtained by chart review, parental interviews, direct patient assessment and biochemical and pathological evaluation.ResultsWe identified five recessive missense mutations in COQ4 segregating with disease in all four families. One mutation was found in a homozygous state in two unrelated Ashkenazi Jewish probands. All patients were female, and presented on the first day of life, and died in the neonatal period or early infancy. Clinical findings included hypotonia (6/6), encephalopathy with EEG abnormalities (4/4), neonatal seizures (3/6), cerebellar atrophy (4/5), cardiomyopathy (5/6) and lactic acidosis (4/6). Autopsy findings in two patients revealed neuron loss and reactive astrocytosis or cerebellar and brainstem hypoplasia and microdysgenesis.ConclusionsMutations in COQ4 cause an autosomal recessive lethal neonatal mitochondrial encephalomyopathy associated with a founder mutation in the Ashkenazi Jewish population. The early mortality in our cohort suggests that COQ4 is an essential component of the multisubunit complex required for CoQ10 biosynthesis.

We show that if a d-tuple of commuting operators S = (S$\\sb i$) has the property that for every polynomial p in d variables p(S) is subnormal then S has an extension to a d-tuple of commuting normal operators.

The goal of the Pacific Ocean Boundary Ecosystem and Climate Study (POBEX) was to diagnose the large-scale climate controls on regional transport dynamics and lower trophic marine ecosystem variability in Pacific Ocean boundary systems. An international team of collaborators shared observational and eddy-resolving modeling data sets collected in the Northeast Pacific, including the Gulf of Alaska (GOA) and the California Current System (CCS), the Humboldt or Peru-Chile Current System (PCCS), and the Kuroshio-Oyashio Extension (KOE) region. POBEX investigators found that a dominant fraction of decadal variability in basin- and regional-scale salinity, nutrients, chlorophyll, and zooplankton taxa is explained by a newly discovered pattern of ocean-climate variability dubbed the North Pacific Gyre Oscillation (NPGO) and the Pacific Decadal Oscillation (PDO). NPGO dynamics are driven by atmospheric variability in the North Pacific and capture the decadal expression of Central Pacific El Niños in the extratropics, much as the PDO captures the low-frequency expression of eastern Pacific El Niños. By combining hindcasts of eddy-resolving ocean models over the period 1950–2008 with model passive tracers and long-term observations (e.g., CalCOFI, Line-P, Newport Hydrographic Line, Odate Collection), POBEX showed that the PDO and the NPGO combine to control low-frequency upwelling and alongshore transport dynamics in the North Pacific sector, while the eastern Pacific El Niño dominates in the South Pacific. Although different climate modes have different regional expressions, changes in vertical transport (e.g., upwelling) were found to explain the dominant nutrient and phytoplankton variability in the CCS, GOA, and PCCS, while changes in alongshore transport forced much of the observed long-term change in zooplankton species composition in the KOE as well as in the northern and southern CCS. In contrast, cross-shelf transport dynamics were linked to mesoscale eddy activity, driven by regional-scale dynamics that are largely decoupled from variations associated with the large-scale climate modes. Preliminary findings suggest that mesoscale eddies play a key role in offshore transport of zooplankton and impact the life cycles of higher trophic levels (e.g., fish) in the CCS, PCCS, and GOA. Looking forward, POBEX results may guide the development of new modeling and observational strategies to establish mechanistic links among climate forcing, mesoscale circulation, and marine population dynamics.

Understanding how and why menopause has evolved is a long-standing challenge across disciplines. Females can typically maximize their reproductive success by reproducing for the whole of their adult life. In humans, however, women cease reproduction several decades before the end of their natural lifespan 1 , 2 . Although progress has been made in understanding the adaptive value of menopause in humans 3 , 4 , the generality of these findings remains unclear. Toothed whales are the only mammal taxon in which menopause has evolved several times 5 , providing a unique opportunity to test the theories of how and why menopause evolves in a comparative context. Here, we assemble and analyse a comparative database to test competing evolutionary hypotheses. We find that menopause evolved in toothed whales by females extending their lifespan without increasing their reproductive lifespan, as predicted by the ‘live-long’ hypotheses. We further show that menopause results in females increasing their opportunity for intergenerational help by increasing their lifespan overlap with their grandoffspring and offspring without increasing their reproductive overlap with their daughters. Our results provide an informative comparison for the evolution of human life history and demonstrate that the same pathway that led to menopause in humans can also explain the evolution of menopause in toothed whales. A comparative analysis tests competing evolutionary hypotheses in toothed whales in which menopause has evolved many times as females extended their overall lifespan but not their reproductive lifespan, increasing their opportunity for intergenerational help without increasing intergenerational reproductive competition.

Social structure is a fundamental aspect of animal populations. In order to understand the function and evolution of animal societies, it is important to quantify how individual attributes, such as age and sex, shape social relationships. Detecting these influences in wild populations under natural conditions can be challenging, especially when social interactions are difficult to observe and broad-scale measures of association are used as a proxy. In this study, we use unoccupied aerial systems to observe association, synchronous surfacing, and physical contact within a pod of southern resident killer whales (Orcinus orca). We show that interactions do not occur randomly between associated individuals, and that interaction types are not interchangeable. While age and sex did not detectably influence association network structure, both interaction networks showed significant social homophily by age and sex, and centrality within the contact network was higher among females and young individuals. These results suggest killer whales exhibit interesting parallels in social bond formation and social life histories with primates and other terrestrial social mammals, and demonstrate how important patterns can be missed when using associations as a proxy for interactions in animal social network studies.

Resolving the geographic extent and timing of coastal shark migrations, as well as their environmental cues, is essential for refining shark management strategies in anticipation of increasing anthropogenic stressors to coastal ecosystems. We employed a regional-scale passive acoustic telemetry array encompassing 300 km of the east Florida coast to assess what factors influence site fidelity of juvenile lemon sharks (Negaprion brevirostris) to an exposed coastal nursery at Cape Canaveral, and to document the timing and rate of their seasonal migrations. Movements of 54 juvenile lemon sharks were monitored for three years with individuals tracked for up to 751 days. While most sharks demonstrated site fidelity to the Cape Canaveral region December through February under typical winter water temperatures, historically extreme declines in ocean temperature were accompanied by rapid and often temporary, southward displacements of up to 190 km along the Florida east coast. From late February through April each year, most sharks initiated a northward migration at speeds of up to 64 km day(-1) with several individuals then detected in compatible estuarine telemetry arrays in Georgia and South Carolina up to 472 km from release locations. Nineteen sharks returned for a second or even third consecutive winter, thus demonstrating strong seasonal philopatry to the Cape Canaveral region. The long distance movements and habitat associations of immature lemon sharks along the US southeast coast contrast sharply with the natal site fidelity observed in this species at other sites in the western Atlantic Ocean. These findings validate the existing multi-state management strategies now in place. Results also affirm the value of collaborative passive arrays for resolving seasonal movements and habitat preferences of migratory coastal shark species not easily studied with other tagging techniques.

Non-consumptive or risk effects imposed by predators can influence prey behaviour over different spatio-temporal scales. Prey vulnerability to predation can also be dependent on abiotic conditions, such as tidal height. We conducted direct field observations of juvenile lemon sharks Negaprion brevirostris in a tidally influenced mangrove-inlet. We also used acoustic tracking to determine the movement patterns of juvenile lemon sharks and their predators (sub-adult lemon sharks) across the tidal cycle. Results showed that greater numbers of juvenile lemon sharks used the mangrove-inlet for longer time periods at deeper and warmer high tide depths. This coincided with an increased presence of potential predators (sub-adult lemon sharks) in the surrounding areas. Furthermore, in accordance with body-size dependent anti-predatory investment, smaller juvenile lemon sharks visited the mangrove inlet more often, spent longer there and left latest on average. Our acoustic tracking data also revealed a tidally-influenced pattern, with both juvenile and sub-adult lemon sharks detected at locations inshore over the high tide and offshore during the low tide. We concluded that the mangrove lake served as a 'refuge' for juvenile lemon sharks over the high tide, providing safe habitat when inshore areas become accessible to large predators, such as sub-adult lemon sharks. We suggest that these decisions are updated through ontogeny and also with daily fluctuations in abiotic factors, such as water depth. This study provides evidence for how intra-specific predator-prey interactions in a top predator species influence juvenile habitat selection, with potential implications for population structure and regulation.

Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD. Lysosomes maintain RPE health via TFEB/E3-regulated autophagy. Here, the authors show deregulated AKT2/SIRT5/TFEB signaling in the RPE inhibits both lysosomal and mitochondrial function and leads to AMD, suggesting this pathway might provide a therapeutic target for AMD.

A species has a post‐reproductive stage if, like humans, a female entering the adult population can expect to live a substantial proportion of their life after their last reproductive event. However, it is conceptually and statistically challenging to distinguish these true post‐reproductive stages from the usual processes of senescence, which can result in females occasionally surviving past their last reproductive event. Hence, despite considerable interest, the taxonomic prevalence of post‐reproductive stages remains unclear and debated. In this study we use life tables constructed from published data on wild populations of mammals, and statistical measures of post‐reproductive lifespans, to distinguish true post‐reproductive stages from artefacts of senescence and demography in 52 species. We find post‐reproductive stages are rare in mammals and are limited to humans and a few species of toothed whales. By resolving this long‐standing debate, we hope to provide clarity for researchers in the field of evolutionary biology and a solid foundation for further studies investigating the evolution and adaptive significance of this unusual life history trait. Despite considerable interest, the taxonomic prevalence of extended human menopause‐like postreproductive stages in mammals remains unclear and debated. In this article, we show that postreproductive lifespans are limited to humans and a couple of species of toothed whale.

In most species the reproductive system ages at the same rate as somatic tissue and individuals continue reproducing until death. However, females of three species – humans, killer whales and short-finned pilot whales – have been shown to display a markedly increased rate of reproductive senescence relative to somatic ageing. In these species, a significant proportion of females live beyond their reproductive lifespan: they have a post-reproductive lifespan. Research into this puzzling life-history strategy is hindered by the difficulties of quantifying the rate of reproductive senescence in wild populations. Here we present a method for measuring the relative rate of reproductive senescence in toothed whales using published physiological data. Of the sixteen species for which data are available (which does not include killer whales), we find that three have a significant post-reproductive lifespan: short-finned pilot whales, beluga whales and narwhals. Phylogenetic reconstruction suggests that female post-reproductive lifespans have evolved several times independently in toothed whales. Our study is the first evidence of a significant post-reproductive lifespan in beluga whales and narwhals which, when taken together with the evidence for post-reproductive lifespan in killer whales, doubles the number of non-human mammals known to exhibit post-reproductive lifespans in the wild.