Unidirectional trans-Atlantic gene flow and a mixed spawning area shape the genetic connectivity of Atlantic bluefin tuna.

The commercially important Atlantic bluefin tuna (Thunnus thynnus), a large migratory fish, has experienced notable recovery aided by accurate resource assessment and effective fisheries management efforts. Traditionally, this species has been perceived as consisting of eastern and western populations, spawning respectively in the Mediterranean Sea and the Gulf of Mexico, with mixing occurring throughout the Atlantic. However, recent studies have challenged this assumption by revealing weak genetic differentiation and identifying a previously unknown spawning ground in the Slope Sea used by Atlantic bluefin tuna of uncertain origin. To further understand the current and past population structure and connectivity of Atlantic bluefin tuna, we have assembled a unique dataset including thousands of genome-wide single-nucleotide polymorphisms (SNPs) from 500 larvae, young of the year and spawning adult samples covering the three spawning grounds and including individuals of other Thunnus species. Our analyses support two weakly differentiated but demographically connected ancestral populations that interbreed in the Slope Sea. Moreover, we also identified signatures of introgression from albacore (Thunnus alalunga) into the Atlantic bluefin tuna genome, exhibiting varied frequencies across spawning areas, indicating strong gene flow from the Mediterranean Sea towards the Slope Sea. We hypothesize that the observed genetic differentiation may be attributed to increased gene flow caused by a recent intensification of westward migration by the eastern population, which could have implications for the genetic diversity and conservation of western populations. Future conservation efforts should consider these findings to address potential genetic homogenization in the species.

Nursery origin of yellowfin tuna in the western Atlantic Ocean: significance of Caribbean Sea and trans-Atlantic migrants.

Natural geochemical markers in the otolith of yellowfin tuna (Thunnus albacares) were used to establish nursery-specific signatures for investigating the origin of fish captured in the western Atlantic Ocean (WAO). Two classes of chemical markers (trace elements, stable isotopes) were used to first establish nursery-specific signatures of age-0 yellowfin tuna from four primary production zones in the Atlantic Ocean: Gulf of Mexico, Caribbean Sea, Cape Verde, and Gulf of Guinea. Next, mixture and individual assignment methods were applied to predict the origin of sub-adult and adult yellowfin tuna from two regions in the WAO (Gulf of Mexico, Mid Atlantic Bight) by relating otolith core signatures (corresponding to age-0 period) to baseline signatures of age-0 fish from each nursery. Significant numbers of migrants from Caribbean Sea and eastern Atlantic Ocean (EAO) production zones (Gulf of Guinea, Cape Verde) were detected in the WAO, suggesting that fisheries in this region were subsidized by outside spawning/nursery areas. Contributions from local production (Gulf of Mexico) were also evident in samples from both WAO fisheries, but highly variable from year to year. High levels of mixing by yellowfin tuna from the different production zones and pronounced interannual trends in nursery-specific contribution rates in the WAO emphasize the complex and dynamic nature of this species' stock structure and population connectivity. Given that geographic shifts in distribution across national or political boundaries leads to governance and management challenges, this study highlights the need for temporally resolved estimates of nursery origin to refine assessment models and promote the sustainable harvest of this species.

Multiple F-Box Proteins Collectively Regulate Cell Development and Pathogenesis in the Human Pathogen Cryptococcus neoformans.

The ubiquitin-proteasome system (UPS) mediates intracellular proteins degradation that influences various cellular functions in eukaryotic cells. The UPS is also involved in the development and virulence of pathogenic fungi. F-box proteins, which are part of the SCF (Skp1-Cullin-F-box protein) ligase, are a key component of UPS and are essential for the recognition of specific substrates. In this study, we identified 20 F-box proteins in C. neoformans and obtained deletion mutants for 19 of them. A comprehensive phenotypic analysis of these mutants revealed the diverse function of F-box proteins in stress response, cell size regulation, sexual reproduction, antifungal drug resistance, and fungal virulence in C. neoformans. The importance of three F-box proteins: Fbp4, Fbp8, and Fbp11, in these cellular functions were characterized in detail. This study provides an overall view of the F-box gene family in C. neoformans, which will lead to a better understanding of the function of fungal SCF E3 ligase-mediated UPS in fungal development and pathogenesis.

Low levels of sibship encourage use of larvae in western Atlantic bluefin tuna abundance estimation by close-kin mark-recapture.

Globally, tunas are among the most valuable fish stocks, but are also inherently difficult to monitor and assess. Samples of larvae of Western Atlantic bluefin tuna Thunnus thynnus (Linnaeus, 1758) from standardized annual surveys in the northern Gulf of Mexico provide a potential source of "offspring" for close-kin mark-recapture (CKMR) estimates of abundance. However, the spatial patchiness and highly skewed numbers of larvae per tow suggest sampled larvae may come from a small number of parents, compromising the precision of CKMR. We used high throughput genomic profiling to study sibship within and among larval tows from the 2016 standardized Gulf-wide survey compared to targeted sampling carried out in 2017. Full- and half-siblings were found within both years, with 12% of 156 samples in 2016 and 56% of 317 samples in 2017 having at least one sibling. There were also two pairs of cross cohort half-siblings. Targeted sampling increased the number of larvae collected per sampling event but resulted in a higher proportion of siblings. The combined effective sample size across both years was about 75% of the nominal size, indicating that Gulf of Mexico larval collections could be a suitable source of juveniles for CKMR in Western Atlantic bluefin tuna.

Characterising a homozygous two-exon deletion in UQCRH: comparing human and mouse phenotypes.

Mitochondrial disorders are clinically and genetically diverse, with isolated complex III (CIII) deficiency being relatively rare. Here, we describe two affected cousins, presenting with recurrent episodes of severe lactic acidosis, hyperammonaemia, hypoglycaemia and encephalopathy. Genetic investigations in both cases identified a homozygous deletion of exons 2 and 3 of UQCRH, which encodes a structural complex III (CIII) subunit. We generated a mouse model with the equivalent homozygous Uqcrh deletion (Uqcrh-/- ), which also presented with lactic acidosis and hyperammonaemia, but had a more severe, non-episodic phenotype, resulting in failure to thrive and early death. The biochemical phenotypes observed in patient and Uqcrh-/- mouse tissues were remarkably similar, displaying impaired CIII activity, decreased molecular weight of fully assembled holoenzyme and an increase of an unexpected large supercomplex (SXL ), comprising mostly of one complex I (CI) dimer and one CIII dimer. This phenotypic similarity along with lentiviral rescue experiments in patient fibroblasts verifies the pathogenicity of the shared genetic defect, demonstrating that the Uqcrh-/- mouse is a valuable model for future studies of human CIII deficiency.

Population connectivity of pelagic megafauna in the Cuba-Mexico-United States triangle.

The timing and extent of international crossings by billfishes, tunas, and sharks in the Cuba-Mexico-United States (U.S.) triangle was investigated using electronic tagging data from eight species that resulted in >22,000 tracking days. Transnational movements of these highly mobile marine predators were pronounced with varying levels of bi- or tri-national population connectivity displayed by each species. Billfishes and tunas moved throughout the Gulf of Mexico and all species investigated (blue marlin, white marlin, Atlantic bluefin tuna, yellowfin tuna) frequently crossed international boundaries and entered the territorial waters of Cuba and/or Mexico. Certain sharks (tiger shark, scalloped hammerhead) displayed prolonged periods of residency in U.S. waters with more limited displacements, while whale sharks and to a lesser degree shortfin mako moved through multiple jurisdictions. The spatial extent of associated movements was generally associated with their differential use of coastal and open ocean pelagic ecosystems. Species with the majority of daily positions in oceanic waters off the continental shelf showed the greatest tendency for transnational movements and typically traveled farther from initial tagging locations. Several species converged on a common seasonal movement pattern between territorial waters of the U.S. (summer) and Mexico (winter).

Correction to: Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders.

Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly.

Correction to: Impact of age at onset and newborn screening on outcome in organic acidurias.

Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly.

Variation in hunting behaviour in neighbouring chimpanzee communities in the Budongo forest, Uganda.

Hunting and sharing of meat is seen across all chimpanzee sites, with variation in prey preferences, hunting techniques, frequencies, and success rates. Here, we compared hunting and meat-eating behaviour in two adjacent chimpanzee communities (Pan troglodytes schweinfurthii) of Budongo Forest, Uganda: the Waibira and Sonso communities. We observed consistent between-group differences in prey-species preferences and in post-hunting behaviour. Sonso chimpanzees show a strong prey preference for Guereza colobus monkeys (Colobus guereza occidentalis; 74.9% hunts), and hunt regularly (1-2 times a month) but with large year-to-year and month-to-month variation. Waibira chimpanzee prey preferences are distributed across primate and duiker species, and resemble those described in an early study of Sonso hunting. Waibira chimpanzees (which include ex-Sonso immigrants) have been observed to feed on red duiker (Cephalophus natalensis; 25%, 9/36 hunts), a species Sonso has never been recorded to feed on (18 years data, 27 years observations), despite no apparent differences in prey distribution; and show less rank-related harassment of meat possessors. We discuss the two most likely and probably interrelated explanations for the observed intergroup variation in chimpanzee hunting behaviour, that is, long-term disruption of complex group-level behaviour due to human presence and possible socially transmitted differences in prey preferences.

Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing.

BACKGROUND: Inborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches. METHODS: We designed and validated a next-generation sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based subpanels and tested 102 individuals, who presented clinically with suspected childhood-onset IEMs. RESULTS: In 51/102 individuals, NGS fully or partially established the molecular cause or identified other actionable diagnoses. Causal mutations were identified significantly more frequently when the biochemical phenotype suggested a specific IEM or a group of IEMs (p<0.0001), demonstrating the pivotal role of prior biochemical testing in guiding NGS analysis. The NGS panel helped to avoid further invasive, hazardous, lengthy or expensive investigations in 69% individuals (p<0.0001). Additional functional testing due to novel or unexpected findings had to be undertaken in only 3% of subjects, demonstrating that the use of NGS does not significantly increase the burden of subsequent follow-up testing. Even where a molecular diagnosis could not be achieved, NGS-based approach assisted in the management and counselling by reducing the likelihood of a high-penetrant genetic cause. CONCLUSION: NGS has significant clinical utility for the diagnosis of IEMs. Biochemical testing and NGS analysis play complementary roles in the diagnosis of IEMs. Incorporating NGS into the diagnostic algorithm of IEMs can improve the accuracy of diagnosis.

Sulfated diesters of okadaic acid and DTX-1: Self-protective precursors of diarrhetic shellfish poisoning (DSP) toxins.

Many toxic secondary metabolites used for defense are also toxic to the producing organism. One important way to circumvent toxicity is to store the toxin as an inactive precursor. Several sulfated diesters of the diarrhetic shellfish poisoning (DSP) toxin okadaic acid have been reported from cultures of various dinoflagellate species belonging to the genus Prorocentrum. It has been proposed that these sulfated diesters are a means of toxin storage within the dinoflagellate cell, and that a putative enzyme mediated two-step hydrolysis of sulfated diesters such as DTX-4 and DTX-5 initially leads to the formation of diol esters and ultimately to the release of free okadaic acid. However, only one diol ester and no sulfated diesters of DTX-1, a closely related DSP toxin, have been isolated leading some to speculate that this toxin is not stored as a sulfated diester and is processed by some other means. DSP components in organic extracts of two large scale Prorocentrum lima laboratory cultures have been investigated. In addition to the usual suite of okadaic acid esters, as well as the free acids okadaic acid and DTX-1, a group of corresponding diol- and sulfated diesters of both okadaic acid and DTX-1 have now been isolated and structurally characterized, confirming that both okadaic acid and DTX-1 are initially formed in the dinoflagellate cell as the non-toxic sulfated diesters.

Key European guidelines for the diagnosis and management of patients with phenylketonuria.

We developed European guidelines to optimise phenylketonuria (PKU) care. To develop the guidelines, we did a literature search, critical appraisal, and evidence grading according to the Scottish Intercollegiate Guidelines Network method. We used the Delphi method when little or no evidence was available. From the 70 recommendations formulated, in this Review we describe ten that we deem as having the highest priority. Diet is the cornerstone of treatment, although some patients can benefit from tetrahydrobiopterin (BH4). Untreated blood phenylalanine concentrations determine management of people with PKU. No intervention is required if the blood phenylalanine concentration is less than 360 µmol/L. Treatment is recommended up to the age of 12 years if the phenylalanine blood concentration is between 360 µmol/L and 600 µmol/L, and lifelong treatment is recommended if the concentration is more than 600 µmol/L. For women trying to conceive and during pregnancy (maternal PKU), untreated phenylalanine blood concentrations of more than 360 µmol/L need to be reduced. Treatment target concentrations are as follows: 120-360 µmol/L for individuals aged 0-12 years and for maternal PKU, and 120-600 µmol/L for non-pregnant individuals older than 12 years. Minimum requirements for the management and follow-up of patients with PKU are scheduled according to age, adherence to treatment, and clinical status. Nutritional, clinical, and biochemical follow-up is necessary for all patients, regardless of therapy.

Correction: Atlantic Bluefin Tuna (Thunnus thynnus) Biometrics and Condition.

[This corrects the article DOI: 10.1371/journal.pone.0141478.].

Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders.

BACKGROUND: Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation. AIMS: Determining the effect of diagnostic and therapeutic interventions on the neurological outcome. METHODS: Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry. RESULTS: About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 µmol/L) best predicted the neurological outcome. CONCLUSIONS: Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment.

Impact of age at onset and newborn screening on outcome in organic acidurias.

BACKGROUND AND AIM: To describe current diagnostic and therapeutic strategies in organic acidurias (OADs) and to evaluate their impact on the disease course allowing harmonisation. METHODS: Datasets of 567 OAD patients from the E-IMD registry were analysed. The sample includes patients with methylmalonic (MMA, n = 164), propionic (PA, n = 144) and isovaleric aciduria (IVA, n = 83), and glutaric aciduria type 1 (GA1, n = 176). Statistical analysis included description and recursive partitioning of diagnostic and therapeutic strategies, and odds ratios (OR) for health outcome parameters. For some analyses, symptomatic patients were divided into those presenting with first symptoms during (i.e. early onset, EO) or after the newborn period (i.e. late onset, LO). RESULTS: Patients identified by newborn screening (NBS) had a significantly lower median age of diagnosis (8 days) compared to the LO group (363 days, p < 0.001], but not compared to the EO group. Of all OAD patients 71 % remained asymptomatic until day 8. Patients with cobalamin-nonresponsive MMA (MMA-Cbl(-)) and GA1 identified by NBS were less likely to have movement disorders than those diagnosed by selective screening (MMA-Cbl(-): 10 % versus 39 %, p = 0.002; GA1: 26 % versus 73 %, p < 0.001). For other OADs, the clinical benefit of NBS was less clear. Reported age-adjusted intake of natural protein and calories was significantly higher in LO patients than in EO patients reflecting different disease severities. Variable drug combinations, ranging from 12 in MMA-Cbl(-) to two in isovaleric aciduria, were used for maintenance treatment. The effects of specific metabolic treatment strategies on the health outcomes remain unclear because of the strong influences of age at onset (EO versus LO), diagnostic mode (NBS versus selective screening), and the various treatment combinations used. CONCLUSIONS: NBS is an effective intervention to reduce time until diagnosis especially for LO patients and to prevent irreversible cerebral damage in GA1 and MMA-Cbl(-). Huge diversity of therapeutic interventions hampers our understanding of optimal treatment.

Atlantic Bluefin Tuna (Thunnus thynnus) Biometrics and Condition.

The compiled data for this study represents the first Atlantic and Mediterranean-wide effort to pool all available biometric data for Atlantic bluefin tuna (Thunnus thynnus) with the collaboration of many countries and scientific groups. Biometric relationships were based on an extensive sampling (over 140,000 fish sampled), covering most of the fishing areas for this species in the North Atlantic Ocean and Mediterranean Sea. Sensitivity analyses were carried out to evaluate the representativeness of sampling and explore the most adequate procedure to fit the weight-length relationship (WLR). The selected model for the WLRs by stock included standardized data series (common measurement types) weighted by the inverse variability. There was little difference between annual stock-specific round weight-straight fork length relationships, with an overall difference of 6% in weight. The predicted weight by month was estimated as an additional component in the exponent of the weight-length function. The analyses of monthly variations of fish condition by stock, maturity state and geographic area reflect annual cycles of spawning and feeding behavior. We update and improve upon the biometric relationships for bluefin currently used by the International Commission for the Conservation of Atlantic Tunas, by incorporating substantially larger datasets than ever previously compiled, providing complete documentation of sources and employing robust statistical fitting. WLRs and other conversion factors estimated in this study differ from the ones used in previous bluefin stock assessments.

Newborn screening for homocystinuria.

BACKGROUND: Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. This is an update of a previously published review. OBJECTIVES: To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 08 June 2015. SELECTION CRITERIA: Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population. DATA COLLECTION AND ANALYSIS: No studies were identified for inclusion in the review. MAIN RESULTS: No studies were identified for inclusion in the review. AUTHORS' CONCLUSIONS: We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken.

A novel type of rhizomelic chondrodysplasia punctata, RCDP5, is caused by loss of the PEX5 long isoform.

Import of peroxisomal matrix proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize proteins carrying peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or 12 other PEX genes cause peroxisome biogenesis disorders, collectively named the Zellweger spectrum disorders (ZSDs), whereas mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). Three additional RCDP types, RCDP2-3-4, are caused, respectively, by mutations in GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L-specific exon 9, results in loss of PEX5L only. Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor for PTS2-tagged proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in patient fibroblasts. Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged proteins.

Treatment Adherence in Type 1 Hereditary Tyrosinaemia (HT1): A Mixed-Method Investigation into the Beliefs, Attitudes and Behaviour of Adolescent Patients, Their Families and Their Health-Care Team.

BACKGROUND: Type 1 hereditary tyrosinaemia (HT1) is a rare metabolic disorder caused by an enzymatic defect in the metabolism of the amino acid tyrosine. Primary treatment for HT1 is nitisinone (Orfadin) in conjunction with a low-tyrosine/phenylalanine diet. The appropriate use of nitisinone medication and adhering to specialist diet is thus central to the successful management of HT1. OBJECTIVE: To date, no published research has examined adherence (to medication and diet) and factors that influence it in the context of HT1. This study aimed to ascertain the extent to which non-adherence is a problem in this patient population, identify perceived barriers and facilitators to treatment adherence and explore the role of illness beliefs and treatment perceptions in treatment management. METHODS: The present study used a combination of qualitative interviews and quantitative survey methods with patients, carers and health-care professionals (HCPs). RESULTS: This study found adherence to medication to be high amongst patients with HT1 and their carers who administer it. However, adherence to diet was reported to be much lower. A key factor influencing adherence to diet was age, with adolescents reported to have most difficulty adhering. CONCLUSIONS: The results indicate that adherence to dietary instructions becomes more problematic as children with HT1 grow older. Greater involvement in managing their condition and in their consultation at an early stage may have a positive impact on future adherence by increasing their investment and understanding of the treatment regime, potentially making adherence rates more stable and less influenced by moving through different life stages.