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The transition from winter to spring represents a major shift in the basal energy source for the Antarctic marine ecosystem from lipids and other sources of stored energy to sunlight. Because sea ice imposes a strong control on the transmission of sunlight into the water column during the polar spring, we hypothesized that the timing of the sea ice retreat influences the timing of the transition from stored energy to photosynthesis. To test the influence of sea ice on water column microbial energy utilization we took advantage of unique sea ice conditions in Arthur Harbor, an embayment near Palmer Station on the western Antarctic Peninsula, during the 2015 spring–summer seasonal transition. Over a 5-week period we sampled water from below land-fast sea ice, in the marginal ice zone at nearby Palmer Station B, and conducted an ice removal experiment with incubations of water collected below the land-fast ice. Whole-community metatranscriptomes were paired with lipidomics to better understand how lipid production and utilization was influenced by light conditions. We identified several different phytoplankton taxa that responded similarly to light by the number of genes up-regulated, and in the transcriptional complexity of this response. We applied a principal components analysis to these data to reduce their dimensionality, revealing that each of these taxa exhibited a strikingly different pattern of gene up-regulation. By correlating the changes in lipid concentration to the first principal component of log fold-change for each taxa we could make predictions about which taxa were associated with different changes in the community lipidome. We found that genes coding for the catabolism of triacylglycerol storage lipids were expressed early on in phytoplankton associated with a Fragilariopsis kerguelensis reference transcriptome. Phytoplankton associated with a Corethron pennatum reference transcriptome occupied an adjacent niche, responding favorably to higher light conditions than F. kerguelensis . Other diatom and dinoflagellate taxa had distinct transcriptional profiles and correlations to lipids, suggesting diverse ecological strategies during the polar winter–spring transition.

Seasonal shifts in phytoplankton accumulation and loss largely follow changes in mixed layer depth, but the impact of mixed layer depth on cell physiology remains unexplored. Here, we investigate the physiological state of phytoplankton populations associated with distinct bloom phases and mixing regimes in the North Atlantic. Stratification and deep mixing alter community physiology and viral production, effectively shaping accumulation rates. Communities in relatively deep, early-spring mixed layers are characterized by low levels of stress and high accumulation rates, while those in the recently shallowed mixed layers in late-spring have high levels of oxidative stress. Prolonged stratification into early autumn manifests in negative accumulation rates, along with pronounced signatures of compromised membranes, death-related protease activity, virus production, nutrient drawdown, and lipid markers indicative of nutrient stress. Positive accumulation renews during mixed layer deepening with transition into winter, concomitant with enhanced nutrient supply and lessened viral pressure. Phytoplankton are important primary producers. Here the authors investigate phytoplankton physiological changes associated with bloom phases and mixing regimes in the North Atlantic, finding that stratification and deep mixing shape accumulation rates by altering physiology and viral production.

Globally averaged, surface particulate nitrogen and phosphorus approximate the 16:1, N:P “Redfield ratio.” In observations, N:P ratios vary latitudinally at ranges attributable to both phytoplankton community composition and physiological acclimation, but their relative contributions to the N:P ratio remain unclear. Here, results from a 29-day mesocosm experiment highlight how inorganic nitrogen and/or phosphorus nutrient supply can affect the bulk particle stoichiometry of a North Pacific Subtropical Gyre plankton community. Nitrogen additions, with and without phosphorus, increase total productivity and diatom abundance, whereas treatments with just phosphorus additions remain similar to the no-nutrient addition control. Continual nitrogen supply without phosphorus results in higher particulate N:P ratios than expected based on the phytoplankton community present. Several P-stress markers identified in those treatments highlight the importance of acclimation in extending particulate N:P ratios beyond the Redfield ratio. Phytoplankton’s ability to maintain growth under P-stress conditions has implications for global carbon cycling. Mesocosm experiments revealed that both phytoplankton community composition and cellular acclimation influence marine particulate C:N:P ratios, with community shifts more sensitive to nitrogen supply and acclimation to the nutrient N:P supply ratio

Lipids comprise more than 20% of sinking organic matter in the ocean and play a crucial role in the carbon cycle. Despite this, our understanding of the processes that control lipid degradation is limited. Here we combined nano-lipidomics and imaging to study the bacterial degradation of diverse algal lipid droplets. Bacteria isolated from natural marine particles exhibited distinct dietary preferences, ranging from selective to promiscuous degraders. Dietary preference was associated with a distinct set of lipid degradation genes rather than with taxonomic origin. The top degrader, Pseudomonas zhaodongensis, rapidly consumed triacylglycerols (TAGs) from lipid extracts while promoting colonization of kin by chemotaxis toward glycerol, the TAG degradation product. Using synthetic communities composed of isolates with distinct dietary preferences, we demonstrated that lipid degradation is modulated by microbial interactions. A particle export model incorporating these dynamics suggests that metabolic specialization and community dynamics influences lipid transport efficiency in the ocean’s mesopelagic zone.

Status epilepticus is a common neurological emergency with considerable associated health-care costs, morbidity, and mortality. The definition of status epilepticus as a prolonged seizure or a series of seizures with incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. Clinical research has focused on early seizure termination in the prehospital setting. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizures is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace. Substantial further research to enable early identification of status epilepticus and efficacy of anti-epileptic drugs will be important to improve outcomes.

High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma. In this dose-finding, first-in-human trial, treatment-naive adults aged 18–75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1–3 days and 10–12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992. Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3–4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1–26·1). The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial. Funded in part by Phase One Foundation, Los Angeles, CA; The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA; The Rogel Cancer Center at The University of Michigan; and the National Cancer Institute, National Institutes of Health.

Evidence for Quaternary climate change in East Africa has been derived from outcrops on land and lake cores and from marine dust, leaf wax, and pollen records. These data have previously been used to evaluate the impact of climate change on hominin evolution, but correlations have proved to be difficult, given poor data continuity and the great distances between marine cores and terrestrial basins where fossil evidence is located. Here, we present continental coring evidence for progressive aridification since about 575 thousand years before present (ka), based on Lake Magadi (Kenya) sediments. This long-term drying trend was interrupted by many wet–dry cycles, with the greatest variability developing during times of high eccentricity-modulated precession. Intense aridification apparent in the Magadi record took place between 525 and 400 ka, with relatively persistent arid conditions after 350 ka and through to the present. Arid conditions in the Magadi Basin coincide with the Mid-Brunhes Event and overlap with mammalian extinctions in the South Kenya Rift between 500 and 400 ka. The 525 to 400 ka arid phase developed in the South Kenya Rift between the period when the last Acheulean tools are reported (at about 500 ka) and before the appearance of Middle Stone Age artifacts (by about 320 ka). Our data suggest that increasing Middle- to Late-Pleistocene aridification and environmental variability may have been drivers in the physical and cultural evolution of Homo sapiens in East Africa.

Exome sequencing has found an excess of de novo mutations in the ∼4,000 most intolerant genes in patients with two classical epileptic encephalopathies (infantile spasms and Lennox–Gastaut syndrome); among them are multiple de novo mutations in GABRB3 and ALG13 . Epilepsy-linked mutations revealed An extensive exome sequencing study of patients with two 'classical' epileptic encephalopathies — infantile spasms and Lennox-Gastaut syndrome — has found an excess of de novo mutations in the approximately 4,000 genes that are the most intolerant to functional genetic variation in the human population. Among them are de novo mutations in GABRB3 and ALG13 , both showing statistical evidence of an association with epileptic encephalopathy. As in autism spectrum disorders, these de novo mutations are enriched in genes regulated by fragile X protein. Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown 1 . Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms ( n = 149) and Lennox–Gastaut syndrome ( n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population ( P = 2.9 × 10 −3 ). Among these are GABRB3 , with de novo mutations in four patients, and ALG13 , with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10 −10 and P = 7.8 × 10 −12 , respectively. Other genes with de novo mutations in this cohort include CACNA1A , CHD2 , FLNA , GABRA1 , GRIN1 , GRIN2B , HNRNPU , IQSEC2 , MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein ( P  < 10 −8 ), as has been reported previously for autism spectrum disorders 2 .

Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7–3·2, p=9·1 × 10−8; familial non-acquired focal epilepsy 3·6, 2·7–4·9, p=1·1 × 10−17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10−8) that were lower than expected from a random sampling of genes. We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment. Genome-wide association meta-analyses identify 26 risk loci for epilepsy, including 19 loci specific to genetic generalized epilepsy. Prioritized candidate genes implicate synaptic processes and overlap with targets of antiseizure medications.