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BACKGROUND: Evolutionary tradeoffs between life-history strategies are important in animal evolution. Because microbes can influence multiple aspects of host physiology, including growth rate and susceptibility to disease or stress, changes in animal-microbial symbioses have the potential to mediate life-history tradeoffs. Scleractinian corals provide a biodiverse, data-rich, and ecologically-relevant host system to explore this idea. RESULTS: Using a comparative approach, we tested if coral microbiomes correlate with disease susceptibility across 425 million years of coral evolution by conducting a cross-species coral microbiome survey (the Global Coral Microbiome Project) and combining the results with long-term global disease prevalence and coral trait data. Interpreting these data in their phylogenetic context, we show that microbial dominance predicts disease susceptibility, and traced this dominance-disease association to a single putatively beneficial symbiont genus, Endozoicomonas. Endozoicomonas relative abundance in coral tissue explained 30% of variation in disease susceptibility and 60% of variation in microbiome dominance across 40 coral genera, while also correlating strongly with high growth rates. CONCLUSIONS: These results demonstrate that the evolution of Endozoicomonas symbiosis in corals correlates with both disease prevalence and growth rate, and suggest a mediating role. Exploration of the mechanistic basis for these findings will be important for our understanding of how microbial symbioses influence animal life-history tradeoffs.

To achieve California’s ambitious climate goals, a shift to hydrogen fuel for some transportation sectors may be essential.In this report, we explore the build-out of a hydrogen fuel distribution system including uptake of light-, medium-, and heavy-duty fuel cell electric vehicles. Our analysis of Base and High Case scenarios includes costs of building and operating a hydrogen vehicle and fuel system and estimates workforce impacts. We consider scenarios with about 125,000 vehicles by 2030 in the Base Case and 250,000 in the high case. This increases by an order of magnitude to 2045. Vehicle and station investment costs associated with the Base Case reach anywhere from $4 to 12 billion USD by 2030 and increase by a factor of eight by 2045. Costs per kg of hydrogen, including fuel transmission to stations and station costs delivered to vehicles, could be in the range of $4 to 8 per kg. This becomes $6 to 10/kg as a final delivered cost, if production of hydrogen were to cost $2/kg. Workforce impacts in the Base Case include 600 to 2,200 jobs created by 2030, rising rapidly thereafter. This report was prepared by the ITS-UC Davis Energy Futures Hydrogen Program in partnership with the UCLA Luskin Center for Innovation.

Over several months, representatives from the U.S. Department of Energy (DOE) Office of Science and National Institutes of Health (NIH) had a number of meetings that lead to the conclusion that innovations in the Nations health care could be realized by more directed interactions between NIH and DOE. It became clear that the expertise amassed and instrumentation advances developed at the DOE physical science laboratories to enable cutting-edge research in particle physics could also feed innovation in medical healthcare. To meet their scientific mission, the DOE laboratories created advances in such technologies as particle beam generation, radioisotope production, high-energy particle detection and imaging, superconducting particle accelerators, superconducting magnets, cryogenics, high-speed electronics, artificial intelligence, and big data. To move forward, NIH and DOE initiated the process of convening a joint workshop which occurred on July 12th and 13th, 2021. This Special Report presents a summary of the findings of the collaborative workshop and introduces the goals of the next one.

Information is the cornerstone of research, from experimental (meta)data and computational processes to complex inventories of reagents and equipment. These 10 simple rules discuss best practices for leveraging laboratory information management systems to transform this large information load into useful scientific findings.

BackgroundThis study aimed to capture the implementation process of the ALIGN Study, (An individualized Pain Plan with Patient and Provider Access for Emergency Department care of Sickle Cell Disease). ALIGN aimed to embed Individualized Pain Plans in the electronic health record (E-IPP) and provide access to the plan for both adult patients with sickle cell disease (SCD) and emergency department providers when a person with SCD comes to the emergency department in vaso-occlusive crises.MethodsSemi-structured interviews were conducted with research teams from the 8 participating sites from the ALIGN study. Seventeen participants (principal investigators and study coordinators) shared their perspectives about the implementation of ALIGN in their sites. Data were analyzed in three phases using open coding steps adapted from grounded theory and qualitative content analysis.ResultsA total of seven overarching themes were identified: (1) the E-IPP structure (location and upkeep) and collaboration with the informatics team, (2) the role of ED champion, (3) the role of research coordinators, (4) research team communication, and communication between research team and clinical team, (5) challenges with the study protocol, (6) provider feedback: addressing over-utilizers, patient mistrust, and the positive feedback about the intervention, and (7) COVID-19 and its effects on study implementation.ConclusionsFindings from this study contribute to learning how to implement E-IPPs for adult patients with SCD in ED. The study findings highlight the importance of early engagement with different team members, a champion from the emergency department, study coordinators with different skills and enhancement of communication and trust among team members. Further recommendations are outlined for hospitals aiming to implement E-IPP for patients with SCD in ED.

BackgroundThe Centers for Disease Control and Prevention and the American Academy of Pediatrics recommend that symptomatic children remain home and get tested to identify potential coronavirus disease 2019 (COVID-19) cases. As the pandemic moves into a new phase, approaches to differentiate symptoms of COVID-19 versus other childhood infections can inform exclusion policies and potentially prevent future unnecessary missed school days.MethodsRetrospective analysis of standardized symptom and exposure screens in symptomatic children 0-18 years tested for SARS-CoV-2 at three outpatient sites April to November 2020. Likelihood ratios (LR), number needed to screen to identify one COVID-19 case, and estimated missed school days were calculated.ResultsOf children studied (N = 2,167), 88.9% tested negative. Self-reported exposure to COVID-19 was the only factor that statistically significantly increased the likelihood of a positive test for all ages (Positive LR, 5-18 year olds: 5.26, 95% confidence interval (CI): 4.37-6.33; 0-4 year olds: 5.87, 95% CI: 4.67-7.38). Across ages 0-18, nasal congestion/rhinorrhea, sore throat, abdominal pain, and nausea/vomiting/diarrhea were commonly reported, and were either not associated or had decreased association with testing positive for COVID-19. The number of school days missed to identify one case of COVID-19 ranged from 19 to 48 across those common symptoms.ConclusionsWe present an approach for identifying symptoms that are non-specific to COVID-19, for which exclusion would likely lead to limited impact on school safety but contribute to school-days missed. As variants and symptoms evolve, students and schools could benefit from reconsideration of exclusion and testing policies for non-specific symptoms, while maintaining testing for those who were exposed.

IntroductionProposed mechanisms of acute traumatic coagulopathy (ATC) include decreased clotting potential due to factor consumption and proteolytic inactivation of factor V (FV) and activated factor V (FVa) by activated protein C (aPC). The role of FV/FVa depletion or inactivation in burn-induced coagulopathy is not well characterized. This study evaluates FV dynamics following burn and nonburn trauma.MethodsBurn and trauma patients were prospectively enrolled. Western blotting was performed on admission plasma to quantitate levels of FV antigen and to assess for aPC or other proteolytically derived FV/FVa degradation products. Statistical analysis was performed with Spearman's, Chi-square, Mann-Whitney U test, and logistic regression.ResultsBurn (n = 60) and trauma (n = 136) cohorts showed similar degrees of FV consumption with median FV levels of 76% versus 73% (P = 0.65) of normal, respectively. Percent total body surface area (TBSA) was not correlated with FV, nor were significant differences in median FV levels observed between low and high TBSA groups. The injury severity score (ISS) in trauma patients was inversely correlated with FV (ρ = -0.26; P = 0.01) and ISS ≥ 25 was associated with a lower FV antigen level (64% versus. 93%; P = 0.009). The proportion of samples showing proteolysis-derived FV was greater in trauma than burn patients (42% versus. 16%; P = 0.0006).ConclusionsIncreasing traumatic injury severity is associated with decreased FV antigen levels, and a greater proportion of trauma patient samples exhibit proteolytically degraded FV fragments. These associations are not present in burns, suggesting that mechanisms underlying FV depletion in burn and nonburn trauma are not identical.

Kidney failure is common in patients with Coronavirus Disease-19 (COVID-19), resulting in increased morbidity and mortality. In an international collaboration, 284 kidney biopsies were evaluated to improve understanding of kidney disease in COVID-19. Diagnoses were compared to five years of 63,575 native biopsies prior to the pandemic and 13,955 allograft biopsies to identify diseases that have increased in patients with COVID-19. Genotyping for APOL1 G1 and G2 alleles was performed in 107 African American and Hispanic patients. Immunohistochemistry for SARS-CoV-2 was utilized to assess direct viral infection in 273 cases along with clinical information at the time of biopsy. The leading indication for native biopsy was acute kidney injury (45.4%), followed by proteinuria with or without concurrent acute kidney injury (42.6%). There were more African American patients (44.6%) than patients of other ethnicities. The most common diagnosis in native biopsies was collapsing glomerulopathy (25.8%), which was associated with high-risk APOL1 genotypes in 91.7% of cases. Compared to the five-year biopsy database, the frequency of myoglobin cast nephropathy and proliferative glomerulonephritis with monoclonal IgG deposits was also increased in patients with COVID-19 (3.3% and 1.7%, respectively), while there was a reduced frequency of chronic conditions (including diabetes mellitus, IgA nephropathy, and arterionephrosclerosis) as the primary diagnosis. In transplants, the leading indication was acute kidney injury (86.4%), for which rejection was the predominant diagnosis (61.4%). Direct SARS-CoV-2 viral infection was not identified. Thus, our multi-center large case series identified kidney diseases that disproportionately affect patients with COVID-19 and demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney.

Fungi are ecologically outstanding decomposers of lignocellulose. Fungal lignocellulose degradation is prominent in saprotrophic Ascomycota and Basidiomycota of the subkingdom Dikarya. Despite ascomycetes dominating the Dikarya inventory of aquatic environments, genome and transcriptome data relating to enzymes involved in lignocellulose decay remain limited to terrestrial representatives of these phyla. We sequenced the genome of an exclusively aquatic ascomycete (the aquatic hyphomycete Clavariopsis aquatica), documented the presence of genes for the modification of lignocellulose and its constituents, and compared differential gene expression between C. aquatica cultivated on lignocellulosic and sugar-rich substrates. We identified potential peroxidases, laccases, and cytochrome P450 monooxygenases, several of which were differentially expressed when experimentally grown on different substrates. Additionally, we found indications for the regulation of pathways for cellulose and hemicellulose degradation. Our results suggest that C. aquatica is able to modify lignin to some extent, detoxify aromatic lignin constituents, or both. Such characteristics would be expected to facilitate the use of carbohydrate components of lignocellulose as carbon and energy sources.

The COVID-19 pandemic has once again highlighted the ubiquity and persistence of health inequities along with our inability to respond to them in a timely and effective manner. There is an opportunity to address the limitations of our current approaches through new models of informatics-enabled research and clinical practice that shift the norm from small- to large-scale patient engagement. We propose augmenting our approach to address health inequities through informatics-enabled citizen science, challenging the types of questions being asked, prioritized, and acted upon. We envision this democratization of informatics that builds upon the inclusive tradition of community-based participatory research (CBPR) as a logical and transformative step toward improving individual, community, and population health in a way that deeply reflects the needs of historically marginalized populations.

BackgroundOver time human skin thins and loses elasticity; topical treatments attempt to reverse this process.ObjectivesThe aim of this study was to assess the efficacy of TransFORM Body Treatment (TFB) in skin rejuvenation compared to a bland moisturizer on the extensor and volar forearms.MethodsBlinded participants were given 2 products to apply on the designated forearms with follow-up at 4, 8, and 12 weeks. Measurements included skin thickness, photography, dermatopathology, cutaneous elasticity determined by 2 different methods, and patient-reported outcomes. All were compared to baseline.ResultsChanges between bland moisturizer and TFB were recorded for the following parameters. (1) Roughness: extensor -0.09 mm for bland moisturizer and -0.26 mm for TFB (P = 0.174); volar 0.01 mm for bland moisturizer and -0.23 mm for TFB (P = 0.004). (2) Recoil velocity: volar -56°/sec for bland moisturizer and -24°/sec for TFB (P = 0.61); extensor -95°/sec for bland moisturizer and -63°/sec for TFB (P = 0.57). Retraction speed: volar -3.25 ms for bland moisturizer and -20.08 ms for TFB (P = 0.33); extensor -2.17 ms for bland moisturizer and -10.83 ms for TFB (P = 0.66). Histologically, TFB resulted in an increase in mucopolysaccharide content, new collagen, and number of elastin fibers in the papillary dermis. Changes in the Rao-Goldman score were also observed: volar -0.17 for bland moisturizer and -0.33 for TFB (P = 0.25); extensor -0.08 for bland moisturizer and -0.17 for TFB (P = 0.36).ConclusionsHistology showed production of new collagen and elastin. Quantification of changes in skin thickness, skin retraction speed, and skin recoil velocity showed trends that agree with the visual data.Level of evidence: 4

The COVID-19 pandemic has once again highlighted the ubiquity and persistence of health inequities along with our inability to respond to them in a timely and effective manner. There is an opportunity to address the limitations of our current approaches through new models of informatics-enabled research and clinical practice that shift the norm from small- to large-scale patient engagement. We propose augmenting our approach to address health inequities through informatics-enabled citizen science, challenging the types of questions being asked, prioritized, and acted upon. We envision this democratization of informatics that builds upon the inclusive tradition of community-based participatory research (CBPR) as a logical and transformative step toward improving individual, community, and population health in a way that deeply reflects the needs of historically marginalized populations.

IntroductionAdvanced age and obesity are reported to increase the risk of opioid-induced respiratory depression (OIRD). Oliceridine, an intravenous opioid, is a G-protein-biased agonist at the µ-opioid receptor that may provide improved safety. The recent phase 3 ATHENA open-label, multicenter study evaluated postoperative use of oliceridine in patients with moderate-to-severe acute pain. This exploratory analysis of the ATHENA data examined the incidence of OIRD in older (≥ 65 years) and/or obese (BMI ≥ 30 kg/m2) patients and analyzed risk factors of OIRD.MethodsPatients aged ≥ 18 years with a score ≥ 4 on an 11-point numeric pain rating scale (NPRS) received IV oliceridine as needed via bolus dosing and/or patient-controlled analgesia (PCA). OIRD occurring within 48 h of last dose of oliceridine was defined using two established definitions: (1) naloxone use, (2) respiratory rate

IntroductionAdvanced age and obesity are reported to increase the risk of opioid-induced respiratory depression (OIRD). Oliceridine, an intravenous opioid, is a G-protein-biased agonist at the µ-opioid receptor that may provide improved safety. The recent phase 3 ATHENA open-label, multicenter study evaluated postoperative use of oliceridine in patients with moderate-to-severe acute pain. This exploratory analysis of the ATHENA data examined the incidence of OIRD in older (≥ 65 years) and/or obese (BMI ≥ 30 kg/m2) patients and analyzed risk factors of OIRD.MethodsPatients aged ≥ 18 years with a score ≥ 4 on an 11-point numeric pain rating scale (NPRS) received IV oliceridine as needed via bolus dosing and/or patient-controlled analgesia (PCA). OIRD occurring within 48 h of last dose of oliceridine was defined using two established definitions: (1) naloxone use, (2) respiratory rate

To understand the vertical variations in carbon fluxes in biologically productive waters, four autonomous carbon flux explorers (CFEs), ship-lowered CTD-interfaced particle-sensitive transmissometer and scattering sensors, and surface-drogued sediment traps were deployed in a filament of offshore flowing, recently upwelled water, during the June 2017 California Current Ecosystem-Long Term Ecological Research process study. The Lagrangian CFEs operating at depths from 100-500 m yielded carbon flux and its partitioning with size from 30 μ m-1 cm at three intensive study locations within the filament and in waters outside the filament. Size analysis codes intended to enable long-term CFE operations independent of ships are described. Different particle classes (anchovy pellets, copepod pellets, and > 1000 μ m aggregates) dominated the 100-150 m fluxes during successive stages of the filament evolution as it progressed offshore. Fluxes were very high at all locations in the filament; below 150 m, flux was invariant or increased with depth at the two locations closer to the coast. Martin curve bfactors (± denotes 95 % confidence intervals) for total particulate carbon flux were + 0.37 ± 0.59, + 0.85 ± 0.31,-0.24 ± 0.68, and-0.45 ± 0.70 at the three successively occupied locations within the plume, and in transitional waters. Interestingly, the flux profiles for all particles < 400 μ m were a much closer fit to the canonical Martin profile (b-0.86); however, most (typically > 90 %) of the particle flux was carried by > 1000 μ m sized aggregates which increased with depth. Mechanisms to explain the factor of 3 flux increase between 150 and 500 m at the mid-plume location are investigated.

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

To understand the vertical variations in carbon fluxes in biologically productive waters, four autonomous carbon flux explorers (CFEs), ship-lowered CTD-interfaced particle-sensitive transmissometer and scattering sensors, and surface-drogued sediment traps were deployed in a filament of offshore flowing, recently upwelled water, during the June 2017 California Current Ecosystem-Long Term Ecological Research process study. The Lagrangian CFEs operating at depths from 100-500 m yielded carbon flux and its partitioning with size from 30 μ m-1 cm at three intensive study locations within the filament and in waters outside the filament. Size analysis codes intended to enable long-term CFE operations independent of ships are described. Different particle classes (anchovy pellets, copepod pellets, and > 1000 μ m aggregates) dominated the 100-150 m fluxes during successive stages of the filament evolution as it progressed offshore. Fluxes were very high at all locations in the filament; below 150 m, flux was invariant or increased with depth at the two locations closer to the coast. Martin curve bfactors (± denotes 95 % confidence intervals) for total particulate carbon flux were + 0.37 ± 0.59, + 0.85 ± 0.31,-0.24 ± 0.68, and-0.45 ± 0.70 at the three successively occupied locations within the plume, and in transitional waters. Interestingly, the flux profiles for all particles < 400 μ m were a much closer fit to the canonical Martin profile (b-0.86); however, most (typically > 90 %) of the particle flux was carried by > 1000 μ m sized aggregates which increased with depth. Mechanisms to explain the factor of 3 flux increase between 150 and 500 m at the mid-plume location are investigated.

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

Fungi are ecologically outstanding decomposers of lignocellulose. Fungal lignocellulose degradation is prominent in saprotrophic Ascomycota and Basidiomycota of the subkingdom Dikarya. Despite ascomycetes dominating the Dikarya inventory of aquatic environments, genome and transcriptome data relating to enzymes involved in lignocellulose decay remain limited to terrestrial representatives of these phyla. We sequenced the genome of an exclusively aquatic ascomycete (the aquatic hyphomycete Clavariopsis aquatica), documented the presence of genes for the modification of lignocellulose and its constituents, and compared differential gene expression between C. aquatica cultivated on lignocellulosic and sugar-rich substrates. We identified potential peroxidases, laccases, and cytochrome P450 monooxygenases, several of which were differentially expressed when experimentally grown on different substrates. Additionally, we found indications for the regulation of pathways for cellulose and hemicellulose degradation. Our results suggest that C. aquatica is able to modify lignin to some extent, detoxify aromatic lignin constituents, or both. Such characteristics would be expected to facilitate the use of carbohydrate components of lignocellulose as carbon and energy sources.

OBJECTIVE: Ubiquitous technologies can be leveraged to construct ecologically relevant metrics that complement traditional psychological assessments. This study aims to determine the feasibility of smartphone-derived real-world keyboard metadata to serve as digital biomarkers of mood. MATERIALS AND METHODS: BiAffect, a real-world observation study based on a freely available iPhone app, allowed the unobtrusive collection of typing metadata through a custom virtual keyboard that replaces the default keyboard. User demographics and self-reports for depression severity (Patient Health Questionnaire-8) were also collected. Using >14 million keypresses from 250 users who reported demographic information and a subset of 147 users who additionally completed at least 1 Patient Health Questionnaire, we employed hierarchical growth curve mixed-effects models to capture the effects of mood, demographics, and time of day on keyboard metadata. RESULTS: We analyzed 86 541 typing sessions associated with a total of 543 Patient Health Questionnaires. Results showed that more severe depression relates to more variable typing speed (P

ObjectiveThe objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus.MethodsSix participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint.ResultsThe treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event.ConclusionsBilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%-80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

The House Observations of Microbial and Environmental Chemistry (HOMEChem) study is a collaborative field investigation designed to probe how everyday activities influence the emissions, chemical transformations and removal of trace gases and particles in indoor air. Sequential and layered experiments in a research house included cooking, cleaning, variable occupancy, and window-opening. This paper describes the overall design of HOMEChem and presents preliminary case studies investigating the concentrations of reactive trace gases, aerosol particles, and surface films. Cooking was a large source of VOCs, CO2, NOx, and particles. By number, cooking particles were predominantly in the ultrafine mode. Organic aerosol dominated the submicron mass, and, while variable between meals and throughout the cooking process, was dominated by components of hydrocarbon character and low oxygen content, similar to cooking oil. Air exchange in the house ensured that cooking particles were present for only short periods. During unoccupied background intervals, particle concentrations were lower indoors than outdoors. The cooling coils of the house ventilation system induced cyclic changes in water soluble gases. Even during unoccupied periods, concentrations of many organic trace gases were higher indoors than outdoors, consistent with housing materials being potential sources of these compounds to the outdoor environment. Organic material accumulated on indoor surfaces, and exhibited chemical signatures similar to indoor organic aerosol.

The House Observations of Microbial and Environmental Chemistry (HOMEChem) study is a collaborative field investigation designed to probe how everyday activities influence the emissions, chemical transformations and removal of trace gases and particles in indoor air. Sequential and layered experiments in a research house included cooking, cleaning, variable occupancy, and window-opening. This paper describes the overall design of HOMEChem and presents preliminary case studies investigating the concentrations of reactive trace gases, aerosol particles, and surface films. Cooking was a large source of VOCs, CO2, NOx, and particles. By number, cooking particles were predominantly in the ultrafine mode. Organic aerosol dominated the submicron mass, and, while variable between meals and throughout the cooking process, was dominated by components of hydrocarbon character and low oxygen content, similar to cooking oil. Air exchange in the house ensured that cooking particles were present for only short periods. During unoccupied background intervals, particle concentrations were lower indoors than outdoors. The cooling coils of the house ventilation system induced cyclic changes in water soluble gases. Even during unoccupied periods, concentrations of many organic trace gases were higher indoors than outdoors, consistent with housing materials being potential sources of these compounds to the outdoor environment. Organic material accumulated on indoor surfaces, and exhibited chemical signatures similar to indoor organic aerosol.

Disease is an emerging threat to coral reef ecosystems worldwide, highlighting the need to understand how environmental conditions interact with coral immune function and associated microbial communities to affect holobiont health. Increased coral disease incidence on reefs adjacent to permanently moored platforms on Australia's Great Barrier Reef provided a unique case study to investigate environment-host-microbe interactions in situ. Here, we evaluate coral-associated bacterial community (16S rRNA amplicon sequencing), immune function (protein-based prophenoloxidase-activating system), and water quality parameters before, during and after a disease event. Over the course of the study, 31% of tagged colonies adjacent to platforms developed signs of white syndrome (WS), while all control colonies on a platform-free reef remained visually healthy. Corals adjacent to platforms experienced significant reductions in coral immune function. Additionally, the corals at platform sites that remained visually healthy throughout the study had reduced bacterial diversity compared to healthy colonies at the platform-free site. Interestingly, prior to the observation of macroscopic disease, corals that would develop WS had reduced bacterial diversity and significantly greater community heterogeneity between colonies compared to healthy corals at the same location. These results suggest that activities associated with offshore marine infrastructure impacts coral immunocompetence and associated bacterial community, which affects the susceptibility of corals to disease.

Disease is an emerging threat to coral reef ecosystems worldwide, highlighting the need to understand how environmental conditions interact with coral immune function and associated microbial communities to affect holobiont health. Increased coral disease incidence on reefs adjacent to permanently moored platforms on Australia's Great Barrier Reef provided a unique case study to investigate environment-host-microbe interactions in situ. Here, we evaluate coral-associated bacterial community (16S rRNA amplicon sequencing), immune function (protein-based prophenoloxidase-activating system), and water quality parameters before, during and after a disease event. Over the course of the study, 31% of tagged colonies adjacent to platforms developed signs of white syndrome (WS), while all control colonies on a platform-free reef remained visually healthy. Corals adjacent to platforms experienced significant reductions in coral immune function. Additionally, the corals at platform sites that remained visually healthy throughout the study had reduced bacterial diversity compared to healthy colonies at the platform-free site. Interestingly, prior to the observation of macroscopic disease, corals that would develop WS had reduced bacterial diversity and significantly greater community heterogeneity between colonies compared to healthy corals at the same location. These results suggest that activities associated with offshore marine infrastructure impacts coral immunocompetence and associated bacterial community, which affects the susceptibility of corals to disease.

Although the early coral reef-bleaching warning system (NOAA/USA) is established, there is no feasible treatment that can minimize temperature bleaching and/or disease impacts on corals in the field. Here, we present the first attempts to extrapolate the widespread and well-established use of bacterial consortia to protect or improve health in other organisms (e.g., humans and plants) to corals. Manipulation of the coral-associated microbiome was facilitated through addition of a consortium of native (isolated from Pocillopora damicornis and surrounding seawater) putatively beneficial microorganisms for corals (pBMCs), including five Pseudoalteromonas sp., a Halomonas taeanensis and a Cobetia marina-related species strains. The results from a controlled aquarium experiment in two temperature regimes (26 °C and 30 °C) and four treatments (pBMC; pBMC with pathogen challenge - Vibrio coralliilyticus, VC; pathogen challenge, VC; and control) revealed the ability of the pBMC consortium to partially mitigate coral bleaching. Significantly reduced coral-bleaching metrics were observed in pBMC-inoculated corals, in contrast to controls without pBMC addition, especially challenged corals, which displayed strong bleaching signs as indicated by significantly lower photopigment contents and Fv/Fm ratios. The structure of the coral microbiome community also differed between treatments and specific bioindicators were correlated with corals inoculated with pBMC (e.g., Cobetia sp.) or VC (e.g., Ruegeria sp.). Our results indicate that the microbiome in corals can be manipulated to lessen the effect of bleaching, thus helping to alleviate pathogen and temperature stresses, with the addition of BMCs representing a promising novel approach for minimizing coral mortality in the face of increasing environmental impacts.

Although the early coral reef-bleaching warning system (NOAA/USA) is established, there is no feasible treatment that can minimize temperature bleaching and/or disease impacts on corals in the field. Here, we present the first attempts to extrapolate the widespread and well-established use of bacterial consortia to protect or improve health in other organisms (e.g., humans and plants) to corals. Manipulation of the coral-associated microbiome was facilitated through addition of a consortium of native (isolated from Pocillopora damicornis and surrounding seawater) putatively beneficial microorganisms for corals (pBMCs), including five Pseudoalteromonas sp., a Halomonas taeanensis and a Cobetia marina-related species strains. The results from a controlled aquarium experiment in two temperature regimes (26 °C and 30 °C) and four treatments (pBMC; pBMC with pathogen challenge - Vibrio coralliilyticus, VC; pathogen challenge, VC; and control) revealed the ability of the pBMC consortium to partially mitigate coral bleaching. Significantly reduced coral-bleaching metrics were observed in pBMC-inoculated corals, in contrast to controls without pBMC addition, especially challenged corals, which displayed strong bleaching signs as indicated by significantly lower photopigment contents and Fv/Fm ratios. The structure of the coral microbiome community also differed between treatments and specific bioindicators were correlated with corals inoculated with pBMC (e.g., Cobetia sp.) or VC (e.g., Ruegeria sp.). Our results indicate that the microbiome in corals can be manipulated to lessen the effect of bleaching, thus helping to alleviate pathogen and temperature stresses, with the addition of BMCs representing a promising novel approach for minimizing coral mortality in the face of increasing environmental impacts.

The magnitude and controls of particulate carbon exported from surface waters and its remineralization at depth are poorly constrained. The Carbon Flux Explorer (CFE), a Lagrangian float-deployed imaging sediment trap, has been designed to optically measure the hourly variations of particle flux to kilometer depths for months to seasons while relaying data in near-real time to shore via satellite without attending ships. The main optical proxy for particle load recorded by the CFE, volume attenuance (VA; units of mATN cm2), while rigorously defined and highly precise, has not been robustly calibrated in terms of particulate organic carbon (POC), nitrogen (PN) and phosphorus (PP). In this study, a novel 3-D-printed particle sampler using cutting edge additive manufacturing was developed and integrated with the CFE. Two such modified floats (CFE-Cals) were deployed a total of 15 times for 18-24 h periods to gain calibration imagery and samples at depths near 150m in four contrasting productivity environments during the June 2017 California Current Ecosystem Long-Term Ecological Research (LTER) process study. Regression slopes for VA: POC and VA: PN (units mATN cm2: mmol; R2, n, p value in parentheses) were 1.01×104 (0.86, 12, < 0.001) and 1:01×105 (0.86, 15, < 0.001), respectively, and were not sensitive to particle size classes or the contrasting environments encountered. PP was not well correlated with VA, reflecting the high lability of P relative to C and N. The volume attenuance flux (VAF) to POC flux calibration is compared to previous estimates.

Many proteins fold into highly regular and repetitive three dimensional structures. The analysis of structural patterns and repeated elements is fundamental to understand protein function and evolution. We present recent improvements to the CE-Symm tool for systematically detecting and analyzing the internal symmetry and structural repeats in proteins. In addition to the accurate detection of internal symmetry, the tool is now capable of i) reporting the type of symmetry, ii) identifying the smallest repeating unit, iii) describing the arrangement of repeats with transformation operations and symmetry axes, and iv) comparing the similarity of all the internal repeats at the residue level. CE-Symm 2.0 helps the user investigate proteins with a robust and intuitive sequence-to-structure analysis, with many applications in protein classification, functional annotation and evolutionary studies. We describe the algorithmic extensions of the method and demonstrate its applications to the study of interesting cases of protein evolution.

The magnitude and controls of particulate carbon exported from surface waters and its remineralization at depth are poorly constrained. The Carbon Flux Explorer (CFE), a Lagrangian float-deployed imaging sediment trap, has been designed to optically measure the hourly variations of particle flux to kilometer depths for months to seasons while relaying data in near-real time to shore via satellite without attending ships. The main optical proxy for particle load recorded by the CFE, volume attenuance (VA; units of mATN cm2), while rigorously defined and highly precise, has not been robustly calibrated in terms of particulate organic carbon (POC), nitrogen (PN) and phosphorus (PP). In this study, a novel 3-D-printed particle sampler using cutting edge additive manufacturing was developed and integrated with the CFE. Two such modified floats (CFE-Cals) were deployed a total of 15 times for 18-24 h periods to gain calibration imagery and samples at depths near 150m in four contrasting productivity environments during the June 2017 California Current Ecosystem Long-Term Ecological Research (LTER) process study. Regression slopes for VA: POC and VA: PN (units mATN cm2: mmol; R2, n, p value in parentheses) were 1.01×104 (0.86, 12, < 0.001) and 1:01×105 (0.86, 15, < 0.001), respectively, and were not sensitive to particle size classes or the contrasting environments encountered. PP was not well correlated with VA, reflecting the high lability of P relative to C and N. The volume attenuance flux (VAF) to POC flux calibration is compared to previous estimates.

The transcription factor MXD3 is an atypical member of the MYC/MAX/MXD transcriptional network and has been previously shown to be an important regulator of cell proliferation. MXD3 has been shown to be overexpressed and to be required for medulloblastoma and acute lymphoblastic leukemia cell proliferation. In this study we leveraged datasets from The Cancer Genome Atlas to examine MXD3 across several cancers. We find that MXD3 transcripts are significantly overexpressed in ~72% of the available datasets. The gene itself is not frequently altered, while the promoter appears to be hypomethylated. We examine the possibility that aberrant regulation of the MXD3 message is the cause of abnormal MXD3 expression across cancers. Specifically, we looked at MXD3 alternative splicing in glioblastoma multiforme (GBM) and find notable functional differences between the splice variants. The 3'UTR confers differential message stability. Furthermore, the different coding sequences lead to different protein stabilities and localizations. Altogether, these data extend our knowledge of MXD3 in the context of human cancers while characterizing a previously unstudied splice variant of MXD3.

Abstract. The magnitude and controls of particulate carbon exported from surface waters and its remineralization at depth are poorly known. The Carbon Flux Explorer (CFE), a Lagrangian float-deployed imaging sediment trap, has been designed to optically measure the hourly variations of particle flux to kilometer depths for months to seasons while relaying data in near-real time to shore via satellite without attending ships. The main optical proxy of particle load recorded by the CFE, volume-attenuance (VA; units of mATN-cm2), while rigorously defined and highly precise, has not been robustly calibrated in terms of particulate organic carbon (POC), nitrogen (PN), and phosphorus (PP). In this study, a novel 3D printed particle sampler using cutting edge additive manufacturing was developed and integrated with the CFE. Two such modified floats (CFE-Cals) were deployed a total of 15 times for 18-24-hour periods to gain calibration imagery and samples at depths near 150 meters in four contrasting productivity environments during the June 2017 California Current Ecosystem – Long Term Ecological Research (LTER) process study. Regression slopes for VA : POC and VA : PN (units mATN-cm2 : mmol; R2 in parentheses) were 10.07 × 103 (0.86), 10.05 × 104 (0.87) respectively and was not sensitive to environment or classes of particles sampled. PP was not strongly correlated with VA.

Abstract. The magnitude and controls of particulate carbon exported from surface waters and its remineralization at depth are poorly known. The Carbon Flux Explorer (CFE), a Lagrangian float-deployed imaging sediment trap, has been designed to optically measure the hourly variations of particle flux to kilometer depths for months to seasons while relaying data in near-real time to shore via satellite without attending ships. The main optical proxy of particle load recorded by the CFE, volume-attenuance (VA; units of mATN-cm2), while rigorously defined and highly precise, has not been robustly calibrated in terms of particulate organic carbon (POC), nitrogen (PN), and phosphorus (PP). In this study, a novel 3D printed particle sampler using cutting edge additive manufacturing was developed and integrated with the CFE. Two such modified floats (CFE-Cals) were deployed a total of 15 times for 18-24-hour periods to gain calibration imagery and samples at depths near 150 meters in four contrasting productivity environments during the June 2017 California Current Ecosystem – Long Term Ecological Research (LTER) process study. Regression slopes for VA : POC and VA : PN (units mATN-cm2 : mmol; R2 in parentheses) were 10.07 × 103 (0.86), 10.05 × 104 (0.87) respectively and was not sensitive to environment or classes of particles sampled. PP was not strongly correlated with VA.

Concentrations of Cd and P were determined in particle samples collected using the multiple unit large volume in situ filtration system (MULVFS) from 50 profiles at 34 different locations throughout the Atlantic, Pacific, and Southern Oceans since 1991. Consistent methodology has been used. This data set of Cd:P in size fractionated particles gives insight into the processes that lead to differences in regional Cd:P particle values as well as how the formation and remineralization of these particles lead to dissolved deep water ratios that increase from the North Atlantic to the North Pacific. With large spatial and temporal variation, this data set allows us to study the effects of an El Niño, upwelling, large-scale in situ Fe fertilization, low-oxygen conditions, and seasonal variation on the Cd:P in particles. Overall, Cd:P tends to be higher (~1–2 mmol/mol) in particles gathered in biologically dynamic waters and is much lower (typically ~0.1 mmol/mol) in oligotrophic regions. Using multiple linear regression analysis, we investigate how euphotic zone parameters important to photosynthesis including nitrate, phosphate, silicate, temperature, and euphotic zone depth affect the Cd:P ratio in particles. Using the results of the analysis, we create global seasonal maps of predicted particulate Cd:P distributions. We find that three factors—local dissolved nitrate, silicate concentrations, and euphotic zone depth—can predict 59% of the variation in particulate Cd:P. We verified our projections using in situ filtration samples collected during GEOTRACES expeditions GA03 (North Atlantic) and GP16 (South Pacific).

Concentrations of Cd and P were determined in particle samples collected using the multiple unit large volume in situ filtration system (MULVFS) from 50 profiles at 34 different locations throughout the Atlantic, Pacific, and Southern Oceans since 1991. Consistent methodology has been used. This data set of Cd:P in size fractionated particles gives insight into the processes that lead to differences in regional Cd:P particle values as well as how the formation and remineralization of these particles lead to dissolved deep water ratios that increase from the North Atlantic to the North Pacific. With large spatial and temporal variation, this data set allows us to study the effects of an El Niño, upwelling, large-scale in situ Fe fertilization, low-oxygen conditions, and seasonal variation on the Cd:P in particles. Overall, Cd:P tends to be higher (~1–2 mmol/mol) in particles gathered in biologically dynamic waters and is much lower (typically ~0.1 mmol/mol) in oligotrophic regions. Using multiple linear regression analysis, we investigate how euphotic zone parameters important to photosynthesis including nitrate, phosphate, silicate, temperature, and euphotic zone depth affect the Cd:P ratio in particles. Using the results of the analysis, we create global seasonal maps of predicted particulate Cd:P distributions. We find that three factors—local dissolved nitrate, silicate concentrations, and euphotic zone depth—can predict 59% of the variation in particulate Cd:P. We verified our projections using in situ filtration samples collected during GEOTRACES expeditions GA03 (North Atlantic) and GP16 (South Pacific).

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.

Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.

Enhancements in clinical-grade next-generation sequencing (NGS) have fueled the advancement of precision medicine in the clinical oncology field. Here, we survey the molecular profiles of 1,113 patients with diverse malignancies who successfully underwent clinical-grade NGS (236-404 genes) in an academic tertiary cancer center. Among the individual tumors examined, the majority showed at least one detectable alteration (97.2%). Among 2,045 molecular aberrations was the involvement of 302 distinct genes. The most commonly altered genes were TP53 (47.0%), CDKN2A (18.0%), TERT (17.0%), and KRAS (16.0%), and the majority of patients had tumors that harbored multiple alterations. Tumors displayed a median of four alterations (range, 0-29). Most individuals had at least one potentially actionable alteration (94.7%), with the median number of potentially actionable alterations per patient being 2 (range, 0-13). A total of 1,048 (94.2%) patients exhibited a unique molecular profile, with either genes altered or loci within the gene(s) altered being distinct. Approximately 13% of patients displayed a genomic profile identical to at least one other patient; although genes altered were the same, the affected loci may have differed. Overall, our results underscore the complex heterogeneity of malignancies and argue that customized combination therapies will be essential to optimize cancer treatment regimens. Cancer Res; 77(22); 6313-20. ©2017 AACR.

BackgroundMonitoring levels and trends in premature mortality is crucial to understanding how societies can address prominent sources of early death. The Global Burden of Disease 2016 Study (GBD 2016) provides a comprehensive assessment of cause-specific mortality for 264 causes in 195 locations from 1980 to 2016. This assessment includes evaluation of the expected epidemiological transition with changes in development and where local patterns deviate from these trends.MethodsWe estimated cause-specific deaths and years of life lost (YLLs) by age, sex, geography, and year. YLLs were calculated from the sum of each death multiplied by the standard life expectancy at each age. We used the GBD cause of death database composed of: vital registration (VR) data corrected for under-registration and garbage coding; national and subnational verbal autopsy (VA) studies corrected for garbage coding; and other sources including surveys and surveillance systems for specific causes such as maternal mortality. To facilitate assessment of quality, we reported on the fraction of deaths assigned to GBD Level 1 or Level 2 causes that cannot be underlying causes of death (major garbage codes) by location and year. Based on completeness, garbage coding, cause list detail, and time periods covered, we provided an overall data quality rating for each location with scores ranging from 0 stars (worst) to 5 stars (best). We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to generate estimates for each location, year, age, and sex. We assessed observed and expected levels and trends of cause-specific deaths in relation to the Socio-demographic Index (SDI), a summary indicator derived from measures of average income per capita, educational attainment, and total fertility, with locations grouped into quintiles by SDI. Relative to GBD 2015, we expanded the GBD cause hierarchy by 18 causes of death for GBD 2016.FindingsThe quality of available data varied by location. Data quality in 25 countries rated in the highest category (5 stars), while 48, 30, 21, and 44 countries were rated at each of the succeeding data quality levels. Vital registration or verbal autopsy data were not available in 27 countries, resulting in the assignment of a zero value for data quality. Deaths from non-communicable diseases (NCDs) represented 72·3% (95% uncertainty interval [UI] 71·2-73·2) of deaths in 2016 with 19·3% (18·5-20·4) of deaths in that year occurring from communicable, maternal, neonatal, and nutritional (CMNN) diseases and a further 8·43% (8·00-8·67) from injuries. Although age-standardised rates of death from NCDs decreased globally between 2006 and 2016, total numbers of these deaths increased; both numbers and age-standardised rates of death from CMNN causes decreased in the decade 2006-16-age-standardised rates of deaths from injuries decreased but total numbers varied little. In 2016, the three leading global causes of death in children under-5 were lower respiratory infections, neonatal preterm birth complications, and neonatal encephalopathy due to birth asphyxia and trauma, combined resulting in 1·80 million deaths (95% UI 1·59 million to 1·89 million). Between 1990 and 2016, a profound shift toward deaths at older ages occurred with a 178% (95% UI 176-181) increase in deaths in ages 90-94 years and a 210% (208-212) increase in deaths older than age 95 years. The ten leading causes by rates of age-standardised YLL significantly decreased from 2006 to 2016 (median annualised rate of change was a decrease of 2·89%); the median annualised rate of change for all other causes was lower (a decrease of 1·59%) during the same interval. Globally, the five leading causes of total YLLs in 2016 were cardiovascular diseases; diarrhoea, lower respiratory infections, and other common infectious diseases; neoplasms; neonatal disorders; and HIV/AIDS and tuberculosis. At a finer level of disaggregation within cause groupings, the ten leading causes of total YLLs in 2016 were ischaemic heart disease, cerebrovascular disease, lower respiratory infections, diarrhoeal diseases, road injuries, malaria, neonatal preterm birth complications, HIV/AIDS, chronic obstructive pulmonary disease, and neonatal encephalopathy due to birth asphyxia and trauma. Ischaemic heart disease was the leading cause of total YLLs in 113 countries for men and 97 countries for women. Comparisons of observed levels of YLLs by countries, relative to the level of YLLs expected on the basis of SDI alone, highlighted distinct regional patterns including the greater than expected level of YLLs from malaria and from HIV/AIDS across sub-Saharan Africa; diabetes mellitus, especially in Oceania; interpersonal violence, notably within Latin America and the Caribbean; and cardiomyopathy and myocarditis, particularly in eastern and central Europe. The level of YLLs from ischaemic heart disease was less than expected in 117 of 195 locations. Other leading causes of YLLs for which YLLs were notably lower than expected included neonatal preterm birth complications in many locations in both south Asia and southeast Asia, and cerebrovascular disease in western Europe.InterpretationThe past 37 years have featured declining rates of communicable, maternal, neonatal, and nutritional diseases across all quintiles of SDI, with faster than expected gains for many locations relative to their SDI. A global shift towards deaths at older ages suggests success in reducing many causes of early death. YLLs have increased globally for causes such as diabetes mellitus or some neoplasms, and in some locations for causes such as drug use disorders, and conflict and terrorism. Increasing levels of YLLs might reflect outcomes from conditions that required high levels of care but for which effective treatments remain elusive, potentially increasing costs to health systems.FundingBill & Melinda Gates Foundation.

We present an overview of the toxicological profile of the fast-acting, lipophilic macrocyclic imine toxins, an emerging family of organic compounds associated with algal blooms, shellfish contamination and neurotoxicity. Worldwide, shellfish contamination incidents are expanding; therefore, the significance of these toxins for the shellfish food industry deserves further study. Emphasis is directed to the dinoflagellate species involved in their production, their chemical structures, and their specific mode of interaction with their principal natural molecular targets, the nicotinic acetylcholine receptors, or with the soluble acetylcholine-binding protein, used as a surrogate receptor model. The dinoflagellates Karenia selliformis and Alexandrium ostenfeldii / A. peruvianum have been implicated in the biosynthesis of gymnodimines and spirolides, while Vulcanodinium rugosum is the producer of pinnatoxins and portimine. The cyclic imine toxins are characterized by a macrocyclic skeleton comprising 14-27 carbon atoms, flanked by two conserved moieties, the cyclic imine and the spiroketal ring system. These phycotoxins generally display high affinity and broad specificity for the muscle type and neuronal nicotinic acetylcholine receptors, a feature consistent with their binding site at the receptor subunit interfaces, composed of residues highly conserved among all nAChRs, and explaining the diverse toxicity among animal species. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.

SummaryWe developed a new software tool, BioJava-ModFinder, for identifying protein modifications observed in 3D structures archived in the Protein Data Bank (PDB). Information on more than 400 types of protein modifications were collected and curated from annotations in PDB, RESID, and PSI-MOD. We divided these modifications into three categories: modified residues, attachment modifications, and cross-links. We have developed a systematic method to identify these modifications in 3D protein structures. We have integrated this package with the RCSB PDB web application and added protein modification annotations to the sequence diagram and structure display. By scanning all 3D structures in the PDB using BioJava-ModFinder, we identified more than 30 000 structures with protein modifications, which can be searched, browsed, and visualized on the RCSB PDB website.Availability and implementationBioJava-ModFinder is available as open source (LGPL license) at ( https://github.com/biojava/biojava/tree/master/biojava-modfinder ). The RCSB PDB can be accessed at http://www.rcsb.org .Contactpwrose@ucsd.edu.

BACKGROUND: Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. OBJECTIVE: To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. METHODS: The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). RESULTS: We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p=0.01). CONCLUSIONS: While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies.

Spheroids formed of mesenchymal stem cells (MSCs) exhibit increased cell survival and trophic factor secretion compared with dissociated MSCs, making them therapeutically advantageous for cell therapy. Presently, there is no consensus for the mechanism of action. Many hypothesize that spheroid formation potentiates cell function by generating a hypoxic core within spheroids of sufficiently large diameters. The purpose of this study was to experimentally determine whether a hypoxic core is generated in MSC spheroids by measuring oxygen tension in aggregates of increasing diameter and correlating oxygen tension values with cell function. MSC spheroids were formed with 15 000, 30 000 or 60 000 cells per spheroid, resulting in radii of 176 ± 8 µm, 251 ± 12 µm and 353 ± 18 µm, respectively. Oxygen tension values coupled with mathematical modelling revealed a gradient that varied less than 10% from the outer diameter within the largest spheroids. Despite the modest radial variance in oxygen tension, cellular metabolism from spheroids significantly decreased as the number of cells and resultant spheroid size increased. This may be due to adaptive reductions in matrix deposition and packing density with increases in spheroid diameter, enabling spheroids to avoid the formation of a hypoxic core. Overall, these data provide evidence that the enhanced function of MSC spheroids is not oxygen mediated.

Meiosis produces haploid gametes through a succession of chromosomal events, including pairing, synapsis, and recombination. Mechanisms that orchestrate these events remain poorly understood. We found that the SUMO (small ubiquitin-like modifier)-modification and ubiquitin-proteasome systems regulate the major events of meiotic prophase in mouse. Interdependent localization of SUMO, ubiquitin, and proteasomes along chromosome axes was mediated largely by RNF212 and HEI10, two E3 ligases that are also essential for crossover recombination. RNF212-dependent SUMO conjugation effected a checkpointlike process that stalls recombination by rendering the turnover of a subset of recombination factors dependent on HEI10-mediated ubiquitylation. We propose that SUMO conjugation establishes a precondition for designating crossover sites via selective protein stabilization. Thus, meiotic chromosome axes are hubs for regulated proteolysis via SUMO-dependent control of the ubiquitin-proteasome system.