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Abstract The absence or presence of a lunar paleomagnetosphere is important because it bears directly on the volatile content of the regolith and exploration targets for Artemis and other missions to the Moon. Recent paleointensity study of samples from the Apollo missions has readdressed this question. Multiple specimens from a young 2-million-year-old glass shows a strong magnetization compatible with that induced by charge-separation in an impact plasma, whereas paleointensities of single crystals yield evidence for null magnetizations spanning 3.9 to 3.2 Ga. Together, these data are consistent with an impact mechanism for the magnetization of some lunar samples, and absence of a long-lived lunar core dynamo and paleomagnetosphere recorded in other samples. Here, we present a dataset that allows researchers to examine replicates of these measurements. For the glass, we present data from specimens that fail standard paleointensity selection criteria but nevertheless imply a complex, changing magnetic field environment. For the single crystals, the replicate measurements further illustrate the initial zero magnetization state of these materials.

Abstract Quiescence, a reversible state of cell-cycle arrest, is an important state during both normal development and cancer progression. For example, in glioblastoma (GBM) quiescent glioblastoma stem cells (GSCs) play an important role in re-establishing the tumour, leading to relapse. While most studies have focused on identifying differentially expressed genes between proliferative and quiescent cells as potential drivers of this transition, recent studies have shown the importance of protein oscillations in controlling the exit from quiescence of neural stem cells. Here, we have undertaken a genome-wide bioinformatic inference approach to identify genes whose expression oscillates and which may be good candidates for controlling the transition to and from the quiescent cell state in GBM. Our analysis identified, among others, a list of important transcription regulators as potential oscillators, including the stemness gene SOX2, which we verified to oscillate in quiescent GSCs. These findings expand on the way we think about gene regulation and introduce new candidate genes as key regulators of quiescence.

Abstract The northeastern Pacific (NEP) Ocean spans the coast of British Columbia (Canada) and is impacted by anthropogenic activities including oil pipeline developments, maritime fossil fuel tanker traffic, industrial chemical effluents, agricultural and urban emissions in tandem with stormwater and wastewater discharges, and forest wildfires. Such events may expose surrounding marine environments to toxic polycyclic aromatic hydrocarbons (PAHs) and impact critical habitats of threatened killer whales (Orcinus orca). We analyzed skeletal muscle and liver samples from stranded Bigg’s killer whales and endangered Southern Resident killer whales (SRKWs) for PAH contamination using LRMS. C3-phenanthrenes/anthracenes (mean: 632 ng/g lw), C4-dibenzothiophenes (mean: 334 ng/g lw), and C4-phenanthrenes/anthracenes (mean: 248 ng/g lw) presented the highest concentrations across all tissue samples. Diagnostic ratios indicated petrogenic-sourced contamination for SRKWs and pyrogenic-sourced burdens for Bigg’s killer whales; differences between ecotypes may be attributed to habitat range, prey selection, and metabolism. A mother-fetus skeletal muscle pair provided evidence of PAH maternal transfer; low molecular weight compounds C3-fluorenes, dibenzothiophene, and naphthalene showed efficient and preferential exposure to the fetus. This indicates in-utero exposure of PAH-contamination to the fetus. Our results show that hydrocarbon-related anthropogenic activities are negatively impacting these top predators; preliminary data found here can be used to improve oil spill and other PAH pollution management and regulation efforts, and inform policy to conserve killer whale habitats in the NEP.

Abstract Biological sciences, drug discovery and medicine rely heavily on cell phenotype perturbation and microscope observation. However, most cellular phenotypic changes are subtle and thus hidden from us by natural cell variability: two cells in the same condition already look different. In this study, we show that conditional generative models can be used to transform an image of cells from any one condition to another, thus canceling cell variability. We visually and quantitatively validate that the principle of synthetic cell perturbation works on discernible cases. We then illustrate its effectiveness in displaying otherwise invisible cell phenotypes triggered by blood cells under parasite infection, or by the presence of a disease-causing pathological mutation in differentiated neurons derived from iPSCs, or by low concentration drug treatments. The proposed approach, easy to use and robust, opens the door to more accessible discovery of biological and disease biomarkers.

Optical satellite data products (e.g., Sentinel-2, PlanetScope, Landsat) require proper validation across diverse ecosystems. This has conventionally been achieved using airborne and more recently unmanned aerial vehicle (UAV) based hyperspectral sensors which constrain operations by both their cost and complexity of use. The MicaSense Altum is an accessible multispectral sensor that integrates a radiometric thermal camera with 5 bands (475 nm–840 nm). In this work we assess the spectral reflectance accuracy of a UAV-mounted MicaSense Altum at 25, 50, 75, and 100 m AGL flight altitudes using the manufacturer provided panel-based reflectance conversion technique for atmospheric correction at the Mer Bleue peatland supersite near Ottawa, Canada. Altum derived spectral reflectance was evaluated through comparison of measurements of six known nominal reflectance calibration panels to in situ spectroradiometer and hyperspectral UAV reflectance products. We found that the Altum sensor saturates in the 475 nm band viewing the 18% reflectance panel, and for all brighter panels for the 475, 560, and 668 nm bands. The Altum was assessed against pre-classified hummock-hollow-lawn microtopographic features using band level pair-wise comparisons and common vegetation indices to investigate the sensor’s viability as a validation tool of PlanetScope Dove 8 band and Sentinel-2A satellite products. We conclude that the use of the Altum needs careful consideration, and its field deployment and reflectance output does not meet the necessary cal/val requirements in the peatland site.

With diminishing returns and high clinical failure rates from traditional preclinical and animal-based drug discovery strategies, more emphasis is being placed on alternative drug discovery platforms. Ex vivo approaches represent a departure from both more traditional preclinical animal-based models and clinical-based strategies and aim to address intra-tumoural and inter-patient variability at an earlier stage of drug discovery. Additionally, these approaches could also offer precise treatment stratification for patients within a week of tumour resection in order to direct tailored therapy. One tumour group that could significantly benefit from such ex vivo approaches are high-grade gliomas, which exhibit extensive heterogeneity, cellular plasticity and therapy-resistant glioma stem cell (GSC) niches. Historic use of murine-based preclinical models for these tumours has largely failed to generate new therapies, resulting in relatively stagnant and unacceptable survival rates of around 12-15 months post-diagnosis over the last 50 years. The near universal use of DNA damaging chemoradiotherapy after surgical resection within standard-of-care (SoC) therapy regimens provides an opportunity to improve current treatments if we can identify efficient drug combinations in preclinical models that better reflect the complex inter-/intra-tumour heterogeneity, GSC plasticity and inherent DNA damage resistance mechanisms. We have therefore developed and optimised a high-throughput ex vivo drug screening platform; GliExP, which maintains GSC populations using immediately dissociated fresh surgical tissue. As a proof-of-concept for GliExP, we have optimised SoC therapy responses and screened 30+ small molecule therapeutics and preclinical compounds against tumours from 18 different patients, including multi-region spatial heterogeneity sampling from several individual tumours. Our data therefore provides a strong basis to build upon GliExP to incorporate combination-based oncology therapeutics in tandem with SoC therapies as an important preclinical alternative to murine models (reduction and replacement) to triage experimental therapeutics for clinical translation and deliver rapid identification of effective treatment strategies for individual gliomas.

Recent studies suggest an increased risk of reinfection with the SARS-CoV-2 Omicron variant compared with previous variants, potentially due to an increased ability to escape immunity specific to older variants, high antigenic divergence of Omicron from earlier virus variants as well as its altered cell entry pathway. The present study sought to investigate epidemiological evidence for differential SARS-CoV-2 reinfection intervals and incidence rates for the Delta versus Omicron variants within Wales. Reinfections in Wales up to February 2022 were defined using genotyping and whole genome sequencing. The median inter-infection intervals for Delta and Omicron were 226 and 192 days, respectively. An incidence rate ratio of 2.17 for reinfection with Omicron compared to Delta was estimated using a conditional Poisson model, which accounted for several factors including sample collection date, age group, area of residence, vaccination and travel status. These findings are consistent with an increased risk of reinfection with the Omicron variant, and highlight the value of monitoring emerging variants that have the potential for causing further waves of cases.

ImportanceThe prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults.ObservationsWe describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science.Conclusions and relevanceRECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions.Clinical trials.gov identifierClinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Abstract The trigger, pace, and nature of the intensification of Northern Hemisphere Glaciation (iNHG) are uncertain, but can be probed by study of ODP Site 1208 North Pacific marine sediments. Herein, we present magnetic proxy data that indicate a 4-fold increase of dust between ~ 2.73 and ~ 2.72 Ma, with subsequent increases at the start of glacials thereafter, indicating a strengthening of the mid-latitude westerlies. Moreover, a permanent shift in dust composition after 2.72 Ma is observed, consistent with drier conditions in the source region and/or the incorporation of material which could not have been transported via the weaker Pliocene winds. The sudden increase in our dust proxy data, a coeval rapid rise in dust recorded by proxy dust data in the North Atlantic (Site U1313), and the Site 1208 shift in dust composition, suggest that the iNHG represents a permanent crossing of a climate threshold toward global cooling and ice sheet growth, ultimately driven by lower atmospheric CO2.

Abstract Ultra-long-acting delivery platforms for HIV pre-exposure prophylaxis (PrEP) may increase adherence and maximize public health benefit. We report on an injectable, biodegradable, and removable in-situ forming implant (ISFI) that is administered subcutaneously and can release the integrase inhibitor cabotegravir (CAB) above protective benchmarks for more than 6 months. CAB ISFIs are well-tolerated in female mice and female macaques showing no signs of toxicity or chronic inflammation. In macaques, median plasma CAB concentrations exceed established PrEP protection benchmarks within 3 weeks and confer complete protection against repeated rectal SHIV challenges. Implant removal via a small incision in 2 macaques at week 12 results in a 7- to 48-fold decrease in plasma CAB levels within 72 hours. Modeling to translate CAB ISFI dosing suggests that a 3 mL injection would exceed protective benchmarks in humans for over 5 months post administration. Our results support the clinical advancement of CAB ISFIs for ultra-long-acting PrEP in humans.

The PI3K enzymes modify phospholipids to regulate cell growth and differentiation. Somatic variants in PI3K are recurrent in cancer and drive a proliferative phenotype. Somatic mosaicism of PIK3R1 and PIK3CA are associated with vascular anomalies and overgrowth syndromes. Germline PIK3R1 variants are associated with varying phenotypes, including immunodeficiency or facial dysmorphism with growth delay, lipoatrophy, and insulin resistance associated with SHORT syndrome. There has been limited study of the molecular mechanism to unify our understanding of how variants in PIK3R1 drive both undergrowth and overgrowth phenotypes. Thus, we compiled genomic variants from cancer and rare vascular anomalies and sought to interpret their effects using an unbiased physics-based simulation approach for the protein complex. We applied molecular dynamics simulations to mechanistically understand how genetic variants affect PIK3R1 and its interactions with PIK3CA. Notably, iSH2 genetic variants associated with undergrowth destabilize molecular interactions with the PIK3CA receptor binding domain in simulations, which is expected to decrease activity. On the other hand, overgrowth and cancer variants lead to loss of inhibitory interactions in simulations, which is expected to increase activity. We find that all disease variants display dysfunctions on either structural characteristics or intermolecular interaction energy. Thus, this comprehensive characterization of novel mosaic somatic variants associated with two opposing phenotypes has mechanistic importance and biomedical relevance and may aid in future therapeutic developments.

With diminishing returns and high clinical failure rates from traditional preclinical and animal-based drug discovery strategies, more emphasis is being placed on alternative drug discovery platforms. Ex vivo approaches represent a departure from both more traditional preclinical animal-based models and clinical-based strategies and aim to address intra-tumoural and inter-patient variability at an earlier stage of drug discovery. Additionally, these approaches could also offer precise treatment stratification for patients within a week of tumour resection in order to direct tailored therapy. One tumour group that could significantly benefit from such ex vivo approaches are high-grade gliomas, which exhibit extensive heterogeneity, cellular plasticity and therapy-resistant glioma stem cell (GSC) niches. Historic use of murine-based preclinical models for these tumours has largely failed to generate new therapies, resulting in relatively stagnant and unacceptable survival rates of around 12-15 months post-diagnosis over the last 50 years. The near universal use of DNA damaging chemoradiotherapy after surgical resection within standard-of-care (SoC) therapy regimens provides an opportunity to improve current treatments if we can identify efficient drug combinations in preclinical models that better reflect the complex inter-/intra-tumour heterogeneity, GSC plasticity and inherent DNA damage resistance mechanisms. We have therefore developed and optimised a high-throughput ex vivo drug screening platform; GliExP, which maintains GSC populations using immediately dissociated fresh surgical tissue. As a proof-of-concept for GliExP, we have optimised SoC therapy responses and screened 30+ small molecule therapeutics and preclinical compounds against tumours from 18 different patients, including multi-region spatial heterogeneity sampling from several individual tumours. Our data therefore provides a strong basis to build upon GliExP to incorporate combination-based oncology therapeutics in tandem with SoC therapies as an important preclinical alternative to murine models (reduction and replacement) to triage experimental therapeutics for clinical translation and deliver rapid identification of effective treatment strategies for individual gliomas.

Measurement(s) Cone length • Cone weight • Cone width • Height • Viable seed number • Viable seed weight • stem diameter • canopy width • needle length • number of buds • budburst timing • height increment • stem diameter increment • growth cessation • seed viability Technology Type(s) sliding caliper • balance • ruler • natural number • measuring tape • budburst scale Factor Type(s) field site location • tree family • tree population Sample Characteristic - Organism Pinus sylvestris Sample Characteristic - Location Scotland

Abstract There is a need for better understanding of the risk of thrombocytopenic, haemorrhagic, thromboembolic disorders following first, second and booster vaccination doses and testing positive for SARS-CoV-2. Self-controlled cases series analysis of 2.1 million linked patient records in Wales between 7th December 2020 and 31st December 2021. Outcomes were the first diagnosis of thrombocytopenic, haemorrhagic and thromboembolic events in primary or secondary care datasets, exposure was defined as 0–28 days post-vaccination or a positive reverse transcription polymerase chain reaction test for SARS-CoV-2. 36,136 individuals experienced either a thrombocytopenic, haemorrhagic or thromboembolic event during the study period. Relative to baseline, our observations show greater risk of outcomes in the periods post-first dose of BNT162b2 for haemorrhagic (IRR 1.47, 95%CI: 1.04–2.08) and idiopathic thrombocytopenic purpura (IRR 2.80, 95%CI: 1.21–6.49) events; post-second dose of ChAdOx1 for arterial thrombosis (IRR 1.14, 95%CI: 1.01–1.29); post-booster greater risk of venous thromboembolic (VTE) (IRR-Moderna 3.62, 95%CI: 0.99–13.17) (IRR-BNT162b2 1.39, 95%CI: 1.04–1.87) and arterial thrombosis (IRR-Moderna 3.14, 95%CI: 1.14–8.64) (IRR-BNT162b2 1.34, 95%CI: 1.15–1.58). Similarly, post SARS-CoV-2 infection the risk was increased for haemorrhagic (IRR 1.49, 95%CI: 1.15–1.92), VTE (IRR 5.63, 95%CI: 4.91, 6.4), arterial thrombosis (IRR 2.46, 95%CI: 2.22–2.71). We found that there was a measurable risk of thrombocytopenic, haemorrhagic, thromboembolic events after COVID-19 vaccination and infection.

New single crystal paleointensity data show that the geomagnetic field was renewed in the early Cambrian after near collapse in the Ediacaran Period. This implies that the innermost/outermost structure of the inner core formed 450 million yrs. ago.

BackgroundThe cochlear implant (CI) has proven to be a successful treatment for patients with severe-to-profound sensorineural hearing loss, however outcome variance exists. We sought to evaluate particular mutations discovered in previously established sensory and neural partition genes and compare post-operative CI outcomes.Materials and methodsUtilizing a prospective cohort study design, blood samples collected from adult patients with non-syndromic hearing loss undergoing CI were tested for 54 genes of interest with high-throughput sequencing. Patients were categorized as having a pathogenic variant in the sensory partition, pathogenic variant in the neural partition, pathogenic variant in both sensory and neural partition, or with no variant identified. Speech perception performance was assessed pre- and 12 months post-operatively. Performance measures were compared to genetic mutation and variant status utilizing a Wilcoxon rank sum test, with PResultsThirty-six cochlear implant patients underwent genetic testing and speech understanding measurements. Of the 54 genes that were interrogated, three patients (8.3%) demonstrated a pathogenic mutation in the neural partition (within TMPRSS3 genes), one patient (2.8%) demonstrated a pathogenic mutation in the sensory partition (within the POU4F3 genes). In addition, 3 patients (8.3%) had an isolated neural partition variance of unknown significance (VUS), 5 patients (13.9%) had an isolated sensory partition VUS, 1 patient (2.8%) had a variant in both neural and sensory partition, and 23 patients (63.9%) had no mutation or variant identified. There was no statistically significant difference in speech perception scores between patients with sensory or neural partition pathogenic mutations or VUS. Variable performance was found within patients with TMPRSS3 gene mutations.ConclusionThe impact of genetic mutations on post-operative outcomes in CI patients was heterogenous. Future research and dissemination of mutations and subsequent CI performance is warranted to elucidate exact mutations within target genes providing the best non-invasive prognostic capability.

In many agroecosystems, brown marmorated stink bugs (Halyomorpha halys) (Hemiptera: Pentatomidae) are polyphagous pests that cause significant economic losses to numerous crops every year. Insectivorous birds may provide a means of sustainable predation of invasive pests, such as H. halys. In forest margins surrounding peach, pecan, and interplanted peach–pecan orchards, we monitored H. halys populations with pheromone-baited traps, mist-netted birds, and collected avian fecal samples for molecular gut content analysis. We screened 257 fecal samples from 19 bird species for the presence of H. halys DNA to determine whether birds provide the biological control of this pest. Overall, we found evidence that four birds from three species consumed H. halys, including Northern cardinal (Cardinalis cardinalisis), Tufted titmouse (Baeolophus bicolor), and Carolina wren (Thryothorus ludovicianus). Halyomorpha halys captured in traps increased over time but did not vary by orchard type. Although incidence of predation was low, this may be an underestimate as a result of our current avian fecal sampling methodology. Because birds are members of the broader food web, future studies are needed to understand avian ecosystem services, especially in terms of pest control, including H. halys and other pest species.

Here, the authors present cryoEMPEM, a method for high-resolution structural analysis of vaccine-elicited polyclonal antibody responses. They apply cryoEMPEM in combination with standard serology experiments to characterize the polyclonal antibody (pAb) responses elicited in rhesus macaques by HIV Env trimer immunogens and were able to determine up to 8 different polyclonal antibody structures in complex with their respective antigen from a single cryoEM dataset.

During the past century, bivalve populations across the globe have collapsed, resulting in negative ecosystem consequences due to their outsized impact on shallow estuaries. In response, there has been strong interest in the restoration of marine bivalve populations. Here, we present a decade-long restoration effort that sought to rebuild a collapsed (99.5% reduction in harvest) and recruitment-limited population of hard clams (Mercenaria mercenaria) in Shinnecock Bay, NY, USA, using spawner sanctuaries: no-harvest zones where adults were planted at high densities (~27 m-2). Between 2012 to 2019, more than 3.2 million clams were planted in 64 discrete sanctuary plots (~1,850 m2 each) located in zones with maximal larval retention and sediment and seawater characteristics that would maximize the conditioning and spawning of adults. Hydrodynamic models, quantification of hard clam larvae, and spatial recruitment patterns demonstrated larvae spawned within sanctuaries were transported to regions where clam densities significantly increased 18-fold over seven years (2015-2021; p

Research has shown that climate change creates warmer temperatures and drier conditions, leading to longer wildfire seasons and increased wildfire risks in the United States. These factors have, in turn, led to increases in the frequency, extent, and severity of wildfires in recent years. Given the danger posed by wildland fires to people, property, wildlife, and the environment, there is an urgent need to provide tools for effective wildfire management. Early detection of wildfires is essential to minimizing potentially catastrophic destruction. To that end, in this paper, we present our work on integrating multiple data sources into SmokeyNet, a deep learning model using spatiotemporal information to detect smoke from wildland fires. We present Multimodal SmokeyNet and SmokeyNet Ensemble for multimodal wildland fire smoke detection using satellite-based fire detections, weather sensor measurements, and optical camera images. An analysis is provided to compare these multimodal approaches to the baseline SmokeyNet in terms of accuracy metrics, as well as time-to-detect, which is important for the early detection of wildfires. Our results show that incorporating weather data in SmokeyNet improves performance numerically in terms of both F1 and time-to-detect over the baseline with a single data source. With a time-to-detect of only a few minutes, SmokeyNet can be used for automated early notification of wildfires, providing a useful tool in the fight against destructive wildfires.

Abstract Ternary intermetallic compound $${\text {Pr}}_2 {\text {Co}}_{0.86} {\text {Si}}_{2.88}$$ Pr 2 Co 0.86 Si 2.88 has been synthesized in single phase and characterized by x-ray diffraction, scanning electron microscopy with energy dispersive x-ray spectroscopy (SEM-EDX) analysis, magnetization, heat capacity, neutron diffraction and muon spin rotation/relaxation ( $$\mu$$ μ SR) measurements. The polycrystalline compound was synthesized in single phase by introducing necessary vacancies in Co/Si sites. Magnetic, heat capacity, and zero-field neutron diffraction studies reveal that the system undergoes magnetic transition below $$\sim$$ ∼ 4 K. Neutron diffraction measurement further reveals that the magnetic ordering is antiferromagnetic in nature with an weak ordered moment. The high temperature magnetic phase has been attributed to glassy in nature consisting of ferromagnetic clusters of itinerant (3d) Co moments as evident by the development of internal field in zero-field $$\mu$$ μ SR below 50 K. The density-functional theory (DFT) calculations suggest that the low temperature magnetic transition is associated with antiferromagnetic coupling between Pr 4f and Co 3d spins. Pr moments show spin fluctuation along with unconventional orbital moment quenching due to crystal field. The evolution of the symmetry and the crystalline electric field environment of Pr-ions are also studied and compared theoretically between the elemental Pr and when it is coupled with other elements such as Co. The localized moment of Pr 4f and itinerant moment of Co 3d compete with each other below $$\sim$$ ∼ 20 K resulting in an unusual temperature dependence of magnetic coercivity in the system.

Summary: Non-human primates (NHP) are widely used for the pre-clinical assessment of antiretrovirals (ARVs) for HIV treatment and prevention. However, the utility of these models is questionable given the differences in ARV pharmacology between humans and macaques. Here, we report a model based on ex vivo ARV exposure and the challenge of mucosal tissue explants to define pharmacological differences between NHPs and humans. For colorectal and cervicovaginal explants in both species, high concentrations of tenofovir (TFV) and maraviroc were predictive of anti-viral efficacy. However, their combinations resulted in increased inhibitory potency in NHP when compared to human explants. In NHPs, higher TFV concentrations were measured in colorectal versus cervicovaginal explants (p = 0.042). In humans, this relationship was inverted with lower levels in colorectal tissue (p = 0.027). TFV-resistance caused greater loss of viral fitness for HIV-1 than SIV. This, tissue explants provide an important bridge to refine and appropriately interpret NHP studies.

Homeostatic synaptic plasticity requires widespread remodeling of synaptic signaling and scaffolding networks, but the role of post-translational modifications in this process has not been systematically studied. Using deep-scale quantitative analysis of the phosphoproteome in mouse neocortical neurons, we found widespread and temporally complex changes during synaptic scaling up and down. We observed 424 bidirectionally modulated phosphosites that were strongly enriched for synapse-associated proteins, including S1539 in the autism spectrum disorder-associated synaptic scaffold protein Shank3. Using a parallel proteomic analysis performed on Shank3 isolated from rat neocortical neurons by immunoaffinity, we identified two sites that were persistently hypophosphorylated during scaling up and transiently hyperphosphorylated during scaling down: one (rat S1615) that corresponded to S1539 in mouse, and a second highly conserved site, rat S1586. The phosphorylation status of these sites modified the synaptic localization of Shank3 during scaling protocols, and dephosphorylation of these sites via PP2A activity was essential for the maintenance of synaptic scaling up. Finally, phosphomimetic mutations at these sites prevented scaling up but not down, while phosphodeficient mutations prevented scaling down but not up. These mutations did not impact baseline synaptic strength, indicating that they gate, rather than drive, the induction of synaptic scaling. Thus, an activity-dependent switch between hypo- and hyperphosphorylation at S1586 and S1615 of Shank3 enables scaling up or down, respectively. Collectively, our data show that activity-dependent phosphoproteome dynamics are important for the functional reconfiguration of synaptic scaffolds and can bias synapses toward upward or downward homeostatic plasticity.

Abstract Tumor cells require nominal increases in protein synthesis in order to maintain high proliferation rates. As such, tumor cells must acquire enhanced ribosome production. How the numerous mutations in tumor cells ultimately achieve this aberrant production is largely unknown. The gene encoding ARF is the most commonly deleted gene in human cancer. ARF plays a significant role in regulating ribosomal RNA synthesis and processing, ribosome export into the cytoplasm, and global protein synthesis. Utilizing ribosome profiling, we show that ARF is a major suppressor of 5′-terminal oligopyrimidine mRNA translation. Genes with increased translational efficiency following loss of ARF include many ribosomal proteins and translation factors. Knockout of p53 largely phenocopies ARF loss, with increased protein synthesis and expression of 5′-TOP encoded proteins. The 5′-TOP regulators eIF4G1 and LARP1 are upregulated in Arf- and p53-null cells.

Background: Neurological impairments (NI) and disability are common among older children in low-and middle-income countries (LMICs). We conducted a systematic review to examine the barriers limiting access and utilization of biomedical and rehabilitative care by children and adolescents with NI in LMICs. Methods: We searched PubMed, Latin America and Caribbean Health Sciences Literature, Global Index Medicus, and Google Scholar for studies published between 01/01/1990 and 14/11/2019 to identify relevant studies. We included all studies reporting on barriers limiting access and utilization of preventive, curative, and rehabilitative care for children aged 0-19 years with NI in five domains: epilepsy, and cognitive, auditory, visual, and motor function impairment. Data from primary studies were synthesized using both qualitative and quantitative approaches. Results: Our literature searches identified 3,258 reports of which 20 were included in the final analysis. Fifteen studies (75.0%) originated from diverse settings in sub-Saharan Africa (SSA). Factors limiting access and utilization of healthcare services in >50% of the studies were: financial constraints (N=17, 85.0%), geographical and physical inaccessibility (N=14, 70.0%), inadequate healthcare resources (N=14, 70.0%), prohibitive culture and beliefs (N=12, 60.0%), and inadequate education/awareness (N=11, 55.0%). Factors reported in

BackgroundLittle is known about how people with multiple sclerosis (MS) and their families comprehend advance care planning (ACP) and its relevance in their lives.AimTo explore under what situations, with whom, how, and why do people with MS and their families engage in ACP.MethodsWe conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach.ResultsParticipants' narratives focused on three major themes: (i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals' accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate ACP-related discussions. Some shared concerns of their lack of confidence when having these discussions.ConclusionThese findings support the need for a whole system strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services.

Several factors contribute to the efficiency of protein expression. Here the authors show that the identity of amino acids encoded by codons at position 3–5 significantly impact translation efficiency and protein expression levels.

The Aleutian Arc is remote and highly active volcanically. Its 4,000 km extent from mainland Alaska to Russia’s Kamchatka peninsula hosts over 140 volcanic centers of which about 50 have erupted in historic times. We present data of volcanic gas samples and gas emission measurements obtained during an expedition to the western-most segment of the arc in September 2015 in order to extend the sparse knowledge on volatile emissions from this remote but volcanically active region. Some of the volcanoes investigated here have not been sampled for gases before this writing. Our data show that all volcanoes host high-temperature magmatic-hydrothermal systems and have gas discharges typical of volcanoes in oceanic arcs. Based on helium isotopes, the western Aleutian Arc segment has minimal volatile contributions from the overriding crust. Volcanic CO2 fluxes from this arc segment are small, compared to the emissions from volcanoes on the Alaska Peninsula and mainland Alaska. The comparatively low CO2 emissions may be related to the lower sediment flux delivered to the trench in this part of the arc.

Summary: We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.

Coastal regions are essential to achieving the Sustainable Development Goals (SDGs) given their importance for human habitation, resource provisioning, employment, and cultural practice. They are also regions where different ecological, disciplinary, and jurisdictional boundaries both overlap and are obscured. We thus propose the land-sea interface as areas where governance systems are most in need of frameworks for systems analysis to meet the SDGs—which are inherently interconnected— and integrate complex interdependencies between human livelihoods, energy, transport, food production, and nutrient flows (among others). We propose a strategic land-sea governance framework built on the sustainable transitions literature to plan for governance to achieve sustainable development across the land-sea interface. To illustrate our proposal, we compare governance planning processes across four case-based scenarios: an industrialized coastal country, a least developed coastal country, a developing coastal country with local dependencies on ocean resources, and a small island developing state primarily dependent on tourism. Through the lens of aligning governance actors and actions vertically (subnational to national), horizontally (across sectors), and programmatically (from goals to implementation), we propose scales at which governance systems may be misaligned, such as where different agencies that affect marine systems have conflicting visions and goals, leading to stalled progress or counterproductive actions. Where possible, we also highlight strategies to align across scales of high level strategic policy, tactical scale institutional mandates and cooperation, and on the ground activities and operations, such as aligning actors based on an analysis of interdependencies of goals.

Nanoparticles are a promising approach to increase immunogenicity of protein antigens for vaccines. Here, Brouwer et al. design self-assembling, two-component protein NPs that present native-like SOSIP trimers of HIV envelope protein and determine immunogenicity in a small animal model.

Multiplexed imaging of synaptic proteins can provide useful information on the heterogeneity of synaptic architecture and plasticity. Here the authors use high affinity locked nucleic acid probes and low affinity DNA imaging probes to achieve multiplexed confocal and super-resolution imaging of synaptic and cytoskeletal proteins.

Patient drug regime compliance is a major issue; sustained release implants could address this. Here, the authors report on a phase inverted in situ forming implant of PLGA for the sustained release of antiretroviral drugs and optimize and demonstrate the release of 6 different drugs over a period of up to a year.

Summary: Linked-read sequencing enables greatly improves haplotype assembly over standard paired-end analysis. The detection of mosaic single-nucleotide variants benefits from haplotype assembly when the model is informed by the mapping between constituent reads and linked reads. Samovar evaluates haplotype-discordant reads identified through linked-read sequencing, thus enabling phasing and mosaic variant detection across the entire genome. Samovar trains a random forest model to score candidate sites using a dataset that considers read quality, phasing, and linked-read characteristics. Samovar calls mosaic single-nucleotide variants (SNVs) within a single sample with accuracy comparable with what previously required trios or matched tumor/normal pairs and outperforms single-sample mosaic variant callers at minor allele frequency 5%–50% with at least 30X coverage. Samovar finds somatic variants in both tumor and normal whole-genome sequencing from 13 pediatric cancer cases that can be corroborated with high recall with whole exome sequencing. Samovar is available open-source at https://github.com/cdarby/samovar under the MIT license. : Biological Sciences; Genomics; Bioinformatics Subject Areas: Biological Sciences, Genomics, Bioinformatics

Summary: Genetic variation of the 16p11.2 deletion locus containing the KCTD13 gene and of CUL3 is linked with autism. This genetic connection suggested that substrates of a CUL3-KCTD13 ubiquitin ligase may be involved in disease pathogenesis. Comparison of Kctd13 mutant (Kctd13−/−) and wild-type neuronal ubiquitylomes identified adenylosuccinate synthetase (ADSS), an enzyme that catalyzes the first step in adenosine monophosphate (AMP) synthesis, as a KCTD13 ligase substrate. In Kctd13−/− neurons, there were increased levels of succinyl-adenosine (S-Ado), a metabolite downstream of ADSS. Notably, S-Ado levels are elevated in adenylosuccinate lyase deficiency, a metabolic disorder with autism and epilepsy phenotypes. The increased S-Ado levels in Kctd13−/− neurons were decreased by treatment with an ADSS inhibitor. Lastly, functional analysis of human KCTD13 variants suggests that KCTD13 variation may alter ubiquitination of ADSS. These data suggest that succinyl-AMP metabolites accumulate in Kctd13−/− neurons, and this observation may have implications for our understanding of 16p11.2 deletion syndrome.

Mapping polyclonal serum responses is critical to rational vaccine design. However, most high-resolution mapping approaches involve isolating and characterizing individual antibodies, which incompletely defines the polyclonal response. Here we use two complementary approaches to directly map the specificities of the neutralizing and binding antibodies of polyclonal anti-HIV-1 sera from rabbits immunized with BG505 Env SOSIP trimers. We used mutational antigenic profiling to determine how all mutations in Env affected viral neutralization and electron microscopy polyclonal epitope mapping (EMPEM) to directly visualize serum Fabs bound to Env trimers. The dominant neutralizing specificities were generally only a subset of the more diverse binding specificities. Additional differences between binding and neutralization reflected antigenicity differences between virus and soluble Env trimer. Furthermore, we refined residue-level epitope specificity directly from sera, revealing subtle differences across sera. Together, mutational antigenic profiling and EMPEM yield a holistic view of the binding and neutralizing specificity of polyclonal sera.

Effective management of aquatic resources, wild and farmed, has implications for the livelihoods of dependent communities, food security, and ecosystem health. Good management requires information on the status of harvested species, yet many gaps remain in our understanding of these species and systems, in particular the lack of taxonomic resolution of harvested species. To assess these gaps we compared the occurrence of landed species (freshwater and marine) from the United Nations Food and Agriculture Organization (FAO) global fisheries production database to those in the International Union for Conservation of Nature (IUCN) Red List and the RAM Legacy Stock Assessment Database, some of the largest and most comprehensive global datasets of consumed aquatic species. We also quantified the level of resolution and trends in taxonomic reporting for all landed taxa in the FAO database. Of the 1,695 consumed aquatic species or groups in the FAO database considered in this analysis, a large portion (35%) are missing from both of the other two global datasets, either IUCN or RAM, used to monitor, manage, and protect aquatic resources. Only a small number of all fished taxa reported in FAO data (150 out of 1,695; 9%) have both a stock assessment in RAM and a conservation assessment in IUCN. Furthermore, 40% of wild caught landings are not reported to the species level, limiting our ability to effectively account for the environmental impacts of wild harvest. Landings of invertebrates (44%) and landings in Asia (>75%) accounted for the majority of harvest without species specific information in 2018. Assessing the overlap of species which are both farmed and fished to broadly map possible interactions – which can help or hinder wild populations - we found 296 species, accounting for 12% of total wild landings globally, and 103 countries and territories that have overlap in the species caught in the wild and produced through aquaculture. In all, our work highlights that while fisheries management is improving in many areas there remain key gaps in data resolution that are critical for fisheries assessments and conservation of aquatic systems into the future.

The size and frequency of wildland fires in the western United States have dramatically increased in recent years. On high-fire-risk days, a small fire ignition can rapidly grow and become out of control. Early detection of fire ignitions from initial smoke can assist the response to such fires before they become difficult to manage. Past deep learning approaches for wildfire smoke detection have suffered from small or unreliable datasets that make it difficult to extrapolate performance to real-world scenarios. In this work, we present the Fire Ignition Library (FIgLib), a publicly available dataset of nearly 25,000 labeled wildfire smoke images as seen from fixed-view cameras deployed in Southern California. We also introduce SmokeyNet, a novel deep learning architecture using spatiotemporal information from camera imagery for real-time wildfire smoke detection. When trained on the FIgLib dataset, SmokeyNet outperforms comparable baselines and rivals human performance. We hope that the availability of the FIgLib dataset and the SmokeyNet architecture will inspire further research into deep learning methods for wildfire smoke detection, leading to automated notification systems that reduce the time to wildfire response.

Maize is the most important crop grown in South Africa, but yields can be severely reduced by extreme high summer average temperatures and low precipitation, potentially adversely affecting both domestic consumption and regional food security exports. To help understand and manage climate risks to food security in Southern Africa it is essential to quantify the present-day likelihood and magnitude of climate extremes in South Africa’s maize-growing region and explore the potential for unprecedented climate conditions which would likely result in record low maize yields. We analyse a large ensemble of initialised climate model simulations, which provides almost 100 times as many plausible present-day summers as the equivalent observational dataset. We quantify the risk of unprecedented climate extremes affecting maize production in South Africa and examine the role of the El Niño-Southern Oscillation. We find that the South African maize region is at risk of experiencing record-breaking hot, cold, dry or wet events under current climatic conditions. We find that the annual chance of unprecedented high temperatures in South Africa is approximately 4%, increasing to 62% during very strong El Niño years. We also find that the chance of exceeding the present day seasonal high temperature record has increased across the 1979–2018 period, being five times more likely now than it was in 1980. These extreme events could result in a record-breaking number of days above the optimum, or even the maximum, temperature for maize production, and lead to more severe floods or droughts. Under climate change scenarios, the magnitude and frequency of climate extremes is projected to increase meaning that the unprecedented extremes studied here could become commonplace in the future. This suggests that significant investment is needed to develop adaptations that manage the climate-related risks to food systems now and build resilience to the projected impacts of climate change.

INTRODUCTION:The demand for musculoskeletal (MSK) care is rising, and is a growing challenge for general practice. Direct access to physiotherapy and other healthcare services may offer appropriate care for MSK pain patients but there is uncertainty regarding the effectiveness or efficiency of this approach in practice. This study aimed to review the evidence regarding characteristics, outcomes, barriers and facilitators of MSK triage and direct access services. METHODS:A comprehensive search of eight databases (including MEDLINE, EMBASE, and Cochrane library) up to February 2018 was conducted to identify studies (trials, cohorts and qualitative evidence) on direct access services for MSK in primary care settings. Using predefined inclusion and exclusion criteria, titles, abstracts, and subsequent full texts were independently screened by reviewers. Methodological quality of eligible studies was assessed using the mixed methods appraisal tool, and extracted data regarding study characteristics and results were independently reviewed. A narrative synthesis and grading of evidence was undertaken. Approaches to MSK triage and direct access were profiled along with their respective outcomes of care relating to patient-oriented and socioeconomic outcomes. Barriers and facilitators of each model of direct access services were also highlighted. RESULTS:9010 unique citations were screened, of which 26 studies were eligible. Three approaches (open access, combination and service pathway models) to MSK triage and direct access shared similar goals but were heterogeneous in application. MSK patients using direct access showed largely similar characteristics (age, sex and duration of symptoms) compared to GP-led care, although they were often younger, slightly more educated and with better socio-economic status than patients seen through GP-led care. Although many studies showed limitations in design or methods, outcomes of care (patient oriented outcomes of pain, and disability) did not show large differences between direct access and GP-led care. In most studies direct access patients were reported to have lower healthcare utilisation (fewer physiotherapy or GP consultations, analgesics or muscle relaxants prescriptions, or imaging procedures) and less time off work compared to GP-led care. DISCUSSION:This study provides insight into the current state of evidence regarding MSK triage and direct access services and highlights potential implications for future research, healthcare services planning, resource utilisation and organising care for MSK patients in primary care. There is consistent, although limited, evidence to suggest that MSK triage and direct access services lead to comparable clinical outcomes with lower healthcare consumption, and can help to manage GP workload. However, due to the paucity of strong empirical data from methodologically robust studies, a scale up and widespread roll out of direct access services cannot as yet be assumed to result in long term health and socio-economic gains. PROSPERO-ID: CRD42018085978.

BackgroundAdvance care planning (ACP) is reported to improve the quality of outcomes of care among those with life-limiting conditions. However, uptake is low among people living with multiple sclerosis (MS) and little is known about why or how people with MS engage in this process of decision-making.AimsTo develop and refine an initial theory on engagement in ACP for people with MS and to identify ways to improve its uptake for those who desire it.MethodsRealist review following published protocol and reporting following Realist and Meta-narrative Evidence Synthesis: Evolving Standards (RAMESES) guidelines. A multi-disciplinary team searched MEDLINE, PsychInfo, CINAHL, Scopus, Web of Science, Embase, Google Scholar in addition to other sources from inception to August 2019. Quantitative or qualitative studies, case reports, and opinion or discussion articles related to ACP and/or end of life discussions in the context of MS were included, as well as one article on physical disability and one on motor neuron disease, that contributed important contextual information. Researchers independently screened abstracts and extracted data from full-text articles. Using abductive and retroductive analysis, each article was examined for evidence to support or refute 'context, mechanism, and outcome' (CMO) hypotheses, using the Integrated Behaviour Model to guide theory development. Quality was assessed according to methodological rigour and relevance of evidence. Those studies providing rich descriptions were synthesised using a realist matrix to identify commonalities across CMO configurations.ResultsOf the 4,034 articles identified, 33 articles were included in the synthesis that supported six CMO hypotheses that identified contexts and mechanisms underpinning engagement in ACP for people with MS and included: acceptance of their situation, prior experiences, confidence, empowerment, fear (of being a burden, of death and of dying) and the desire for autonomy. Acceptance of self as a person with a life-limiting illness was imperative as it enabled people with MS to see ACP as pertinent to them. We identified the context of MS-its long, uncertain disease trajectory with periods of stability punctuated by crisis-inhibited triggering of mechanisms. Similarly, the absence of skills and confidence in advanced communication skills among health professionals prevented possibilities for ACP discussions taking place.ConclusionAlthough mechanisms are inhibited by the context of MS, health professionals can facilitate greater uptake of ACP among those people with MS who want it by developing their skills in communication, building trusting relationships, sharing accurate prognostic information and sensitively discussing death and dying.

Understanding health and mortality in killer whales (Orcinus orca) is crucial for management and conservation actions. We reviewed pathology reports from 53 animals that stranded in the eastern Pacific Ocean and Hawaii between 2004 and 2013 and used data from 35 animals that stranded from 2001 to 2017 to assess association with morphometrics, blubber thickness, body condition and cause of death. Of the 53 cases, cause of death was determined for 22 (42%) and nine additional animals demonstrated findings of significant importance for population health. Causes of calf mortalities included infectious disease, nutritional, and congenital malformations. Mortalities in sub-adults were due to trauma, malnutrition, and infectious disease and in adults due to bacterial infections, emaciation and blunt force trauma. Death related to human interaction was found in every age class. Important incidental findings included concurrent sarcocystosis and toxoplasmosis, uterine leiomyoma, vertebral periosteal proliferations, cookiecutter shark (Isistius sp.) bite wounds, excessive tooth wear and an ingested fish hook. Blubber thickness increased significantly with body length (all p < 0.001). In contrast, there was no relationship between body length and an index of body condition (BCI). BCI was higher in animals that died from trauma. This study establishes a baseline for understanding health, nutritional status and causes of mortality in stranded killer whales. Given the evidence of direct human interactions on all age classes, in order to be most successful recovery efforts should address the threat of human interactions, especially for small endangered groups of killer whales that occur in close proximity to large human populations, interact with recreational and commercial fishers and transit established shipping lanes.

A large number of RNA binding proteins (RBPs) and miRNAs bind to the 3′ untranslated regions of mRNA, but methods to dissect their function and interactions are lacking. Here the authors introduce post-transcriptional regulatory element sequencing (PTRE-seq) to dissect sequence preferences, interactions and consequences of RBP and miRNA binding.

Eliciting broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal, but available immunogens expose epitopes for development of non-nAbs. Here, the authors use computational and structure-guided design to develop improved native-like envelope trimers and analyze Ab response in animal models.

Stink bugs (Hemiptera: Pentatomidae) are polyphagous pests that cause significant economic losses to a variety of crops. Although many species have been documented to aggregate within agricultural fields, much less is known regarding the timing and distribution of adults and nymphs within and between surrounding non-crop habitat. Therefore, we explored the spatiotemporal distribution of Euschistus servus (Say), Euschistus tristigmus (Say), and Chinavia hilaris (Say), three species of North American origin, and examined whether distribution patterns varied between species according to habitat. Stink bugs were monitored weekly for three years within an 18 km2 grid of pheromone-baited traps. We tested whether habitat affected distribution patterns, used spatial analysis by distance indices (SADIE) to identify aggregations, and visualized distributions with interpolated maps. Overall, E. servus adults were captured in crops, whereas E. tristigmus adults and nymphs were mainly captured in forests. Accordingly, distribution patterns of E. tristigmus were relatively stable over time, whereas aggregations of adult E. servus varied over space, and the timing of aggregations reflected the phenology of major crops. Chinavia hilaris was most often captured in forest, followed by crop habitat. Pest management strategies for stink bugs may require an area-based management approach that accounts for movement in agricultural fields and surrounding habitat.

Abstract Ecological thresholds, which represent points of rapid change in ecological properties, are of major scientific and societal concern. However, very little research has focused on empirically testing the occurrence of thresholds in temperate terrestrial ecosystems. To address this knowledge gap, we tested whether a number of biodiversity, ecosystem functions and ecosystem condition metrics exhibited thresholds in response to a gradient of forest dieback, measured as changes in basal area of living trees relative to areas that lacked recent dieback. The gradient of dieback was sampled using 12 replicate study areas in a temperate forest ecosystem. Our results provide novel evidence of several thresholds in biodiversity (namely species richness of ectomycorrhizal fungi, epiphytic lichen and ground flora); for ecological condition (e.g. sward height, palatable seedling abundance) and a single threshold for ecosystem function (i.e. soil respiration rate). Mechanisms for these thresholds are explored. As climate-induced forest dieback is increasing worldwide, both in scale and speed, these results imply that threshold responses may become increasingly widespread.