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Understanding the distribution and characterization of natural and non-natural materials on the surface and near-subsurface is important for the development of infrastructure projects. This may be a challenge in highly urbanized areas, where outcrops are scarce, and anthropogenic activities have altered the morphological expression of the landscape. This study tests the integration of ground-penetrating radar (GPR), borehole drilling, aerial imagery, geological mapping, and aerial laser scanning as complementary mapping tools for determining the stratigraphy of glacial and post-glacial Quaternary sediments, the depth to the bedrock, and the distribution of anthropogenic material in Mosvatnet, a lake in Stavanger, Norway. The integration proved to be efficient and enabled the generation of a 3D holistic model, which provided a broad understanding of the subsurface geology and the induced anthropogenic changes in the area through time. Bedrock, till, fluvioglacial, and lacustrine geological units were modeled. Accumulations of post-glacial organic matter were mapped, and the distribution of non-natural infill material was determined. The interpreted dataset suggests that the eastern shoreline of Mosvatnet has artificially prograded about one hundred meters westward since the 1930s and the elevation of the corresponding area has increased by about ten meters relative to the lake level.

BackgroundInternational guidelines for the treatment of patients with pulmonary arterial hypertension (PAH) recommend the use of risk stratification to optimise therapy to achieve and maintain a low-risk profile. However, recommended methods require hospital-based investigations. We sought to develop a method for daily, remote risk evaluation.MethodsConsecutive patients (n=5820) with pulmonary hypertension (PH) were identified from the ASPIRE registry and stepwise Cox regression applied to identify parameters associated with survival. A physiological risk score was applied to all patients and survival assessed by the Kaplan-Meier method. Physical activity was measured in patients with PAH implanted with insertable cardiac monitors (ICM, n=80) to provide a remote measure of exercise capacity. In patients with PAH and implanted pulmonary artery pressure (PAP) monitor and ICM (n=28) we undertook a time-stratified bidirectional case–crossover study to determine the physiology of therapeutic escalation (TE) and clinical worsening and a remote physiological risk score applied to the data.ResultsAge, male sex, PH aetiology, WHO functional class (FC), incremental shuttle walk-distance (ISWD), heart rate reserve (HRR) and total pulmonary resistance (TPR) as independent predictors of survival. Mortality increased with each decile of baseline physiological risk (pConclusionRemote risk evaluation may facilitate personalised medicine and proactive management. The physiological risk score accurately stratifies patients with PH and may be applied to remote monitoring data for early evaluation of clinical efficacy and detection of clinical worsening.

This study was funded by an investigator-initiated research grant from Insmed (Bridgewater, NJ, USA). The authors acknowledge the funding and logistical support from the UK National Institute for Health and Care Research. Background: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. Methods: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. Findings: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. Interpretation: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19. Publisher PDF

Background Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear. Research Question Do patients hospitalized with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using 1H and 129Xe MRI between 6 and 52 weeks following hospitalization? Study Design and Methods Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022. The imaging protocol was as follows: 1H ultra-short echo time, contrast-enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion-weighted, and 129Xe spectroscopic imaging of gas exchange. Results Nine patients were recruited (age 57 ± 14 [median ± interquartile range] years; six of nine patients were male). Patients underwent MRI at 6 (n = 9), 12 (n = 9), 25 (n = 6), and 51 (n = 8) weeks following hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients exhibited impaired 129Xe gas transfer (RBC to membrane fraction), but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6- to 25-week period. At 12 weeks, all patients with lung perfusion data (n = 6) showed an increase in both pulmonary blood volume and flow compared with 6 weeks, although this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared with 6-week examinations; however, 129Xe gas transfer remained abnormally low at weeks 12, 25, and 51. Interpretation 129Xe gas transfer was impaired up to 1 year following hospitalization in patients who were hospitalized with COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation was normal at 52 weeks.

A requirement for PKCε in exiting from the Aurora B dependent abscission checkpoint is associated with events at the midbody, however, the recruitment, retention and action of PKCε in this compartment are poorly understood. Here, the prerequisite for 14-3-3 complex assembly in this pathway is directly linked to the phosphorylation of Aurora B S227 at the midbody. However, while essential for PKCε control of Aurora B, 14-3-3 association is shown to be unnecessary for the activity-dependent enrichment of PKCε at the midbody. This localisation is demonstrated to be an autonomous property of the inactive PKCε D532N mutant, consistent with activity-dependent dissociation. The C1A and C1B domains are necessary for this localisation, while the C2 domain and inter-C1 domain (IC1D) are necessary for retention at the midbody. Furthermore, it is shown that while the IC1D mutant retains 14-3-3 complex proficiency, it does not support Aurora B phosphorylation, nor rescues division failure observed with knockdown of endogenous PKCε. It is concluded that the concerted action of multiple independent events facilitates PKCε phosphorylation of Aurora B at the midbody to control exit from the abscission checkpoint.

IntroductionMicrovascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pathophysiological pulmonary changes during the post-acute period in these patients remains unclear.MethodsPatients who were hospitalised due to COVID-19 pneumonia underwent a pulmonary1H and129Xe MRI protocol at 6, 12, 25 and 51 weeks after hospital admission. The imaging protocol included: ultra-short echo time, dynamic contrast enhanced lung perfusion,129Xe lung ventilation,129Xe diffusion weighted and129Xe 3D spectroscopic imaging of gas exchange.Results9 patients were recruited and underwent MRI at 6 (n=9), 12 (n=9), 25 (n=6) and 51 (n=8) weeks after hospital admission. Patients with signs of interstitial lung damage at 3 months were excluded from this study. At 6 weeks after hospital admission, patients demonstrated impaired129Xe gas transfer (RBC:M) but normal lung microstructure (ADC, LmD). Minor ventilation abnormalities present in four patients were largely resolved in the 6–25 week period. At 12 week follow up, all patients with lung perfusion data available (n=6) showed an increase in both pulmonary blood volume and flow when compared to 6 weeks, though this was not statistically significant. At 12 week follow up, significant improvements in129Xe gas transfer were observed compared to 6-week examinations, however129Xe gas transfer remained abnormally low at weeks 12, 25 and 51. Changes in129Xe gas transfer correlated significantly with changes in pulmonary blood volume and TLCOZ-score.ConclusionsThis study demonstrates that multinuclear MRI is sensitive to functional pulmonary changes in the follow up of patients who were hospitalised with COVID-19. Impairment of xenon transfer may indicate damage to the pulmonary microcirculation.

The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious. This Review discusses protein kinase C (PKC) isoforms in cancer, in particular focusing on their functional properties in the context of tumour suppression or promotion, target validation, PKC pharmacology and therapeutic exploitation.

The Parkinson's disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafishgch1mutant (gch1–/–), using CRISPR/Cas technology.gch1–/–zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 d postfertilization (dpf), movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase (Th) protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-DOPA treatment ofgch1–/–larvae improved survival without ameliorating the motor phenotype. RNAseq ofgch1–/–larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphologic and functional evidence of microglial activation ingch1–/–. The results of our study suggest that GCH1 deficiency may unmask early, subclinical parkinsonism and only indirectly contribute to neuronal cell death via immune-mediated mechanisms. Our work highlights the importance of functional validation for genome-wide association studies (GWAS) risk factors and further emphasizes the important role of inflammation in the pathogenesis of PD.SIGNIFICANCE STATEMENTGenome-wide association studies have now identified at least 90 genetic risk factors for sporadic Parkinson's disease (PD). Zebrafish are an ideal tool to determine the mechanistic role of genome-wide association studies (GWAS) risk genes in a vertebrate animal model. The discovery of GTP cyclohydrolase 1 (GCH1) as a genetic risk factor for PD was counterintuitive, GCH1 is the rate-limiting enzyme in the synthesis of dopamine (DA), mutations had previously been described in the non-neurodegenerative movement disorder dopa-responsive dystonia (DRD). Rather than causing DAergic cell death (as previously hypothesized by others), we now demonstrate that GCH1 impairs tyrosine hydroxylase (Th) homeostasis and activates innate immune mechanisms in the brain and provide evidence of microglial activation and phagocytic activity.

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the UK to accelerate population coverage with a single dose. At this time, trial data was lacking, and we addressed this in a study of UK healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a sub-study of 589 individuals, we show that this single dose induces SARS-CoV-2 neutralizing antibody (NAb) responses and a sustained B and T cell response to spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared to the conventional 3-4 week regimen, accompanied by enrichment of CD4+ T cells expressing IL2. Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective, immunogenic protocol., After giving a primary dose, delaying administration of a second dose of BNT162b2 COVID-19 vaccine up to 6-14 weeks continues to provide strong protection and contributes to favorable antibody, B cell, and T cell responses.

The majority of people with depression in the United States either never seek treatment or gravitate exclusively to antidepressant medication (ADM), despite the existence of other effective treatments, such as cognitive-behavioral therapy (CBT). Reluctance to use psychotherapy is partly due to lack of appropriate mental health literacy and perceptions of low treatment acceptability (appropriateness for a given problem) and credibility (treatment logicalness, and whether the patient expects improvement). In the current investigation, we examined whether providing psychoeducation about CBT for depression would change participant perceptions of the treatment's acceptability and credibility. We recruited 554 (female n = 314; 57%) participants across two online studies, and assessed their baseline perceptions of CBT and ADM using modified Treatment Acceptability (TAAS) and Treatment Credibility and Expectancy (CEQ) scales. Participants were subsequently presented with evidence-based, expert-vetted psychoeducational materials describing CBT and ADM, and were asked to recomplete the TAAS and CEQ. In Study 1, participants endorsed significantly higher CBT-CEQ (credibility/expectancy) scores postpsychoeducation. In Study 2, participants endorsed significantly lower CBT-TAAS (acceptability), and among those with no exposure to depression treatments, endorsed significantly higher CBT-CEQ scores postpsychoeducation. In both studies, there were no perceptual changes of ADM after the psychoeducation. Finally, in Study 2, endorsement of a biological model of depression and depressive symptoms were negatively predictive of CBT's acceptability and credibility and expectancy postpsychoeducation. Perceptions of credibility and expectancy of CBT for depression appear malleable even after exposure to brief psychoeducation, whereas shifting perceptions of CBT's acceptability may require more extensive intervention.

Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early microglial activation in a zebrafish model of Gaucher's disease (gba1-/-). miR-155 is a master regulator of inflammation and has been implicated in a wide range of different neurodegenerative disorders. The observed miR-155 upregulation preceded the subsequent development of widespread pathology with marked neuroinflammation, closely resembling human Gaucher's disease pathology. We now report similar increases of miR-155 expression in mammalian models of GD, confirming that miR-155 upregulation is a shared feature in glucocerebrosidase (GCase) deficiency across different species. Using CRISPR/Cas9 mutagenesis we then generated a miR-155 mutant zebrafish line (miR-155-/-) with completely abolished miR-155 expression. Unexpectedly, loss of miR-155 did not mitigate either the reduced lifespan or the robust inflammatory phenotypes of gba1-/- mutant zebrafish. Our data demonstrate that neither neuroinflammation nor disease progression in GCase deficiency are dependent on miR-155 and suggest that miR-155 inhibition would not be a promising therapeutic target in Gaucher's disease.

Background We previously reported up-regulation of tigarb (the zebrafish orthologue of human TIGAR, T P53 – I nduced G lycolysis and A poptosis R egulator) in a zebrafish pink1−/− model of Parkinson’s disease (PD). Genetic inactivation of tigarb led to the rescue of dopaminergic neurons and mitochondrial function in pink−/− zebrafish. The aim of this study was to determine the relevance of TIGAR for human PD, investigate its disease specificity and identify relevant upstream and downstream mechanisms. Materials and methods TIGAR Immunohistochemistry, using a range of antibodies, was undertaken for detailed assessment of TIGAR in formalin-fixed, paraffin-embedded tissue from post mortem brains of PD patients and other neurodegenerative disorders (n = 10 controls, 10 PD cases, 10 dementia with Lewy bodies, 5 motor neurone disease (MND), 3 multiple system atrophy (MSA)) and complemented by immunohistochemistry for p53, hexokinase I (HK-I) and hexokinase II (HK-II; n = 4 control, 4 PD, and 4 dementia with Lewy bodies). Results TIGAR was detected in Lewy bodies and Lewy neurites in the substantia nigra of sporadic PD and Dementia with Lewy bodies (DLB) patients. Staining of adjacent sections and double staining confirmed the presence of TIGAR alongside alpha-synuclein in these LB and neurites. In contrast, TIGAR-positive aggregates were not seen in cortical Lewy bodies. TIGAR protein was also absent in both TDP-43-positive inclusions in MND and glial cytoplasmic inclusions in MSA. Subsequent investigation of the TIGAR-upstream regulator p53 and the downstream targets HK-I and HK-II in PD brains suggested a possible mild increase in HK-I. Conclusions TIGAR protein, is present in SN Lewy bodies of both sporadic PD and DLB. The absence of TIGAR protein in the pathological inclusions of MND or MSA suggests disease specificity and further raises the possibility that TIGAR may be involved in PD pathogenesis.

On March 26, 2019, in keeping with President Trump's Space Policy Directive-1, Vice President Pence charged NASA with landing the first woman and the next man on the South Pole of the Moon by 2024, followed by a sustained presence on and around the Moon by 2028. NASA's Human Landing System (HLS) Program is responsible for the final mode of transportation in deep space that will carry humans to and from the surface of the Moon, to be designed and developed by American companies for NASA's Artemis lunar exploration program. This paper examines the approach for Artemis human landing systems for both the initial missions and future sustained missions. While achieving the 2024 goal requires a focus on speed and the use of mature technologies, planning toward sustained operations to and from the lunar surface requires a focus on reliability and reusability. The two approaches, however, are not mutually exclusive, as demonstrated by the HLS prime contractors' integrated lander system proposals. On April 30, 2020, NASA announced that Blue Origin of Kent, Washington, Dynetics (a Leidos company) of Huntsville, Alabama, and SpaceX of Hawthorne, California, were the awardees for NASA's Human Landing System contracts under Appendix H of the NextSTEP-2 Broad Agency Announcement. The companies began work in a 10-month base period during which NASA teams worked with the companies to streamline the review of required products and to share the agency's expertise in human spaceflight systems development. Following the base period, NASA will determine which companies will develop the human landers for the initial missions, including the 2024 landing, and which companies will develop landers for future sustained missions toward the end of the decade.

Induced pluripotent stem cell- (iPSC) derived neural cultures from amyotrophic lateral sclerosis (ALS) patients can model disease phenotypes. However, heterogeneity arising from genetic and experimental variability limits their utility, impacting reproducibility and the ability to track cellular origins of pathogenesis. Here, we present methodologies using single-cell RNA-sequencing (scRNA-seq) analysis to address these limitations. By repeatedly differentiating and applying scRNA-seq to motor neurons (MNs) from healthy, familial ALS, sporadic ALS, and genome-edited iPSC lines across multiple patients, batches, and platforms, we account for genetic and experimental variability towards identifying unified and reproducible ALS signatures. Combining HOX and developmental gene expression with global clustering, we anatomically classified cells into rostrocaudal, progenitor, and postmitotic identities. By relaxing statistical thresholds, we discovered genes in iPSC-MNs that were concordantly dysregulated in postmortem MNs and yielded predictive ALS markers in other human and mouse models. Our approach thus revealed early, convergent, and MN-resolved signatures of ALS.

The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious.

BackgroundThe additive mechanistic effect of genetic risk variants for Parkinson’s disease (PD) is a plausible but largely unproven hypothesis. We investigated the mechanistic interaction between the two lysosomal PD risk genes glucocerebrosidase 1 (GBA1) and sphingomyelinase 1 (SMPD1) in complementing model systems.MethodsUsing CRISPR/Cas gene editing, smpd1 mutant (smpd1-/-) zebrafish were generated and crossed to our previously characterised gba1-/- zebrafish line, generating double knockouts (gba1-/-;smpd1-/-). Spontaneous motor behaviour and survival were assessed in WT, single mutants and double mutants. HPLC-based sphingolipid quantification was combined with RNAseq based pathway analysis, assessment of the mitochondrial respiratory chain and quantification of lipid membrane oxidation for in-depth assessment of cellular health across all four genotypes. We also determined the effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) inactivation on autophagy and alpha-synuclein homeostasis in the human neuronal cell line SH-SY5Y.ResultsUnexpectedly, ASM deficiency rescued the marked behavioural phenotype and prolonged survival in gba1-/-;smpd1-/- double-mutant zebrafish compared to gba1-/-. RNAseq-based pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. We identified complete reciprocal rescue of mitochondrial respiratory chain function and abolished lipid membrane oxidation in gba1-/-;smpd1-/- compared to gba1-/- or smpd1-/- as the underlying rescue mechanism. The complementing in vitro experiments demonstrated an unexpected reduction of α-synuclein levels in human cell lines with combined GCase and ASM deficiency.ConclusionsOur study highlights the importance of functional validation for any putative mechanistic interactions between genetic risk factors and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect.

Coronavirus disease 2019 can cause significant mortality in the elderly in long-term care facilities (LTCF). We describe 4 LTCF outbreaks where mass testing identified a high proportion of asymptomatic infections (4%–41% in healthcare workers and 20%–75% in residents), indicating that symptom-based screening alone is insufficient for monitoring for COVID-19 transmission.

OBJECTIVES This research examined whether people's causal explanations of depression were associated with acceptability and efficacy-related treatment perceptions and likelihood to choose cognitive behavioural therapy (CBT) and antidepressant medication (ADM) as depression treatments. DESIGN A cross-sectional internet-based design was used. METHODS A general population sample was used over a clinical sample to study those who had not yet chosen to enter treatment. A total of 422 individuals were recruited through a crowdsourcing platform to complete an online survey. Measures included perceived causes of depression, perceived acceptability, efficacy and choice likelihood for ADM and CBT, and demographics. RESULTS Those with biological causal explanations of depression were more favourable towards ADM on all three perceptual measures of acceptability, efficacy and likelihood to choose ADM as a treatment for depression. Personality/character-related causal explanations of depression were positively related to perceived efficacy and likelihood to choose CBT as a depression treatment. Those endorsing environmental stress causes of depression were more likely to choose CBT as a treatment for depression. CONCLUSIONS Results indicated that people's beliefs about the causes of depression were related to their perceptions of and likelihoods to choose ADM and CBT as depression treatments. PRACTITIONER POINTS Provides evidence of how different causal explanations of depression influence sufferers' likelihoods to choose ADM and CBT as possible treatments for their depression. Provides support for exploring potential patients' causal explanations about depression prior to recommending a treatment regimen.

In this study, Spatial Multi-Criteria Evaluation and the least cost path analysis were applied to find the optimal by-pass road alignment in the Tlokweng Planning Area in Botswana. One-At-a-Time sensitivity analysis and the statistical test for zero proportion were used to investigate the robustness of the entire model. Four alternative by-pass roads were produced stressing economic, environmental, and social suitability as well as trade-offs between the groups. The results showed that the social alternative performs best. Sensitivity analysis and statistical test for zero proportion revealed four criteria as sensitive.

SummaryInduced pluripotent stem cell (iPSC) derived neural cultures from amyotrophic lateral sclerosis (ALS) patients can reflect disease phenotypes targetable by treatments. However, widely used differentiation protocols produce mixtures of progenitors, neurons, glia, and other cells at various developmental stages and rostrocaudal neural tube segments. Here we present a methodology using single-cell RNA sequencing analysis to distinguish cell type expression in C9orf72 ALS, sporadic ALS, control, and genome-edited cultures across multiple subjects, experiments, and commercial platforms. Combinations of HOX and developmental gene expression with global clustering classified rostrocaudal, progenitor, and mantle zone fates. This demonstrated that iPSC-differentiated cells recapitulate fetal hindbrain and spinal cord development and resolved early, reproducible, and motor neuron-specific signatures of familial and sporadic ALS. This includes downregulated ELAVL3 expression, which persists into disease endstages. Single-cell analysis thus yielded predictive ALS markers in other human and mouse models which were otherwise undiscovered through bulk omics assays.

Ecosystem service valuation may be a relevant method for assisting policy makers in environmental related decisions. However, a number of problematic aspects of the calculations, including consistency of economy (e.g., purchasing price, production price, perceived value) and determining which ecosystem subservices to include (e.g. include disservices or only beneficial services), contribute to uncertainty in the final valuations. However, ecosystem service valuations currently lack 1) a quantification of total uncertainty in ecosystem service values as a result of the uncertainties in the subservices, and 2) an analysis of the relative sensitivity of total ecosystem service values to uncertainties in various subservices. In a previous study, we have computed a spatial distribution of global ecosystem services by disaggregating production values over the spatial existence of each subservice by country. Nineteen subservices arranged under nine services from four categories were calculated totalling approximately 1.3 trillion international dollars for 2005. Our current study aims to perform an error propagation analysis and a sensitivity analysis of the Food Service. The Food Service, which is comprised of nine subservices, accounts for 99.8% of the total global ecosystem service value. It is extremely important to understand the reliability of the valuation of this service because it greatly contributes and overshadows the other services.Hereto, the cattle and sheep indicators in the Livestock Subservice and the apple orchard indicator in the Fruit Subservice are analyzed. The Livestock Subservice accounts for the majority of the Food Service and is comprised of cattle, sheep, buffalo, poultry, pig, and goat. The cattle and sheep indicators have three main sources of uncertainty: the animal weight, the production value, and the number of animals per hectare for meat versus the number of animals for dairy use. The uncertainty in animal weight varies considerably by species and is important because the production value is the international dollar per live-weight ton. The production values are published with designations as either a direct calculation or an estimated figure. In the case of animal population data, RMSE were provided as part of the data release.The Fruit Subservice is the fourth largest contributor to the total Food Subservice value. It was chosen because the input data sets are different than the top three contributors to the Food Subservice (i.e. Livestock, Dairy, and Crops). The apple orchard indicator has two main sources of uncertainty: the production value and the production area. The uncertainty in the production values are qualified as unofficial figures by the data producer, while the production area followed agricultural land use, rather than mapped apple orchards.Both an error propagation analysis of the defined uncertainties and a sensitivity analysis provide insight into the robustness into the computed ecosystem service assessment. Presenting and understanding uncertainty and sensitivity of ecosystem service assessments is consequential for incorporating ecosystem service assessments into climate change mitigation strategies.

In response to the 2018 White House Space Policy Directive-1, to lead an innovative and sustainable lunar exploration, and to the Vice President's March 2019 direction to do so by 2024, NASA is working to establish humanity's presence on and around the Moon by: 1) sending payloads to its surface, 2) assembling the Gateway outpost in orbit and 3) demonstrating the first human lunar landings since 1972. NASA's Artemis program is implementing a multi-faceted and coordinated agency-wide approach with a focus on the lunar South Pole. The Artemis missions will demonstrate new technologies, capabilities and business approaches needed for future exploration, including Mars. Assessing options to accelerate development of required systems, NASA is utilizing public-private engagements through the Human Exploration and Operations (HEO) Mission Directorate's NextSTEP Broad Agency Announcements. The design, development and demonstration of the Human Landing System (HLS) is expected to be led by commercial partners. Utilizing efforts across mission directorates, the Artemis effort will benefit from programs from the Science Mission Directorate (SMD) and Space Technology Mission Directorate (STMD). SMD's Commercial Lunar Payload Services (CLPS) initiative will procure commercial robotic lunar delivery services and the development of science instruments and technology demonstration payloads. The Space Technology Mission Directorate (STMD) portfolio of technology advancements relative to HLS include lunar lander components and technologies for pointing, navigation and tracking, fuel storage and transfer, autonomy and mobility, communications, propulsion and power. In addition to describing the objectives and requirements of the 2024 Artemis mission, this paper will present NASA's approach to accessing the lunar surface with an affordable human-rated landing system, current status and the role of U.S. industry in 2024 and for a sustainable lunar presence.

The additive effect of genetic risk variants on overall disease risk is a plausible but frequently unproven hypothesis. To test this hypothesis, we assessed the biological effect of combined glucocerebrosidase (GCase) and acid sphingomyelinase (ASM) deficiency. Variants in both glucocerebrosidase1 (GBA1) and sphingomyelinase (SMPD1) are genetic risk factors for Parkinson’s disease. Unexpectedly, ASM deficiency resulted in normalized behaviour and prolonged survival in gba1−/−;smpd1−/− double-mutant zebrafish compared to gba1−/−. RNAseq-based pathway analysis confirmed a profound rescue of neuronal function and intracellular homeostasis. We identified complete reciprocal rescue of mitochondrial respiratory chain function and abolished lipid membrane oxidation in gba1−/−;smpd1−/− compared to gba1−/− or smpd1−/− as the underlying rescue mechanism. Complementing in vitro experiments demonstrated an unexpected reduction of α-synuclein levels in human cell lines with combined GCase and ASM deficiency. Our study highlights the importance of functional validation for any putative interactions between genetic risk factors and their overall effect on disease-relevant mechanisms rather than readily assuming an additive effect.SummaryThe additive effect of genetic risk variants on disease risk is a popular but typically unproven hypothesis. We investigated this hypothesis mechanistically for Parkinson’s disease risk factors and provide evidence of an unexpected rescue effect on neuronal function and survival.

The rate of obesity has been growing around the world and, along with it, the obesity stigma. Obesity bias is based on perceptions that the condition is in a person’s control and is a character flaw for which one is responsible. These negative perceptions drive weight discrimination in the workplace that exists at every level from CEOs to HR professionals to coworkers and covers hiring, assignment, and advancement decisions. The workplace weight bias creates damaging impacts for obese and overweight persons, organizations, and society. This chapter examines the role of the obesity stigma in the workplace, its pervasiveness, false assumptions that drive it, and the possible ways of reducing it.

Duration of bed rest among critically ill patients in ICU has been associated with development of persistent weakness that can last for more than five years. Commencing early exercise interventions in ICU is likely to reduce critically ill patients’ physical dysfunction. However, critically ill patients often experience prolonged periods of bed rest and inactivity.\ud \ud This study examined the timing of commencement of exercise interventions, including sitting out of bed and upright mobilisation, following physiological stability in critically ill patients and describes key clinical outcomes.\ud \ud Participants included consecutive patients admitted for >48 hours to a 25-bed Australian mixed medical and surgical adult ICU between July 2009 and June 2014. Time taken for patients to achieve neurological, cardiorespiratory and cardiovascular (physiological) stability was calculated and timing of initial sitting out of bed and upright mobilisation was recorded.\ud \ud A small number of patients (n=206, 6.0%) did not achieve physiological stability. A substantial proportion of patients (n=1377, 40.1%) did not complete any mobilisation or sitting activities. For patients (n=1851, 53.9%) who did undertake mobilisation or sitting activities, activity commenced a median (IQR) of 3.6 (2.0, 7.7) days after ICU admission. This represented a median (IQR) delay after physiological stability of 2.3 (1.3, 4.4) days for mobilisation and 2.7 (1.5, 5.7) days for sitting. In-hospital mortality was 14.3% (n=491) for patients who did not participate in exercise interventions, compared to 2.6% (n=89) for patients who exercised whilst in ICU.

Consumers have been slow to switch to more fuel efficient vehicles, in spite of the threat of a future global shortage of fossil fuels. To understand consumer reluctance to adopt hybrid automotive technology, this chapter begins by reviewing consumer decision-making with regard to consumer automotive purchases. We examine the market for fuel efficient vehicles (FEVs) and alternate fuel vehicles (AFVs), including a discussion of consumer willingness to trade personal comfort in order to buy more fuel efficient vehicles, and consumer price sensitivity with regard to purchasing higher-priced alternative fuel vehicles including hybrid-electric vehicles. We discuss the tenuous link between environmental attitudes and behavior, and outline the role of social marketing in creating behavior change relating to automotive purchase decisions.