Persistent influence of precession on northern ice sheet variability since the early Pleistocene.

Prior to ~1 million years ago (Ma), variations in global ice volume were dominated by changes in obliquity; however, the role of precession remains unresolved. Using a record of North Atlantic ice rafting spanning the past 1.7 million years, we find that the onset of ice rafting within a given glacial cycle (reflecting ice sheet expansion) consistently occurred during times of decreasing obliquity whereas mass ice wasting (ablation) events were consistently tied to minima in precession. Furthermore, our results suggest that the ubiquitous association between precession-driven mass wasting events and glacial termination is a distinct feature of the mid to late Pleistocene. Before then (increasing), obliquity alone was sufficient to end a glacial cycle, before losing its dominant grip on deglaciation with the southward extension of Northern Hemisphere ice sheets since ~1 Ma.

A dusty veil shading Betelgeuse during its Great Dimming.

Red supergiants are the most common final evolutionary stage of stars that have initial masses between 8 and 35 times that of the Sun1. During this stage, which lasts roughly 100,000 years1, red supergiants experience substantial mass loss. However, the mechanism for this mass loss is unknown2. Mass loss may affect the evolutionary path, collapse and future supernova light curve3 of a red supergiant, and its ultimate fate as either a neutron star or a black hole4. From November 2019 to March 2020, Betelgeuse-the second-closest red supergiant to Earth (roughly 220 parsecs, or 724 light years, away)5,6-experienced a historic dimming of its visible brightness. Usually having an apparent magnitude between 0.1 and 1.0, its visual brightness decreased to 1.614 ± 0.008 magnitudes around 7-13 February 20207-an event referred to as Betelgeuse's Great Dimming. Here we report high-angular-resolution observations showing that the southern hemisphere of Betelgeuse was ten times darker than usual in the visible spectrum during its Great Dimming. Observations and modelling support a scenario in which a dust clump formed recently in the vicinity of the star, owing to a local temperature decrease in a cool patch that appeared on the photosphere. The directly imaged brightness variations of Betelgeuse evolved on a timescale of weeks. Our findings suggest that a component of mass loss from red supergiants8 is inhomogeneous, linked to a very contrasted and rapidly changing photosphere.

Role legitimacy, comfort and confidence providing tobacco, alcohol and other drug care: a cross-sectional study of Australian early-career general practitioners.

Australian general practitioners (GPs) see most Australians each year and, as tobacco, alcohol and other drug use (substance use) are common, GPs often see problematic, risky or dependent substance use. This study aimed to explore early-career GPs' role legitimacy, comfort and confidence managing patients with problematic use of tobacco, alcohol, psychoactive pharmaceutical or illicit substances.Using the '5A's framework: Ask, Assess, Advise, Assist and Arrange, we surveyed 251 early-career GPs (GP registrars) on role legitimacy, confidence managing patient substance use, and sources of clinical information, advice and support.There was strong agreement that managing substance use is a GP's role, with high levels of confidence 'Asking' (screening) about tobacco and alcohol use, which decreased across other substance classes. Early-career GPs reported lower levels of confidence 'Assessing' and 'Advising' (brief interventions); and much lower levels of confidence 'Assisting' (treating) and 'Arranging' (follow up and/or referral) for patients with substance issues across all substances, including tobacco. Participants were most likely to seek advice from senior colleagues in their practice.Early-career GPs reported lower than optimal levels of confidence for all substances. Our findings have important implications for educators globally. Education that improves confidence across all 5As for high-prevalence substances (tobacco and alcohol) while focusing on increasing comfort screening and improving understanding of referral pathway options for low-prevalence substances may improve early-career GPs' confidence. This could increase engagement in managing substance use issues potentially leading to better health and wellbeing outcomes for patients.

Embryonic liver developmental trajectory revealed by single-cell RNA sequencing in the Foxa2eGFP mouse.

The liver and gallbladder are among the most important internal organs derived from the endoderm, yet the development of the liver and gallbladder in the early embryonic stages is not fully understood. Using a transgenic Foxa2eGFP reporter mouse line, we performed single-cell full-length mRNA sequencing on endodermal and hepatic cells isolated from ten embryonic stages, ranging from E7.5 to E15.5. We identified the embryonic liver developmental trajectory from gut endoderm to hepatoblasts and characterized the transcriptome of the hepatic lineage. More importantly, we identified liver primordium as the nascent hepatic progenitors with both gut and liver features and documented dynamic gene expression during the epithelial-hepatic transition (EHT) at the stage of liver specification during E9.5-11.5. We found six groups of genes switched on or off in the EHT process, including diverse transcripitional regulators that had not been previously known to be expressed during EHT. Moreover, we identified and revealed transcriptional profiling of gallbladder primordium at E9.5. The present data provides a high-resolution resource and critical insights for understanding the liver and gallbladder development.

A single fast radio burst localized to a massive galaxy at cosmological distance.

Fast radio bursts (FRBs) are brief radio emissions from distant astronomical sources. Some are known to repeat, but most are single bursts. Nonrepeating FRB observations have had insufficient positional accuracy to localize them to an individual host galaxy. We report the interferometric localization of the single-pulse FRB 180924 to a position 4 kiloparsecs from the center of a luminous galaxy at redshift 0.3214. The burst has not been observed to repeat. The properties of the burst and its host are markedly different from those of the only other accurately localized FRB source. The integrated electron column density along the line of sight closely matches models of the intergalactic medium, indicating that some FRBs are clean probes of the baryonic component of the cosmic web.

Urinary piperacillin/tazobactam pharmacokinetics in vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriaceae.

Urinary tract infections caused by multidrug-resistant Enterobacteriaceae are a growing burden worldwide. Recent studies of urinary pharmacokinetics described high piperacillin/tazobactam (TZP) concentrations in urine, but it is unknown whether this results in treatment efficacy. This study investigated the pharmacodynamics of TZP in a static in vitro model for Enterobacteriaceae to determine the concentration-effect relationship and ultimately the required free (unbound) time above the minimum inhibitory concentration (fT>MIC) required for bacterial killing. The static simulation model investigated TZP fT>MIC between 0% and 100%. Resistant Escherichia coli and Klebsiella pneumoniae isolates with piperacillin/tazobactam MICs of 4096/512, 1024/128 and 128/16 mg/L were investigated; two of the three organisms were carbapenemase-producers. Clinical efficacy was determined as a 3-log reduction over the dosing interval by comparing interval growth with controls. TZP was observed to exhibit time dependence for all organisms. The fT>MIC was determined to be 37.5%, 37.5% and 50% for MICs of 4096/512, 1024/128 and 128/16 mg/L, respectively. Linear regression identified the overall target to be 49.85 ± 16.9% fT>MIC. In conclusion, bactericidal activity against TZP-resistant Enterobacteriaceae occurred at 49.85 ± 16.9% fT>MIC. This suggests that highly resistant urinary organisms, including carbapenemase-producers, with MICs up to 4096/512 mg/L could be treated with TZP. Further investigations are required to elucidate urinary breakpoints and to explore the impact of different resistance mechanisms.

Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype.

Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis. To date, only one missense mutation in MMP14, encoding the membrane-bound matrix metalloprotease 14, has been reported in WS patients. Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS. Functional analysis demonstrated that this mutation, in contrast to previously reported human and murine MMP14 mutations, does not affect MMP14's transport to the cell membrane. Instead, it partially impairs MMP14's proteolytic activity. This residual activity likely accounts for the mitigated phenotype observed in our patients. Based on our observations as well as previously published data, we hypothesize that MMP14's catalytic activity is the prime determinant of disease severity. Given the limitations of our in vitro assays in addressing the consequences of MMP14 dysfunction, we generated a novel mmp14a/b knockout zebrafish model. The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density owing to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.

The century experiment: the first twenty years of UC Davis' Mediterranean agroecological experiment.

The Century Experiment at the Russell Ranch Sustainable Agriculture Facility at the University of California, Davis provides long-term agroecological data from row crop systems in California's Central Valley starting in 1993. The Century Experiment was initially designed to study the effects of a gradient of water and nitrogen availability on soil properties and crop performance in ten different cropping systems to measure tradeoffs and synergies between agricultural productivity and sustainability. Currently systems include 11 different cropping systems-consisting of four different crops and a cover crop mixture-and one native grass system. This paper describes the long-term core data from the Century Experiment from 1993-2014, including crop yields and biomass, crop elemental contents, aerial-photo-based Normalized Difference Vegetation Index data, soil properties, weather, chemical constituents in irrigation water, winter weed populations, and operational data including fertilizer and pesticide application amounts and dates, planting dates, planting quantity and crop variety, and harvest dates. This data set represents the only known long-term set of data characterizing food production and sustainability in irrigated and rainfed Mediterranean annual cropping systems. There are no copyright restrictions associated with the use of this dataset.

Neurodevelopmental synaptopathies: Insights from behaviour in rodent models of synapse gene mutations.

The genomic revolution has begun to unveil the enormous complexity and heterogeneity of the genetic basis of neurodevelopmental disorders such as such epilepsy, intellectual disability, autism spectrum disorder and schizophrenia. Increasingly, human mutations in synapse genes are being identified across these disorders. These neurodevelopmental synaptopathies highlight synaptic homeostasis pathways as a convergence point underlying disease mechanisms. Here, we review some of the key pre- and postsynaptic genes in which penetrant human mutations have been identified in neurodevelopmental disorders for which genetic rodent models have been generated. Specifically, we focus on the main behavioural phenotypes that have been documented in these animal models, to consolidate our current understanding of how synapse genes regulate key behavioural and cognitive domains. These studies provide insights into better understanding the basis of the overlapping genetic and cognitive heterogeneity observed in neurodevelopmental disorders.

Re-engineered RNA-Guided FokI-Nucleases for Improved Genome Editing in Human Cells.

Clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 enables us to generate targeted sequence changes in the genomes of cells and organisms. However, off-target effects have been a persistent problem hampering the development of therapeutics based on CRISPR/Cas9 and potentially confounding research results. Efforts to improve Cas9 specificity, like the development of RNA-guided FokI-nucleases (RFNs), usually come at the cost of editing efficiency and/or genome targetability. To overcome these limitations, we engineered improved chimeras of RFNs that enable higher cleavage efficiency and provide broader genome targetability, while retaining high fidelity for genome editing in human cells. Furthermore, we developed a new RFN ortholog derived from Staphylococcus aureus Cas9 and characterize its utility for efficient genome engineering. Finally, we demonstrate the feasibility of RFN orthologs to functionally hetero-dimerize to modify endogenous genes, unveiling a new dimension of RFN target design opportunities.

Potential Benefits of Ameliorating Metabolic and Nutritional Abnormalities in People With Profound Developmental Disabilities.

BACKGROUND: People with profound developmental disabilities have some of the most severe neurological impairments seen in society, have accelerated mortality due to huge medical challenges, and yet are often excluded from scientific studies. They actually have at least 2 layers of conditions: (1) the original disability and (2) multiple under-recognized and underexplored metabolic and nutritional imbalances involving minerals (calcium, zinc, and selenium), amino acids (taurine, tryptophan), fatty acids (linoleic acid, docosahexaenoic acid, arachidonic acid, adrenic acid, Mead acid, plasmalogens), carnitine, hormones (insulinlike growth factor 1), measures of oxidative stress, and likely other substances and systems. SUMMARY: This review provides the first list of metabolic and nutritional abnormalities commonly found in people with profound developmental disabilities and, based on the quality of life effects of similar abnormalities in neurotypical people, indicates the potential effects of these abnormalities in this population which often cannot communicate symptoms. KEY MESSAGES: We propose that improved understanding and management of these disturbed mechanisms would enhance the quality of life of people with profound developmental disabilities. Such insights may also apply to people with other conditions associated with disability, including some diseases requiring stem cell implantation and living in microgravity.

Molecular gas in the halo fuels the growth of a massive cluster galaxy at high redshift.

The largest galaxies in the universe reside in galaxy clusters. Using sensitive observations of carbon monoxide, we show that the Spiderweb galaxy-a massive galaxy in a distant protocluster-is forming from a large reservoir of molecular gas. Most of this molecular gas lies between the protocluster galaxies and has low velocity dispersion, indicating that it is part of an enriched intergalactic medium. This may constitute the reservoir of gas that fuels the widespread star formation seen in earlier ultraviolet observations of the Spiderweb galaxy. Our results support the notion that giant galaxies in clusters formed from extended regions of recycled gas at high redshift.

Cranial Arterial Patterning in Greyhounds: Another Case of Internal Intraspecific Variation.

The greyhound is a dog breed highly specialized to run fast (17 m/s) over short distances (Usherwood and Wilson, 2005). As a result, there are many anatomical structures correlated with this sprinting function. The branching patterns of vasculature supplying blood to the head, forelimbs and thorax (subclavian arteries and its branches) were described in 34 adult greyhound cadavers (22 male, 12 female) (donated with owner consent and used under a memorandum of understanding with the University of Adelaide Animal Ethics Committee) from silicone casts of the arch of the aorta and the cranial arteries. Chi-squared analysis was used to test for pattern frequency differences, and t-tests were used to analyse the differences between sex and symmetry. All measurements were scaled to a fixed measure, the Open Thorax Length (OTL), to correct for size variation between individuals. Significant differences were found between the left and right subclavian arteries in the greyhound. The length to the first branch as a percentage of the OTL was greater in the right subclavian artery than the left subclavian artery (P < 0.001). The interval between the first and last branches (branching interval) as a percentage of the OTL was larger in the left subclavian artery than the right subclavian artery (P < 0.001). The reason for these differences remains unclear. Nonetheless, intraspecific variations of the branching patterns of the subclavian arteries have been described in the greyhound, thus suggesting that breed-specific variations in the cardiovascular system are likely to occur throughout domestic dogs.

Development, Evaluation and Implementation of Chief Complaint Groupings to Activate Data Collection: A Multi-Center Study of Clinical Decision Support for Children with Head Trauma.

BACKGROUND: Overuse of cranial computed tomography scans in children with blunt head trauma unnecessarily exposes them to radiation. The Pediatric Emergency Care Applied Research Network (PECARN) blunt head trauma prediction rules identify children who do not require a computed tomography scan. Electronic health record (EHR) based clinical decision support (CDS) may effectively implement these rules but must only be provided for appropriate patients in order to minimize excessive alerts. OBJECTIVES: To develop, implement and evaluate site-specific groupings of chief complaints (CC) that accurately identify children with head trauma, in order to activate data collection in an EHR. METHODS: As part of a 13 site clinical trial comparing cranial computed tomography use before and after implementation of CDS, four PECARN sites centrally developed and locally implemented CC groupings to trigger a clinical trial alert (CTA) to facilitate the completion of an emergency department head trauma data collection template. We tested and chose CC groupings to attain high sensitivity while maintaining at least moderate specificity. RESULTS: Due to variability in CCs available, identical groupings across sites were not possible. We noted substantial variability in the sensitivity and specificity of seemingly similar CC groupings between sites. The implemented CC groupings had sensitivities greater than 90% with specificities between 75-89%. During the trial, formal testing and provider feedback led to tailoring of the CC groupings at some sites. CONCLUSIONS: CC groupings can be successfully developed and implemented across multiple sites to accurately identify patients who should have a CTA triggered to facilitate EHR data collection. However, CC groupings will necessarily vary in order to attain high sensitivity and moderate-to-high specificity. In future trials, the balance between sensitivity and specificity should be considered based on the nature of the clinical condition, including prevalence and morbidity, in addition to the goals of the intervention being considered.

Biomechanical study of different plate configurations for distal humerus osteosynthesis.

Fractures of the distal humerus are most commonly fixed by open reduction and internal fixation, using plates and screws, either in a locking or in a non-locking construct. Three different plating systems are commonly used in practice. The most important differences between them are in plate orientation, which affects both the rigidity of the osteosynthesis and invasiveness of the surgical procedure. Unfortunately, there is no common agreement between surgeons about which plate configuration brings the best clinical outcome. In this study, we investigate the theoretical rigidity of plate osteosyntheses considering two types of AO/ASIF configurations (90° angle between plates), Mayo clinic (Acumed) configuration (180° between plates) and dorsal fixation of both plates. We also compared the results for cases with and without contact between the bone fragments. In the case of no bone contact, the Mayo clinic plate configuration is found to be the most rigid, followed by both AO/ASIF plate configurations, and the least rigid system is the Korosec plate configuration. On the other hand, no significant differences between all types of fixation configurations are found in cases with contact in-between the bone fragments. Our findings show that this contact is very important and can compensate for the lack of load carrying capacity of the implants. This could therefore incite other implant fixation solutions, leading to less invasive surgical procedures and consequently improved clinical outcome.

Valvular dystrophy associated filamin A mutations reveal a new role of its first repeats in small-GTPase regulation.

Filamin A (FlnA) is a ubiquitous actin binding protein which anchors various transmembrane proteins to the cell cytoskeleton and provides a scaffold to many cytoplasmic signaling proteins involved in actin cytoskeleton remodeling in response to mechanical stress and cytokines stimulation. Although the vast majority of FlnA binding partners interact with the carboxy-terminal immunoglobulin like (Igl) repeats of FlnA, little is known on the role of the amino-N-terminal repeats. Here, using cardiac mitral valvular dystrophy associated FlnA-G288R and P637Q mutations located in the N-terminal Igl repeat 1 and 4 respectively as a model, we identified a new role of FlnA N-terminal repeats in small Rho-GTPases regulation. Using FlnA-deficient melanoma and HT1080 cell lines as expression systems we showed that FlnA mutations reduce cell spreading and migration capacities. Furthermore, we defined a signaling network in which FlnA mutations alter the balance between RhoA and Rac1 GTPases activities in favor of RhoA and provided evidences for a role of the Rac1 specific GTPase activating protein FilGAP in this process. Together our work ascribed a new role to the N-terminal repeats of FlnA in Small GTPases regulation and supports a conceptual framework for the role of FlnA mutations in cardiac valve diseases centered around signaling molecules regulating cellular actin cytoskeleton in response to mechanical stress.

Marine ecosystem responses to Cenozoic global change.

The future impacts of anthropogenic global change on marine ecosystems are highly uncertain, but insights can be gained from past intervals of high atmospheric carbon dioxide partial pressure. The long-term geological record reveals an early Cenozoic warm climate that supported smaller polar ecosystems, few coral-algal reefs, expanded shallow-water platforms, longer food chains with less energy for top predators, and a less oxygenated ocean than today. The closest analogs for our likely future are climate transients, 10,000 to 200,000 years in duration, that occurred during the long early Cenozoic interval of elevated warmth. Although the future ocean will begin to resemble the past greenhouse world, it will retain elements of the present "icehouse" world long into the future. Changing temperatures and ocean acidification, together with rising sea level and shifts in ocean productivity, will keep marine ecosystems in a state of continuous change for 100,000 years.

A novel technique for the treatment of infected metalwork in orthopaedic patients using skin closure over irrigated negative pressure wound therapy dressings.

INTRODUCTION: There has been recent interest in the use of negative pressure wound therapy (NWPT) as an adjunct to parenteral antibiotics in the treatment of infection in orthopaedic patients with metalwork in situ. To address some of the limitations of standard NPWT in this situation, the senior author has developed a modified method of treatment for infected metalwork (excluding arthroplasty) in orthopaedic patients that includes irrigation and skin closure over the standard NPWT dressing. METHODS: This retrospective study examined the outcome of a case series of 16 trauma and orthopaedic patients with deep infection involving metalwork in whom this modified form of NPWT was used. In conjunction with standard parenteral antibiotic therapy and a multidisciplinary approach, this modified technique included serial debridements in theatre, irrigation and negative pressure dressings over a white polyvinyl alcohol foam (KCI, Kidlington, UK) as well as closure of the skin over the foam. RESULTS: Among the 16 patients, there was a variety of upper and lower limb as well as spinal trauma and elective cases. In all 16 patients, there was successful resolution of the infection with no early or unplanned removal of any metalwork required. CONCLUSIONS: Patients with infected metalwork are a heterogeneous group, and often suffer high morbidity and mortality. The modified NPWT technique shows potential as an adjunct in the treatment of complex orthopaedic patients with infected metalwork.