Challenges simulating the AMOC in climate models.

The latest assessment report from the Intergovernmental Panel on Climate Change concluded that the Atlantic Meridional Overturning Circulation (AMOC) was very likely to decline over the twenty-first century under all emissions scenarios; however, there was low confidence in the magnitude of the decline. Recent research has highlighted that model biases in the mean climate state can affect the AMOC in its mean state, variability and its response to climate change. Hence, understanding and reducing these model biases is critical for reducing uncertainty in the future changes of the AMOC and in its impacts on the wider climate. We discuss how model biases, in particular salinity biases, influence the AMOC and deep convection. We then focus on biases in the UK HadGEM3-GC3-1 climate model and how these biases change with resolution. We also discuss ongoing model development activities that affect these biases, and highlight priorities for improved representation of processes, such as the position of the North Atlantic Current, transports in narrow boundary current, resolution (or improved parameterization) of eddies and spurious numerical mixing in overflows. This article is part of a discussion meeting issue 'Atlantic overturning: new observations and challenges'.

Advancing novel therapies for neurodegeneration through an innovative model for industry-academia collaborations: A decade of the Eisai-UCL experience.

External innovation initiatives in the pharmaceutical industry have become an integral part of research and development. Collaborations have been built to enhance innovation, mitigate risk, and share cost, especially for neurodegenerative diseases, a therapeutic area that has suffered from high attrition rates. This article outlines the Eisai-University College London (UCL) Drug Discovery and Development Collaboration as a case study of how to implement a productive industry-academic partnership. In the first 10 years, seven projects have been established and the first project, a novel anti-tau antibody for Alzheimer's disease, has entered clinical trials, providing early validation of this collaboration model.

Formation of giant iron oxide-copper-gold deposits by superimposed episodic hydrothermal pulses.

Iron oxide-copper-gold (IOCG) deposits are a globally important source of copper, gold and critical commodities. Despite their relevance, IOCG deposits remain an ill-defined clan, with a range of characteristics that has complicated development of the general genetic model. Here we focus on the Candelaria IOCG deposit in Chile and reveal that by using micro-textural and compositional variations in actinolite, a common alteration mineral found in many IOCG deposits, we can constrain the evolution of these systems. We demonstrate that Candelaria formed by the superposition of at least two pulses of mineralization with a late Cu-rich event overprinting and superimposed over an early, and probably higher temperature, iron oxide-apatite (IOA) mineralization event. These distinct pulses were likely caused by episodic injections of magmatic-hydrothermal fluids from crystallizing magmas at depth. Our data provide empirical evidence of grain-to-deposit scale compositional and potentially temperature changes in an IOCG system. The results support the use of actinolite chemistry as a novel approach to understand the formation of IOCG deposits and a potential tool for vectoring in exploration.

A globally consistent local-scale assessment of future tropical cyclone risk.

There is considerable uncertainty surrounding future changes in tropical cyclone (TC) frequency and intensity, particularly at local scales. This uncertainty complicates risk assessments and implementation of risk mitigation strategies. We present a novel approach to overcome this problem, using the statistical model STORM to generate 10,000 years of synthetic TCs under past (1980-2017) and future climate (SSP585; 2015-2050) conditions from an ensemble of four high-resolution climate models. We then derive high-resolution (10-km) wind speed return period maps up to 1000 years to assess local-scale changes in wind speed probabilities. Our results indicate that the probability of intense TCs, on average, more than doubles in all regions except for the Bay of Bengal and the Gulf of Mexico. Our unique and innovative methodology enables globally consistent comparison of TC risk in both time and space and can be easily adapted to accommodate alternative climate scenarios and time periods.

Projected Future Changes in Tropical Cyclones Using the CMIP6 HighResMIP Multimodel Ensemble.

Future changes in tropical cyclone properties are an important component of climate change impacts and risk for many tropical and midlatitude countries. In this study we assess the performance of a multimodel ensemble of climate models, at resolutions ranging from 250 to 25 km. We use a common experimental design including both atmosphere-only and coupled simulations run over the period 1950-2050, with two tracking algorithms applied uniformly across the models. There are overall improvements in tropical cyclone frequency, spatial distribution, and intensity in models at 25 km resolution, with several of them able to represent very intense storms. Projected tropical cyclone activity by 2050 generally declines in the South Indian Ocean, while changes in other ocean basins are more uncertain and sensitive to both tracking algorithm and imposed forcings. Coupled models with smaller biases suggest a slight increase in average TC 10 m wind speeds by 2050.

Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease.

Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer's disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species ("seeds") containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical development.

Dissecting the Re-Os molybdenite geochronometer.

Rhenium and osmium isotopes have been used for decades to date the formation of molybdenite (MoS2), a common mineral in ore deposits and the world's main source of molybdenum and rhenium. Understanding the distribution of parent 187Re and radiogenic daughter 187Os isotopes in molybdenite is critical in interpreting isotopic measurements because it can compromise the accurate determination and interpretation of mineralization ages. In order to resolve the controls on the distribution of these elements, chemical and isotope mapping of MoS2 grains from representative porphyry copper-molybdenum deposits were performed using electron microprobe and nano-scale secondary ion mass spectrometry. Our results show a heterogeneous distribution of 185,187Re and 192Os isotopes in MoS2, and that both 187Re and 187Os isotopes are not decoupled as previously thought. We conclude that Re and Os are structurally bound or present as nanoparticles in or next to molybdenite grains, recording a complex formation history and hindering the use of microbeam techniques for Re-Os molybdenite dating. Our study opens new avenues to explore the effects of isotope nuggeting in geochronometers.

Mitochondrial permeability transition pore: sensitivity to opening and mechanistic dependence on substrate availability.

Mitochondrial Ca2+ uptake has a key role in cellular Ca2+ homeostasis. Excessive matrix Ca2+ concentrations, especially when coincident with oxidative stress, precipitate opening of an inner mitochondrial membrane, high-conductance channel: the mitochondrial permeability transition pore (mPTP). mPTP opening has been implicated as a final cell death pathway in numerous diseases and therefore understanding conditions dictating mPTP opening is crucial for developing targeted therapies. Here, we have investigated the impact of mitochondrial metabolic state on the probability and consequences of mPTP opening. Isolated mitochondria were energised using NADH- or FADH2-linked substrates. The functional consequences of Ca2+-induced mPTP opening were assessed by Ca2+ retention capacity, using fluorescence-based analysis, and simultaneous measurements of mitochondrial Ca2+ handling, membrane potential, respiratory rate and production of reactive oxygen species (ROS). Succinate-induced, membrane potential-dependent reverse electron transfer sensitised mitochondria to mPTP opening. mPTP-induced depolarisation under succinate subsequently inhibited reverse electron transfer. Complex I-driven respiration was reduced after mPTP opening but sustained in the presence of complex II-linked substrates, consistent with inhibition of complex I-supported respiration by leakage of matrix NADH. Additionally, ROS generated at complex III did not sensitise mitochondria to mPTP opening. Thus, cellular metabolic fluxes and metabolic environment dictate mitochondrial functional response to Ca2+ overload.

Identification of ER-000444793, a Cyclophilin D-independent inhibitor of mitochondrial permeability transition, using a high-throughput screen in cryopreserved mitochondria.

Growing evidence suggests persistent mitochondrial permeability transition pore (mPTP) opening is a key pathophysiological event in cell death underlying a variety of diseases. While it has long been clear the mPTP is a druggable target, current agents are limited by off-target effects and low therapeutic efficacy. Therefore identification and development of novel inhibitors is necessary. To rapidly screen large compound libraries for novel mPTP modulators, a method was exploited to cryopreserve large batches of functionally active mitochondria from cells and tissues. The cryopreserved mitochondria maintained respiratory coupling and ATP synthesis, Ca2+ uptake and transmembrane potential. A high-throughput screen (HTS), using an assay of Ca2+-induced mitochondrial swelling in the cryopreserved mitochondria identified ER-000444793, a potent inhibitor of mPTP opening. Further evaluation using assays of Ca2+-induced membrane depolarisation and Ca2+ retention capacity also indicated that ER-000444793 acted as an inhibitor of the mPTP. ER-000444793 neither affected cyclophilin D (CypD) enzymatic activity, nor displaced of CsA from CypD protein, suggesting a mechanism independent of CypD inhibition. Here we identified a novel, CypD-independent inhibitor of the mPTP. The screening approach and compound described provides a workflow and additional tool to aid the search for novel mPTP modulators and to help understand its molecular nature.

Enhanced cellular preservation by clay minerals in 1 billion-year-old lakes.

Organic-walled microfossils provide the best insights into the composition and evolution of the biosphere through the first 80 percent of Earth history. The mechanism of microfossil preservation affects the quality of biological information retained and informs understanding of early Earth palaeo-environments. We here show that 1 billion-year-old microfossils from the non-marine Torridon Group are remarkably preserved by a combination of clay minerals and phosphate, with clay minerals providing the highest fidelity of preservation. Fe-rich clay mostly occurs in narrow zones in contact with cellular material and is interpreted as an early microbially-mediated phase enclosing and replacing the most labile biological material. K-rich clay occurs within and exterior to cell envelopes, forming where the supply of Fe had been exhausted. Clay minerals inter-finger with calcium phosphate that co-precipitated with the clays in the sub-oxic zone of the lake sediments. This type of preservation was favoured in sulfate-poor environments where Fe-silicate precipitation could outcompete Fe-sulfide formation. This work shows that clay minerals can provide an exceptionally high fidelity of microfossil preservation and extends the known geological range of this fossilization style by almost 500 Ma. It also suggests that the best-preserved microfossils of this time may be found in low-sulfate environments.

Changes in global net radiative imbalance 1985-2012.

Combining satellite data, atmospheric reanalyses, and climate model simulations, variability in the net downward radiative flux imbalance at the top of Earth's atmosphere (N) is reconstructed and linked to recent climate change. Over the 1985-1999 period mean N (0.34 ± 0.67 Wm-2) is lower than for the 2000-2012 period (0.62 ± 0.43 Wm-2, uncertainties at 90% confidence level) despite the slower rate of surface temperature rise since 2000. While the precise magnitude of N remains uncertain, the reconstruction captures interannual variability which is dominated by the eruption of Mount Pinatubo in 1991 and the El Niño Southern Oscillation. Monthly deseasonalized interannual variability in N generated by an ensemble of nine climate model simulations using prescribed sea surface temperature and radiative forcings and from the satellite-based reconstruction is significantly correlated (r∼0.6) over the 1985-2012 period.

The use of Enhancing Quality Use of Medication Self-Reported Questionniare (EQUIM-SRQ) among mental health consumers: a pilot study.

OBJECTIVE: To assess the applicability, interpretability and potential limitations of an adverse event screening questionnaire (the Enhancing Quality Use of Medication Self-Reported Questionnaire [EQUIM-SRQ]) in an Australian mental health outpatient population. METHOD: Questionnaires were distributed amongst two Australian adult mental health clinics for completion either at the clinic (onsite), or externally (postal option), during March-May 2011. Assistance was offered to participants completing the questionnaire onsite. Clients who were visited in their homes by clinic staff were invited to participate as external participants. RESULTS: Of 160 questionnaires distributed, 29 (18%) were completed. Of those, 22 were completed onsite, and seven were completed externally. Of the questionnaires completed onsite, 11 were fully completed, with 4 participants requiring assistance. A further 11 questionnaires were partially completed, with 2 participants requiring assistance. Of the questionnaires completed externally, 5 were fully completed. CONCLUSION: Although the response rate was low, the EQUIM-SRQ was applicable, interpretable and acceptable when completed or partially completed questionnaires were assessed. The potential exists to apply the EQUIM-SRQ in further research, and thereafter, clinical practice.

Age-dependent maintenance of motor control and corticostriatal innervation by death receptor 3.

Death receptor 3 is a proinflammatory member of the immunomodulatory tumor necrosis factor receptor superfamily, which has been implicated in several inflammatory diseases such as arthritis and inflammatory bowel disease. Intriguingly however, constitutive DR3 expression has been detected in the brains of mice, rats, and humans, although its neurological function remains unknown. By mapping the normal brain expression pattern of DR3, we found that DR3 is expressed specifically by cells of the neuron lineage in a developmentally regulated and region-specific pattern. Behavioral studies on DR3-deficient (DR3(ko)) mice showed that constitutive neuronal DR3 expression was required for stable motor control function in the aging adult. DR3(ko) mice progressively developed behavioral defects characterized by altered gait, dyskinesia, and hyperactivity, which were associated with elevated dopamine and lower serotonin levels in the striatum. Importantly, retrograde tracing showed that absence of DR3 expression led to the loss of corticostriatal innervation without significant neuronal loss in aged DR3(ko) mice. These studies indicate that DR3 plays a key nonredundant role in the retention of normal motor control function during aging in mice and implicate DR3 in progressive neurological disease.

Developing the next-generation climate system models: challenges and achievements.

Although climate models have been improving in accuracy and efficiency over the past few decades, it now seems that these incremental improvements may be slowing. As tera/petascale computing becomes massively parallel, our legacy codes are less suitable, and even with the increased resolution that we are now beginning to use, these models cannot represent the multiscale nature of the climate system. This paper argues that it may be time to reconsider the use of adaptive mesh refinement for weather and climate forecasting in order to achieve good scaling and representation of the wide range of spatial scales in the atmosphere and ocean. Furthermore, the challenge of introducing living organisms and human responses into climate system models is only just beginning to be tackled. We do not yet have a clear framework in which to approach the problem, but it is likely to cover such a huge number of different scales and processes that radically different methods may have to be considered. The challenges of multiscale modelling and petascale computing provide an opportunity to consider a fresh approach to numerical modelling of the climate (or Earth) system, which takes advantage of the computational fluid dynamics developments in other fields and brings new perspectives on how to incorporate Earth system processes. This paper reviews some of the current issues in climate (and, by implication, Earth) system modelling, and asks the question whether a new generation of models is needed to tackle these problems.

Evaluation of a point-of-care immunodot assay for predicting results of allergen-specific intradermal and immunoglobulin E serological tests.

Immunotherapy to prevent recurrence of clinical signs of atopic dermatitis (AD) is based on intradermal or serological tests that assist in identifying allergen-specific immunoglobulin E hypersensitivities. Unfortunately, the results of such tests can be negatively influenced by several factors, which include the age of the patients, the season of testing and the administration of anti-allergic drugs. Screening to predict when these expensive tests will be useful would benefit owners of dogs with AD. The objectives of this study were to determine whether a point-of-care allergen-specific immunodot assay (Allercept E-Screen, Heska Corp., Ft Collins, CO, USA) could predict results of either intradermal or Allercept full panel serological tests in atopic dogs. Thirty dogs living in the south-eastern USA were diagnosed with AD in accordance with current standards. Allergen-specific intradermal, serological and E-Screen tests were performed in all subjects. For flea, house dust mite and pollen allergens altogether, results of the E-Screen assay agreed with those of intradermal and serological tests in 26/30 dogs (87%) and 25/30 dogs (83%), respectively. In this group of dogs, the probabilities of obtaining intradermal or serological tests positive for these allergens were 70 and 67%, respectively. If either skin or serum tests were performed only in dogs with positive E-Screen tests, the probability of obtaining positive results would be increased from 70 to 95% and from 67 to 90%, respectively. In this population of dogs with AD, results of the E-Screen point-of-care immunodot assay was found to often agree with those of allergen-specific intradermal or Allercept tests for selected allergen groups.

Effects of continuous rate intravenous infusion of butorphanol on physiologic and outcome variables in horses after celiotomy.

A randomized, controlled, blinded clinical trial was performed to determine whether butorphanol administered by continuous rate infusion (CRI) for 24 hours after abdominal surgery would decrease pain and surgical stress responses and improve recovery in horses. Thirty-one horses undergoing exploratory celiotomy for abdominal pain were randomly assigned to receive butorphanol CRI (13 microg/kg/h for 24 hours after surgery; treatment) or isotonic saline (control). All horses received flunixin meglumine (1.1 mg/kg IV q12h). There were no significant differences between treatment and control horses in preoperative or operative variables. Treatment horses had significantly lower plasma cortisol concentration compared with control horses at 2, 8, 12, 24, 36, and 48 hours after surgery. Mean weight loss while hospitalized was significantly less for treatment horses than control horses, whether expressed as total decrease in body weight (13.9+/-3.4 and 27.9+/-4.5 kg, respectively) or as a percentage decrease in body weight (2.6+/-0.7 and 6.3+/-1.1%, respectively). Treatment horses were significantly delayed in time to first passage of feces (median times of 15 and 4 hours, respectively). Treatment horses had significantly improved behavior scores during the first 24 hours after surgery, consistent with the conclusion that they experienced less pain during that time. Butorphanol CRI during the immediate postoperative period significantly decreased plasma cortisol concentrations and improved recovery characteristics in horses undergoing abdominal surgery.

The Umgeni bridge, a resin bonded pontic using a preformed fibre post an aesthetic procedure of low biological and fiscal cost.

A missing anterior tooth or open embrasures destroys the aesthetics of a smile. The replacement of a missing anterior tooth is one of the most rewarding and challenging aspects of restorative dentistry. There are a number of techniques to do this, however, most involve the use of a technician, which means additional cost to the patient and multiple visits. In today's financial climate with practice expenses climbing and medical aid remuneration dwindling, one must seek methods to reduce costs and provide patients with more affordable dentistry. In addition, in crisis situations such as the traumatic loss of a tooth an immediate replacement technique albeit temporary is necessary. To replace a missing anterior tooth directly and immediately presents a rewarding challenge to the clinician. The Umgeni bridge named after the river that flows on the north side of Durban, is particularly useful in replacing congenitally missing laterals after completion of orthodontic treatment in the case of congenitally missing laterals and cleft palates.

Constipation, laxative use, and colon cancer in a North Carolina population.

OBJECTIVE: The aim of this study was to determine whether bowel movement frequency and laxative use and type were associated with risk of colon cancer in white and black men and women. METHODS: We conducted a population-based, case-control study with equal representation by blacks. Eligible subjects between ages 40 and 80 yr residing in urban and rural communities in North Carolina were asked about bowel habits and laxatives during face-to-face interviews. There were 643 cases (349 white, 294 black) and 1048 controls (611 white, 437 black). RESULTS: Constipation, defined as fewer than three reported bowel movements per wk, was associated with a greater than two-fold risk of colon cancer (OR 2.36; 95% CI = 1.41-3.93) adjusted for age, race, sex, and relevant confounders. The association was greater for women (OR 2.69; 95% CI = 1.46-4.94) than for men (OR 1.73; 95% CI = 0.61-4.88) and stronger in blacks than whites. Black women had the highest risk (OR 3.42; 95% CI = 1.60-7.34), which remained significant (OR 3.21; 95% CI = 1.46-7.04) even after excluding subjects with late stage (distant) disease. The OR for constipation was slightly higher for distal than for proximal colon cancers. There was no association with laxative use (OR 0.88; 95% CI = 0.69-1.11). Fiber commercial laxatives appeared to exert a protective effect in a small subgroup. CONCLUSIONS: This study provides support for a positive association between constipation and increased risk for colon cancer. Women, especially black women with constipation, seem to be at the highest risk.

Prostaglandin E2 and reactive oxygen metabolite damage in the cecum in a pony model of acute colitis.

The objective of this project was to determine early tissue biochemical events associated with increased colonic secretion during the acute stage of castor-oil-induced colitis by measuring cecal mucosal and submucosal malondialdehyde (MDA) and prostaglandin E2 (PGE2), levels in ponies. Intestinal tissue (inflamed or healthy) samples were obtained from 4 age- and sex-matched Shetland ponies. Biochemical methods were used to determine MDA and PGE2 levels in intestinal tissue samples from inflamed and healthy equine intestine. Inflamed tissue MDA and PGE2 levels increased with time after castor oil challenge and correlated with granulocyte infiltration, as determined by myeloperoxidase levels in a companion study. Elevated intestinal tissue MDA levels suggest that lipid peroxidation could be attributed to reactive oxygen metabolites (ROM) released from stimulated, recruited, and resident granulocytes. Tissue levels of MDA and PGE2 suggest a role for granulocyte-derived mediators of intestinal inflammation in the massive secretory response in cases of acute equine colitis. Tissue MDA and PGE2 levels may be useful laboratory tools to quantify and characterize intestinal secretory inflammatory responses in acute inflammatory conditions in the equine colon.