Search

Glacial terminations are marked by a re-organisation of the different components of the climate system. In particular, rapid ice sheet disintegration leads to multiple complex feedback loops that are still poorly understood. To further investigate this aspect, we use here a fully coupled Northern Hemisphere ice sheet–climate model to perform numerical experiments of the last two glacial terminations. We show that even if the first-order climate trajectory is similar for the two terminations, the difference in terms of solar insolation leads to important changes for the ice sheet–climate system. Warmer temperatures during the penultimate termination are compatible with higher sea level during the last interglacial period with respect to the Holocene. We simulate a last interglacial Greenland contribution to sea level rise of about 2 m of sea level equivalent. We also simulate warmer subsurface Southern Ocean, compatible with an additional contribution from the Antarctic ice sheet. In addition, even without considering freshwater flux to the ocean resulting from ice sheet melting, the two terminations display different Atlantic overturning circulation sensitivity, this circulation being more prone to collapses during the penultimate termination. Finally, with additional sensitivity experiments we show that, for the two terminations, the Northern Hemisphere insolation is the main driver for the ice sheet retreat even if vegetation changes have also to be taken into account to simulate the full deglaciation. Conversely, even though it impacts the temperature, greenhouse gas concentration change alone does not explain the amplitude of ice sheet retreat and only modulates its timing.

Abstract As part of the R2D2 (Rare Decays with Radial Detector) R &D, the use of a gas detector with a spherical or cylindrical cathode, equipped with a single anode and operating at high pressure, was studied for the search of rare phenomena such as neutrinoless double-beta decay. The presented measurements were obtained with a cylindrical detector, covering gas pressures ranging from 1 to 10 bar in argon and 1 to 6 bar in xenon, using both a point-like source of $$^{210} $$ 210 Po (5.3 MeV $$\alpha $$ α ) and a diffuse source of $$^{222}$$ 222 Rn (5.5 MeV $$\alpha $$ α ). Analysis and interpretation of the data were developed using the anodic current waveform. Similar detection performances were achieved with both gases, and comparable energy resolutions were measured with both sources. As long as the purity of the gas was sufficient, no significant degradation of the measured energy was observed by increasing the pressure. At the highest operating pressure, an energy resolution better than 1.5% full-width at half-maximum (FWHM) was obtained for both gaseous media, although optimal noise conditions were not reached.

Stable water isotopes are used to infer changes in the hydrological cycle for different climate periods and various climatic archives. Following previous developments of δ18O in the coupled climate model of intermediate complexity, iLOVECLIM, we present here the implementation of the 1H2H16O and 1H217O water isotopes in the different components of this model and calculate the associated secondary markers deuterium excess (d-excess) and oxygen-17 excess (17O-excess) in the atmosphere and ocean. So far, the latter has only been modelled by the atmospheric model LMDZ4. Results of a 5000-year equilibrium simulation under preindustrial conditions are analysed and compared to observations and several isotope-enabled models for the atmosphere and ocean components. In the atmospheric component, the model correctly reproduces the first-order global distribution of the δ2H and d-excess as observed in the data (R=0.56 for δ2H and 0.36 for d-excess), even if local differences are observed. The model–data correlation is within the range of other water-isotope-enabled general circulation models. The main isotopic effects and the latitudinal gradient are properly modelled, similarly to previous water-isotope-enabled general circulation model simulations, despite a simplified atmospheric component in iLOVECLIM. One exception is observed in Antarctica where the model does not correctly estimate the water isotope composition, a consequence of the non-conservative behaviour of the advection scheme at a very low moisture content. The modelled 17O-excess presents a too-important dispersion of the values in comparison to the observations and is not correctly reproduced in the model, mainly because of the complex processes involved in the 17O-excess isotopic value. For the ocean, the model simulates an adequate isotopic ratio in comparison to the observations, except for local areas such as the surface of the Arabian Sea, a part of the Arctic and the western equatorial Indian Ocean. Data–model evaluation also presents a good match for the δ2H over the entire water column in the Atlantic Ocean, reflecting the influence of the different water masses.

ABSTRACT: Improving health and welfare outcomes for replacement and surplus dairy calves is important for the sustainability of the dairy industry. Dairy farmers and veterinarians hold expertise in calf management and have valuable perspectives on how to practically motivate improvements. The objective of this study was to determine strategies that could improve the care calves receive on dairy farms from the perspective of dairy farmers and their herd veterinarians. Two veterinary clinics specializing in dairy practice in British Columbia, Canada, and 21 of their client dairy farms participated in the project. Following a meeting in which calf colostrum management was discussed between farmers and their herd veterinarian, participant interviews were conducted. Separate interviews were conducted for the farmers (n = 27 farmers from 21 farms) and their herd veterinarians (n = 7, with 1 to 5 farms that each vet worked with enrolled in the study) using tailored semi-structured question guides. Interviews (n = 42) were transcribed and coded following inductive thematic analysis methodology. The themes identified included strategies for farmers, veterinarians, and calf buyers, as well as contexts that influenced the dairy farmers' internal motivation to provide good calf care. Results indicated that farmers could optimize their calf management through fostering engagement of calf care personnel or by enlisting technology. Veterinarians could provide support to farms by being actively involved in calf monitoring, assisting in developing operating protocols, and setting goals, and especially by using farm-specific data to guide their management recommendations. Calf buyers could communicate with and provide accountability to farmers and improve their purchasing strategies to encourage farms to raise more vigorous surplus calves. Farmers' personal values, social networks, and relationships with different dairy industry stakeholders influenced their concern about the standards of their calf care practices. These findings provide guidance on how dairy farmers could achieve or be prompted to achieve improvements in their calf care practices.

California is the largest agricultural economy in the United States; however, its current and projected climate risks pose significant challenges. Farmers will need to adapt to climate change in their farming practices. The goal of this needs assessment was to understand farmers' perceptions and experiences with climate change exposures; the risk management practices they currently use; and what tools and resources would assist them in making strategic decisions. A statewide survey was conducted through Qualtrics with farmers (n = 341). Results showed that 67% of the farmers agree (agree + strongly agree) that climate change is happening, and 53.1% agreed that actions are required. Moreover, historically underrepresented farmers were very concerned about climate change-related impacts related to water, temperatures, and natural disasters. Farmers are currently implementing adaptation practices related to water management, soil health, and renewable energy and are also seeking insurance and government assistance programs to increase agricultural resilience. They also expressed interest and a high need for information on those adaptation practices to acquire skills and knowledge to manage various challenges of farming in variable climates. Also, the assessment established that farmers (47.5%) use decision-support tools, mostly weather stations (22.4%); and 51.9% indicated their interest in using online tools designed to translate climate information into forms that support production decision-making. Farmers (60.8%) responded that they would or may attend workshops to learn about adaptation practices. The findings of this needs assessment will inform the development of extension education programs on climate-smart agriculture for farmers in California and elsewhere.

ABSTRACT: This study used realistic evaluation to determine how, and in which circumstances, providing dairy farmers with benchmarked data on their calves can motivate improved colostrum management practices. Dairy farmers from British Columbia, Canada, were recruited through 2 veterinary clinics that offered benchmarking of calf data as part of their services. For approximately 8 wk, blood samples were collected from newborn calves to evaluate serum total protein concentrations as an indicator of the effectiveness of the farmer's colostrum management. These data were analyzed separately for heifer calves (“replacement calves”) and non-replacement calves, including males and beef crossbred females (“surplus calves”). The results of these analyses were benchmarked against other participating herds and presented to dairy farmers (n = 27) by their herd veterinarian (n = 7). Follow-up interviews were conducted separately with the farmers and veterinarians after each meeting to determine their perspectives on the utility of this benchmarking strategy. Therefore, a total of 42 interviews were coded, and realistic evaluation was used to determine common contexts and mechanisms that contributed to the success or failure of the benchmark meeting, with success characterized by farmers' expressed intention to improve their colostrum management practices. Four important contexts were identified that influenced the outcome of the benchmark meetings: (1) farm resources (e.g., facility limitations), (2) the farmer's perception of their calf performance, (3) management strategies, and (4) the farmer's personal values. Depending on these contexts, some farmers intended to improve their calf care practices based on resources the benchmark meeting provided, which included illustrative data and veterinary advice. These resources motivated change through influencing farmer decision-making, which depended on the value they saw in the data as a decision-making tool. The economic or moral interest farmers expressed in their surplus calves also influenced whether farmers intended to implement management changes. Recommendations for future implementation of benchmarking include targeting producers who are motivated to improve and who value the future performance of their calves, those who have engaged calf care personnel, and those who prefer data-driven decision-making. This study supports the important role veterinarians can play in motivating improved calf care practices through providing benchmarking services.

Abstract Whether a compound prolongs cardiac repolarization independent of changes in beat rate is a critical question in drug research and development. Current practice is to resolve this in two steps. First, the QT interval is corrected for the influence of rate and then statistical significance is tested. There is renewed interest in improving the sensitivity of nonclinical corrected QT interval (QTc) assessment with modern studies having greater data density than previously utilized. The current analyses examine the effects of moxifloxacin or vehicle on the QT interval in nonhuman primates (NHPs) using a previously described one‐step method. The primary end point is the statistical sensitivity of the assessment. Publications suggest that for a four animal crossover (4 × 4) in NHPs the minimal detectable difference (MDD) is greater than or equal to 10 ms, whereas in an eight animal crossover the MDD is ~6.5 ms. Using the one‐step method, the MDD for the four animal NHP assessments was 3 ms. In addition, the one‐step model accounted for day‐to‐day differences in the heart rate and QT‐rate slope as well as drug‐induced changes in these parameters. This method provides an increase in the sensitivity and reduces the number of animals necessary for detecting potential QT change and represents “best practice” in nonclinical QTc assessment in safety pharmacology studies.

IntroductionSocio-indexical cues to gender and vocal affect often interact and sometimes lead listeners to make differential judgements of affective intent based on the gender of the speaker. Previous research suggests that rising intonation is a common cue that both women and men produce to communicate lack of confidence, but listeners are more sensitive to this cue when it is produced by women. Some speech perception theories assume that listeners will track conditional statistics of speech and language cues (e.g., frequency of the socio-indexical cues to gender and affect) in their listening and communication environments during speech perception. It is currently less clear if these conditional statistics will impact listener ratings when context varies (e.g., number of talkers).MethodsTo test this, we presented listeners with vocal utterances from one female and one male-pitched voice (single talker condition) or many female/male-pitched voices (4 female voices; 4 female voices pitch-shifted to a male range) to examine how they impacted perceptions of talker confidence.ResultsResults indicated that when one voice was evaluated, listeners defaulted to the gender stereotype that the female voice using rising intonation (a cue to lack of confidence) was less confident than the male-pitched voice (using the same cue). However, in the multi-talker condition, this effect went away and listeners equally rated the confidence of the female and male-pitched voices.DiscussionFindings support dual process theories of information processing, such that listeners may rely on heuristics when speech perception is devoid of context, but when there are no differentiating qualities across talkers (regardless of gender), listeners may be ideal adapters who focus on only the relevant cues.

ABSTRACTSalmonella is the only bacterium able to enter a host cell by the two known mechanisms: trigger and zipper. The trigger mechanism relies on the injection of bacterial effectors into the host cell through the Salmonella type III secretion system 1. In the zipper mechanism, mediated by the invasins Rck and PagN, the bacterium takes advantage of a cellular receptor for invasion. This study describes the transcriptomic reprogramming of the IEC-6 intestinal epithelial cell line to Salmonella Typhimurium strains that invaded cells by a trigger, a zipper, or both mechanisms. Using S. Typhimurium strains invalidated for one or other entry mechanism, we have shown that IEC-6 cells could support both entries. Comparison of the gene expression profiles of exposed cells showed that irrespective of the mechanism used for entry, the transcriptomic reprogramming of the cell was nearly the same. On the other hand, when gene expression was compared between cells unexposed or exposed to the bacterium, the transcriptomic reprogramming of exposed cells was significantly different. It is particularly interesting to note the modulation of expression of numerous target genes of the aryl hydrocarbon receptor showing that this transcription factor was activated by S. Typhimurium infection. Numerous genes associated with the extracellular matrix were also modified. This was confirmed at the protein level by western-blotting showing a dramatic modification in some extracellular matrix proteins. Analysis of a selected set of modulated genes showed that the expression of the majority of these genes was modulated during the intracellular life of S. Typhimurium.

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1468-2427.2009.00919_6.x Byline: Parama Roy (1) Author Affiliation: (1)University of California, Davis

During the last deglaciation, the climate evolves from a cold state at the Last Glacial Maximum (LGM) at 21 ka (thousand years ago) with large ice sheets to the warm Holocene at ∼9 ka with reduced ice sheets. The deglacial ice sheet melt can impact the climate through multiple ways: changes of topography and albedo, bathymetry and coastlines, and freshwater fluxes (FWFs). In the PMIP4 (Paleoclimate Modelling Intercomparison Project – Phase 4) protocol for deglacial simulations, these changes can be accounted for or not depending on the modelling group choices. In addition, two ice sheet reconstructions are available (ICE-6G_C and GLAC-1D). In this study, we evaluate all these effects related to ice sheet changes on the climate using the iLOVECLIM model of intermediate complexity. We show that the two reconstructions yield the same warming to a first order but with a different amplitude (global mean temperature of 3.9 ∘C with ICE-6G_C and 3.8 ∘C with GLAC-1D) and evolution. We obtain a stalling of temperature rise during the Antarctic Cold Reversal (ACR, from ∼14 to ∼12 ka) similar to proxy data only with the GLAC-1D ice sheet reconstruction. Accounting for changes in bathymetry in the simulations results in a cooling due to a larger sea ice extent and higher surface albedo. Finally, freshwater fluxes result in Atlantic meridional overturning circulation (AMOC) drawdown, but the timing in the simulations disagrees with proxy data of ocean circulation changes. This questions the causal link between reconstructed freshwater fluxes from ice sheet melt and recorded AMOC weakening.

The primary objective of this study was to demonstrate the non-inferiority between lidocaine-impregnated ligation bands (LLBs) and control bands (CBs) with respect to the efficacy of castration and tail docking. Secondary objectives were to compare castration and tail-docking success, evaluate local site reactions, and compare average daily gain (ADG) between the treatment groups. A total of 238 male lambs were enrolled and randomly assigned to receive LLBs or CBs on their tail and scrotum. Lambs were weighed, had a health assessment, and the band site was observed on −3, 7, 14, 21, 28, 35, and 42 days after the bands were applied. A linear regression model was built to assess average daily gain, whereas a repeated measures model was used to evaluate body weight differences at each of the measured timepoints. Furthermore, logistic regression models were used to evaluate associations with casting outcomes. Few differences were noted between treatment groups with respect to casting success for the scrotum and tail and ADG over the entire experimental period. Non-inferiority calculations demonstrated no differences in tail docking and scrotal casting success, with casting occurring for the majority of animals by d 21 and d 42 for castration and tail docking, respectively. However, lambs receiving LLBs gained more weight from d −3 to 7 (+0.03 kg/d; 95% CI: 0 to 0.07), which may be an indication of effective pain control during the first week following band application. Overall, the use of an LLB does not affect the time to successful casting of the tail and could improve short-term growth when compared to a control band. Further studies are needed to compare LLBs to multimodal methods of pain relief.

This study aimed to assess the effective tissue concentrations of the current standard of care for pain mitigation in calves during castration (injectable lidocaine) and to assess the ability of a lidocaine-loaded elastration band (LLB) to deliver effective concentrations into the scrotal tissue over time. This study comprised two different trials: (1) effective concentrations of injectable lidocaine in the scrotal tissue; and (2) the in vivo delivery of effective concentrations of lidocaine from LLBs placed on the calf scrotums. Sensation in the scrotal tissue was assessed by electrocutaneous stimulation. Injectable lidocaine allowed for short-term anesthesia for up to 60 min, highlighting the importance of finding additional strategies to mitigate long-term pain. An elastomeric ligation band impregnated with lidocaine could provide a suitable alternative, as it yielded tissue levels of lidocaine that approached EC50 and exceeded EC95 at 2 and 72 h following application, respectively, and remained above those levels for at least 28 days after application. Further studies are warranted to compare the use of LLBs to injectable local anesthetics.

This study presents the application of an interactive downscaling in Europe using iLOVECLIM (a model of intermediate complexity), increasing its atmospheric resolution from 5.56 to 0.25∘ kilometric. A transient simulation using the appropriate climate forcings for the entire Holocene (11.5–0 ka BP) was done for both the standard version of the model and with an interactive downscaling applied. Our results show that simulations from downscaling present spatial variability that agrees better with proxy-based reconstructions and other climate models as compared to the standard model. The downscaling scheme simulates much higher (by at least a factor of 2) precipitation maxima and provides detailed information in mountainous regions. We focus on examples from the Scandes mountains, the Alps, the Scottish Highlands, and the Mediterranean. The higher spatial resolution of the downscaling provides a more realistic overview of the topography and gives local climate information, such as precipitation and temperature gradient, that is important for paleoclimate studies. With downscaling, we simulate similar trends and spatial patterns of the precipitation changes reconstructed by other proxy studies (for example in the Alps) as compared to the standard version. Our downscaling tool is numerically cheap, implying that our model can perform kilometric, multi-millennial simulations and is suitable for future studies.

The spatio-temporal structure of natural climate variability has to be taken into account when unravelling observed climatic changes and simulating future climate change. However, based on the comparison of temperature reconstructions and climate model simulations covering the past 2 millennia, it has been argued that climate models are biased. They would simulate too little temporal temperature variability and too high correlations between temperature time series from different continents. One of the proposed causes is the lack of internal climate variability in climate models on centennial timescales, for instance variability related to the Atlantic meridional overturning circulation (AMOC). We present a perturbed-parameter ensemble with the iLOVECLIM Earth system model containing various levels of AMOC-related internal climate variability to investigate the effect on the spatio-temporal temperature variability structure. The model ensemble shows that enhanced AMOC variability indeed leads to more continental-scale temperature variability, but it also increases the spatio-temporal temperature correlations between different continents. However, combining the iLOVECLIM results with CMIP5 model results and various PAGES-2k temperature field reconstructions, we show overall agreement for the magnitude of continental temperature variability in models and reconstructions, but both the simulated and the reconstructed ranges are large. This is even more true when considering higher-order metrics like inter-continental temperature correlations or temperature variability land–sea contrasts. For such metrics, uncertainties in both model results and temperature reconstructions are so large that they hamper our ability to constrain simulated spatio-temporal structure of centennial temperature variability. As a result, we cannot determine the importance of AMOC variability for the climatic evolution over the past 2 millennia.

Background: This Clinical Practice Guideline (CPG) for the management of obesity in adults in Ireland, adapted from the Canadian CPG, defines obesity as a complex chronic disease characterised by excess or dysfunctional adiposity that impairs health. The guideline reflects substantial advances in the understanding of the determinants, pathophysiology, assessment, and treatment of obesity. Summary: It shifts the focus of obesity management toward improving patient-centred health outcomes, functional outcomes, and social and economic participation, rather than weight loss alone. It gives recommendations for care that are underpinned by evidence-based principles of chronic disease management; validate patients’ lived experiences; move beyond simplistic approaches of “eat less, move more” and address the root drivers of obesity. Key Messages: People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of body weight. Education is needed for all healthcare professionals in Ireland to address the gap in skills, increase knowledge of evidence-based practice, and eliminate bias and stigma in healthcare settings. We call for people living with obesity in Ireland to have access to evidence-informed care, including medical, medical nutrition therapy, physical activity and physical rehabilitation interventions, psychological interventions, pharmacotherapy, and bariatric surgery. This can be best achieved by resourcing and fully implementing the Model of Care for the Management of Adult Overweight and Obesity. To address health inequalities, we also call for the inclusion of obesity in the Structured Chronic Disease Management Programme and for pharmacotherapy reimbursement, to ensure equal access to treatment based on health-need rather than ability to pay.

The desertification and vegetation feedbacks of the “green Sahara” during the last interglacial (LIG) and the Holocene have been investigated by many studies. Yet the abruptness of climate and vegetation changes and their interactions are still under discussion. In this study, we apply an Earth system model of intermediate complexity (iLOVECLIM) in combination with two dynamical vegetation models (VECODE and LPJ-GUESS) to simulate climate–vegetation changes during the Holocene and the LIG to compare the patterns of North African vegetation evolutions and mechanisms of their feedbacks during these two interglacials. Our results confirmed the existence of the green Sahara during the early LIG, which is as an analogue to the green Sahara during the Holocene. During both interglacials, an overall consistent transition from vegetated Sahara to desert is shown in our results, but the amplitudes of these transitions vary. These simulated Sahara vegetation transitions are nearly linearly related to the summer insolation declines at 20∘ N, resulting in faster declines of vegetation cover during the LIG than in the Holocene. The decline of vegetation cover peaks at 25% kyr−1 at around 122 ka, while during the Holocene the steepest vegetation cover decline is 10 % kyr−1 at around 6 ka. Our results suggest net positive vegetation feedbacks to climate during the two interglacials. During the early LIG and Holocene, vegetation strengthens precipitation by a factor of 2 to 3 through the vegetation–albedo feedback when the vegetation cover is greater than 60 %. Vegetation cover decreases with declines of the incoming moisture transport by the atmosphere due to the reduced summer insolation at 20∘ N, weakening the summer monsoon during both interglacials. This desertification is accelerated when the positive vegetation–albedo feedback cannot offset the reduction of precipitation due to a weaker summer monsoon. The impacts of this positive vegetation feedback on precipitation decrease with decreased vegetation cover, during which the impacts of negative vegetation–evaporation feedbacks increase, accelerating the loss of soil moisture and vegetation cover. Overall, the net positive vegetation feedback is strong during the early phases of both interglacials, but the vegetation transition is more abrupt during the LIG than during the Holocene due to the more rapid changes in summer insolation during the LIG. The main difference between the two interglacials is the rate of precipitation change, which is relatively gradual during the Holocene, leading to a more gradual vegetation transition in comparison to the LIG.

The development of novel antimicrobial technologies for the food industry represents an important strategy to improve food safety. Antimicrobial photodynamic disinfection (aPDD) is a method that can inactivate microbes without the use of harsh chemicals. aPDD involves the administration of a non-toxic, light-sensitive substance, known as a photosensitizer, followed by exposure to visible light at a specific wavelength. The objective of this study was to screen the antimicrobial photodynamic efficacy of 32 food-safe pigments tested as candidate photosensitizers (PSs) against pathogenic and food-spoilage bacterial suspensions as well as biofilms grown on relevant food contact surfaces. This screening evaluated the minimum bactericidal concentration (MBC), minimum biofilm eradication concentration (MBEC), and colony forming unit (CFU) reduction against Salmonella enterica, methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas fragi, and Brochothrix thermosphacta. Based on multiple characteristics, including solubility and the ability to reduce the biofilms by at least 3 log10 CFU/sample, 4 out of the 32 PSs were selected for further optimization against S. enterica and MRSA, including sunset yellow, curcumin, riboflavin-5′-phosphate (R-5-P), and erythrosin B. Optimized factors included the PS concentration, irradiance, and time of light exposure. Finally, 0.1% w/v R-5-P, irradiated with a 445 nm LED at 55.5 J/cm2, yielded a “max kill” (upwards of 3 to 7 log10 CFU/sample) against S. enterica and MRSA biofilms grown on metallic food contact surfaces, proving its potential for industrial applications. Overall, the aPDD method shows substantial promise as an alternative to existing disinfection technologies used in the food processing industry.

Obesity is a major driving factor in the incidence, progression, and poor treatment response in gastrointestinal cancers. Herein, we conducted a comprehensive analysis of the impact of obesity and its resulting metabolic perturbations across four gastrointestinal cancer types, namely, oesophageal, gastric, liver, and colorectal cancer. Importantly, not all obese phenotypes are equal. Obese adipose tissue heterogeneity depends on the location, structure, cellular profile (including resident immune cell populations), and dietary fatty acid intake. We discuss whether adipose heterogeneity impacts the tumorigenic environment. Dietary fat quality, in particular saturated fatty acids, promotes a hypertrophic, pro-inflammatory adipose profile, in contrast to monounsaturated fatty acids, resulting in a hyperplastic, less inflammatory adipose phenotype. The purpose of this review is to examine the impact of obesity, including dietary fat quality, on adipose tissue biology and oncogenesis, specifically focusing on lipid metabolism and inflammatory mechanisms. This is achieved with a particular focus on gastrointestinal cancers as exemplar models of obesity-associated cancers.

The objectives of this study were to assess the pharmacokinetics and pharmacodynamics of the current standard-of-care for pain mitigation in lambs during castration and tail docking (injectable lidocaine) and assess the ability of Lidocaine-Loaded Bands (LLBs) to deliver therapeutic concentrations into the contacted tissues over time. The study was comprised of four different trials: (1) investigation of in vitro release of lidocaine from LLBs; (2) pharmacokinetics and pharmacodynamics of injectable lidocaine in scrotal and tail tissue; (3) pharmacokinetics and pharmacodynamics of in vivo delivery of lidocaine with LLBs placed on the tail and scrotum of lambs; and (4) a “proof-of-concept” study comparing the sensation of control- versus LLB-banded tail tissue over time. The use of injectable lidocaine provides effective short-term anesthesia for 120 to 180 min following the injection; however, additional strategies are needed to manage long-term pain. The use of an LLB could provide an alternative where tissue lidocaine concentrations meet or exceed the EC50 for at least 21–28 days and, based on electrostimulation data, provides local anesthesia for at least 3 days when compared to a control band. Further studies are needed to compare the use of an injectable local anesthetic to the LLBs.

Abstract Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling may constitute a novel mechanism promoting T2D-associated HFpEF such that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.

Abstract Background Nowadays, more people are treating dogs as family members. This reflects their increased attention towards their nutrition, with renewed interest for non-conventional diets such as Biologically Appropriate Raw Food/ Bones and Raw Food in United States (BARF) or homemade. In previous studies, owners feeding their dog non-conventional diets reported lower levels of trust in veterinary advice. The aim of the study was to identify differences in lifestyle between owners feeding dogs non-conventional diets and those feeding conventional diets (i.e., dry/wet pet food) to give further insight for improving communication between veterinarians and owners. Results A total of 426 surveys were usable. Fifteen percent of the participants lived in the metropole of Paris and had more than one dog (mean 1.72 dogs). Thirty-eight percent of the survey respondents stated that their dogs were fed exclusively with non-conventional diets, while 55% declared using conventional diets alone (not considering treats). The study canine population was for the most part neutered (63%) and purebred (68%). Amongst owners feeding conventional diets exclusively, 47% determined how much food to feed by consulting the feeding guidelines on the packaging, and only 28% said that the amount of food was prescribed by their veterinarian or veterinary nurse. Out of the participants feeding non-conventional diets, 65% declared that the information for formulating the recipes was gathered on the internet or in non-veterinary books. When compared with owners feeding exclusively conventional diets, those feeding non-conventional diets were living more frequently outside the metropole of Paris, had fewer children (0.23 ± 0.57 vs 0.37 ± 0.78; p = 0.03) and had more frequently other animals. They also dewormed less often their pets, walked their dog more each day (91 vs 78%; p

Abstract Background Precision nutrition is highly topical. However, no studies have explored the interindividual variability in response to nutrition interventions for sarcopenia. The purpose of this study was to determine the magnitude of interindividual variability in response to two nutrition supplementation interventions for sarcopenia and metabolic health, after accounting for sources of variability not attributable to supplementation. Methods A 24 week, randomized, double‐blind, placebo‐controlled trial tested the impact of leucine‐enriched protein (LEU‐PRO), LEU‐PRO plus long‐chain n‐3 PUFA (LEU‐PRO+n‐3) or control (CON) supplementation in older adults (n = 83, 71 ± 6 years) at risk of sarcopenia. To estimate the true interindividual variability in response to supplementation (free of the variability due to measurement error and within‐subject variation), the standard deviation of individual responses (SDR) was computed and compared with the minimally clinically important difference (MCID) for appendicular lean mass (ALM), leg strength, timed up‐and‐go (TUG), and serum triacylglycerol (TG) concentration. Clinically meaningful interindividual variability in response to supplementation was deemed to be present when the SDR positively exceeded the MCID. The probability that individual responses were clinically meaningful, and the phenotypic, dietary, and behavioural determinants of response to supplementation were examined. Results The SDR was below the MCID for ALM (LEU‐PRO: −0.12 kg [90% CI: −0.38, 0.35], LEU‐PRO+n‐3: −0.32 kg [−0.45, 0.03], MCID: 0.21 kg), TUG (LEU‐PRO: 0.58 s [0.18, 0.80], LEU‐PRO+n‐3: 0.73 s [0.41, 0.95], MCID: 0.9 s) and TG (LEU‐PRO: −0.38 mmol/L [−0.80, 0.25], LEU‐PRO+n‐3: −0.44 mmol/L [−0.63, 0.06], MCID: 0.1 mmol/L), indicating no meaningful interindividual variability in response to either supplement. The SDR exceeded the MCID (19 Nm) for strength in response to LEU‐PRO (25 Nm [−29, 45]) and LEU‐PRO+n‐3 (23 Nm [−29, 43]) supplementation but the effect was uncertain, evidenced by wide confidence intervals. In the next stage of analysis, similar proportions of participant responses were identified as very likely, likely, possibly, unlikely, and very unlikely to represent clinically meaningful improvements across the LEU‐PRO, LEU‐PRO+n‐3, and CON groups (P > 0.05). Baseline LC n‐3 PUFA status, habitual protein intake, and numerous other phenotypic and behavioural factors were not determinants of response to LEU‐PRO or LEU‐PRO+n‐3 supplementation. Conclusions Applying a novel, robust methodological approach to precision nutrition, we show that there was minimal interindividual variability in changes in ALM, muscle function, and TG in response to LEU‐PRO and LEU‐PRO+n‐3 supplementation in older adults at risk of sarcopenia.

Milk-derived peptides are known to confer anti-inflammatory effects. We hypothesised that milk-derived cell-penetrating peptides might modulate inflammation in useful ways. Using computational techniques, we identified and synthesised peptides from the milk protein Alpha-S1-casein that were predicted to be cell-penetrating using a machine learning predictor. We modified the interpretation of the prediction results to consider the effects of histidine. Peptides were then selected for testing to determine their cell penetrability and anti-inflammatory effects using HeLa cells and J774.2 mouse macrophage cell lines. The selected peptides all showed cell penetrating behaviour, as judged using confocal microscopy of fluorescently labelled peptides. None of the peptides had an effect on either the NF-κB transcription factor or TNFα and IL-1β secretion. Thus, the identified milk-derived sequences have the ability to be internalised into the cell without affecting cell homeostatic mechanisms such as NF-κB activation. These peptides are worthy of further investigation for other potential bioactivities or as a naturally derived carrier to promote the cellular internalisation of other active peptides.

Abstract Numerous studies have demonstrated the key role of the Salmonella Pathogenicity Island 1-encoded type III secretion system (T3SS1) apparatus as well as its associated effectors in the invasion and intracellular fate of Salmonella in the host cell. Several T3SS1 effectors work together to control cytoskeleton networks and induce massive membrane ruffles, allowing pathogen internalization. Salmonella resides in a vacuole whose maturation requires that the activity of T3SS1 subverts early stages of cell signaling. Recently, we identified five cell lines in which Salmonella Typhimurium enters without using its three known invasion factors: T3SS1, Rck and PagN. The present study investigated the intracellular fate of Salmonella Typhimurium in one of these models, the murine hepatocyte cell line AML12. We demonstrated that both wild-type Salmonella and T3SS1-invalidated Salmonella followed a common pathway leading to the formation of a Salmonella containing vacuole (SCV) without classical recruitment of Rho-GTPases. Maturation of the SCV continued through an acidified phase that led to Salmonella multiplication as well as the formation of a tubular network resembling Salmonella induced filaments (SIF). The fact that in the murine AML12 hepatocyte, the T3SS1 mutant induced an intracellular fate resembling to the wild-type strain highlights the fact that Salmonella Typhimurium invasion and intracellular survival can be completely independent of T3SS1.

The last deglaciation offers an unique opportunity to understand the climate–ice-sheet interactions in a global warming context. In this paper, to tackle this question, we use an Earth system model of intermediate complexity coupled to an ice sheet model covering the Northern Hemisphere to simulate the last deglaciation and the Holocene (26–0 ka). We use a synchronous coupling every year between the ice sheet and the rest of the climate system and we ensure a closed water cycle considering the release of freshwater flux to the ocean due to ice sheet melting. Our reference experiment displays a gradual warming in response to the forcings, with no abrupt changes. In this case, while the amplitude of the freshwater flux to the ocean induced by ice sheet retreat is realistic, it is sufficient to shut down the Atlantic meridional overturning circulation from which the model does not recover within the time period simulated. However, with reduced freshwater flux we are nonetheless able to obtain different oceanic circulation evolutions, including some abrupt transitions between shut-down and active circulation states in the course of the deglaciation. The inclusion of a parameterisation for the sinking of brines around Antarctica also produces an abrupt recovery of the Atlantic meridional overturning circulation, absent in the reference experiment. The fast oceanic circulation recoveries lead to abrupt warming phases in Greenland. Our simulated ice sheet geometry evolution is in overall good agreement with available global reconstructions, even though the abrupt sea level rise at 14.6 ka is underestimated, possibly because the climate model underestimates the millennial-scale temperature variability. In the course of the deglaciation, large-scale grounding line instabilities are simulated both for the Eurasian and North American ice sheets. The first instability occurs in the Barents–Kara seas for the Eurasian ice sheet at 14.5 ka. A second grounding line instability occurs ca. 12 ka in the proglacial lake that formed at the southern margin of the North American ice sheet. With additional asynchronously coupled experiments, we assess the sensitivity of our results to different ice sheet model choices related to surface and sub-shelf mass balance, ice deformation and grounding line representation. While the ice sheet evolutions differ within this ensemble, the global climate trajectory is only weakly affected by these choices. In our experiments, only the abrupt shifts in the oceanic circulation due to freshwater fluxes are able to produce some millennial-scale variability since no self-generating abrupt transitions are simulated without these fluxes.

Abstract Background Rapid spread of SARS-CoV-2 has led to a global pandemic, resulting in the need for rapid assays to allow diagnosis and prevention of transmission. Reverse transcription-polymerase chain reaction (RT-PCR) provides a gold standard assay for SARS-CoV-2 RNA, but instrument costs are high and supply chains are potentially fragile, motivating interest in additional assay methods. Reverse transcription and loop-mediated isothermal amplification (RT-LAMP) provides an alternative that uses orthogonal and often less expensive reagents without the need for thermocyclers. The presence of SARS-CoV-2 RNA is typically detected using dyes to report bulk amplification of DNA; however, a common artifact is nonspecific DNA amplification, which complicates detection. Results Here we describe the design and testing of molecular beacons, which allow sequence-specific detection of SARS-CoV-2 genomes with improved discrimination in simple reaction mixtures. To optimize beacons for RT-LAMP, multiple locked nucleic acid monomers were incorporated to elevate melting temperatures. We also show how beacons with different fluorescent labels can allow convenient multiplex detection of several amplicons in “single pot” reactions, including incorporation of a human RNA LAMP-BEAC assay to confirm sample integrity. Comparison of LAMP-BEAC and RT-qPCR on clinical saliva samples showed good concordance between assays. To facilitate implementation, we developed custom polymerases for LAMP-BEAC and inexpensive purification procedures, which also facilitates increasing sensitivity by increasing reaction volumes. Conclusions LAMP-BEAC thus provides an affordable and simple SARS-CoV-2 RNA assay suitable for population screening; implementation of the assay has allowed robust screening of thousands of saliva samples per week.

Changes in water mass distribution are considered to be a significant contributor to the atmospheric CO2 concentration drop to around 186 ppm recorded during the Last Glacial Maximum (LGM). Yet simulating a glacial Atlantic Meridional Overturning Circulation (AMOC) in agreement with paleotracer data remains a challenge, with most models from previous Paleoclimate Modelling Intercomparison Project (PMIP) phases showing a tendency to simulate a strong and deep North Atlantic Deep Water (NADW) instead of the shoaling inferred from proxy records of water mass distribution. Conversely, the simulated Antarctic Bottom Water (AABW) is often reduced compared to its pre-industrial volume, and the Atlantic Ocean stratification is underestimated with respect to paleoproxy data. Inadequate representation of surface conditions, driving deep convection around Antarctica, may explain inaccurately simulated bottom water properties in the Southern Ocean. We investigate here the impact of a range of surface conditions in the Southern Ocean in the iLOVECLIM model using nine simulations obtained with different LGM boundary conditions associated with the ice sheet reconstruction (e.g., changes of elevation, bathymetry, and land–sea mask) and/or modeling choices related to sea-ice export, formation of salty brines, and freshwater input. Based on model–data comparison of sea-surface temperatures and sea ice, we find that only simulations with a cold Southern Ocean and a quite extensive sea-ice cover show an improved agreement with proxy records of sea ice, despite systematic model biases in the seasonal and regional patterns. We then show that the only simulation which does not display a much deeper NADW is obtained by parameterizing the sinking of brines along Antarctica, a modeling choice reducing the open-ocean convection in the Southern Ocean. These results highlight the importance of the representation of convection processes, which have a large impact on the water mass properties, while the choice of boundary conditions appears secondary for the model resolution and variables considered in this study.

In 2016-17, shellfish harvesting closed for the first time in Narragansett Bay, Rhode Island, USA, from domoic acid (DA), a neurotoxin produced by diatoms of the Pseudo-nitzschia genus. Pseudo-nitzschia have occurred frequently for over 60 years in Narragansett Bay’s Long-Term Plankton Time Series (NBPTS), therefore it is surprising that the first closure only recently occurred. Pseudo-nitzschia species are known to vary in their toxin production, thus species identification is critical for understanding the underlying ecological causes of these harmful algal blooms (HABs). DNA in plankton biomass can be preserved for many years, so molecular barcoding of archived samples is useful for delineation of taxa over time. This study used amplification of the Pseudo-nitzschia-specific 18S-5.8S rDNA internal transcribed spacer region 1 (ITS1) in plankton samples and high throughput sequencing to characterize Pseudo-nitzschia species composition over a decade in Narragansett Bay, including eight years before the 2016-17 closures and two years following. This metabarcoding method can discriminate nearly all known Pseudo-nitzschia species. Several species recur as year-round residents in Narragansett Bay (P. pungens var. pungens, P. americana, P. multiseries, and P. calliantha). Various other species increased in frequency after 2015, and some appeared for the first time during the closure period. Notably, P. australis, a species prevalent in US West Coast HABs and known for high DA production, was not observed in Narragansett Bay until the 2017 closure but has been present in several years after the closures. Annual differences in Pseudo-nitzschia composition were correlated with physical and chemical conditions, predominantly water temperature. The long-term composition trends of Pseudo-nitzschia in Narragansett Bay serve as a baseline for identifying the introduction of new species, understanding shifting assemblages that contributed to the 2016-17 closures, and monitoring species that may be cause for future concern.

Predictions begin with an extrapolation of the properties of their underlying representations to forecast a future state not presently in evidence. For numerical predictions, sets of numbers are summarized and the result forms the basis of and constrains numerical predictions. One open question is how the accuracy of underlying representations influences predictions, particularly numerical predictions. It is possible that inaccuracies in individual number representations are randomly distributed and averaged over during summarization (e.g., wisdom of crowds). It is also possible that inaccuracies are not random and lead to errors in predictions. We investigated this question by measuring the accuracy of individual number representations of 279 children ages 8–12 years, using a 0–1,000 number line, and numerical predictions, measured using a home run derby task. Consistent with prior research, our results from mixed random effects models evaluating percent absolute error (PAE; prediction error) demonstrated that third graders’ representations of individual numbers were less accurate, characterized by overestimation errors, and were associated with overpredictions (i.e., predictions above the set mean). Older children had more accurate individual number representations and a slight tendency to underpredict (i.e., predictions below the set mean). The results suggest that large, systematic inaccuracies appear to skew predictions while small, random errors appear to be averaged over during summarization. These findings add to our understanding of summarization and its role in numerical predictions.