Search

Calorie restriction is associated with enhanced intestinal regeneration after irradiation, but the requirement of autophagy for this process is not known. Our data support the premise that intestinal epithelial autophagy is required for the regenerative benefit of calorie restriction. We also report that luminal levels of primary bile acid glycocholic acid are modulated by epithelial cell autophagy during calorie restriction with direct effects on epithelial stem cell function.

The road to employment is not often easy for individuals with intellectual and developmental disabilities (IDD). Families know firsthand the complexities and challenges of obtaining employment for their members with extensive support needs. The purpose of this qualitative study was to identify the critical barriers they encounter in this important pursuit. We interviewed 60 parents (and other caregivers) whose family members with intellectual disability and/or autism had sought and/or obtained paid work. The difficulties they described were extensive and multifaceted. Specifically, participants identified 64 different barriers attributed to six primary areas: individuals, families, schools, service systems, workplaces, and communities. Their unique insights amplify the need for new approaches for promoting integrated employment. We offer recommendations for research and practice aimed at better understanding and ameliorating barriers to meaningful work for adults with IDD.

Linker for activation of T cells (LAT) is a central adaptor protein in proximal T cell activation. A key element of its adaptor function is the efficiency with which LAT interacts with its binding partners. Such efficiency is controlled by the local concentration of LAT as well as the vicinity to up- and downstream interaction partners, i.e. LAT localization. Several factors control LAT localization. LAT is a palmitoylated transmembrane protein and traffics between vesicular compartments and the plasma membrane. Membrane heterogeneity and protein-protein interactions can drive LAT clustering, at scales from a few to hundreds if not more molecules. LAT vesicular trafficking through the small, crowded cytoplasm of a T cell and the commonly nm scale clusters are difficult to access experimentally, in particular in the physiological interaction of T cells binding to antigen presenting cells (APCs) with a highly undulating interface. Only in recent years have technological advances begun to provide better access. Based on such advances, three elements of LAT localization are discussed in conjunction: vesicular trafficking as it regulates LAT transport towards, insertion into, and removal from the plasma membrane; LAT clustering as it increases local LAT concentrations; LAT-anchored supramolecular signaling complexes as they embed LAT in a dense network of interaction partners. Consistent with the important role of LAT localization for its function, each of these processes regulates LAT activity and the efficiency of T cell activation.

International audience; Ice losses from the Greenland and Antarctic ice sheets have accelerated since the 1990s, accounting for a significant increase in the global mean sea level. Here, we present a new 29-year record of ice sheet mass balance from 1992 to 2020 from the Ice Sheet Mass Balance Inter-comparison Exercise (IMBIE). We compare and combine 50 independent estimates of ice sheet mass balance derived from satellite observations of temporal changes in ice sheet flow, in ice sheet volume, and in Earth's gravity field. Between 1992 and 2020, the ice sheets contributed 21.0±1.9 mm to global mean sea level, with the rate of mass loss rising from 105 Gt yr−1 between 1992 and 1996 to 372 Gt yr−1 between 2016 and 2020. In Greenland, the rate of mass loss is 169±9 Gt yr−1 between 1992 and 2020, but there are large inter-annual variations in mass balance, with mass loss ranging from 86 Gt yr−1 in 2017 to 444 Gt yr−1 in 2019 due to large variability in surface mass balance. In Antarctica, ice losses continue to be dominated by mass loss from West Antarctica (82±9 Gt yr−1) and, to a lesser extent, from the Antarctic Peninsula (13±5 Gt yr−1). East Antarctica remains close to a state of balance, with a small gain of 3±15 Gt yr−1, but is the most uncertain component of Antarctica's mass balance. The dataset is publicly available at https://doi.org/10.5285/77B64C55-7166-4A06-9DEF-2E400398E452 (IMBIE Team, 2021).

Strong immune responses in primary colorectal cancer correspond with better patient survival following surgery compared with tumors with predominantly stromal microenvironments. However, biomarkers to identify patients with colorectal cancer liver metastases (CRLM) with good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary colorectal cancer and CRLM and to interrogate the underlying functional biology that drives disease progression. Samples from patients undergoing synchronous resection of primary colorectal cancer and CRLM were evaluated in detail through histological assessment, panel genomic and bulk transcriptomic assessment, IHC, and GeoMx spatial transcriptomics (ST) analysis. High immune infiltration of metastases was associated with improved cancer-specific survival. Bulk transcriptomic analysis was confounded by stromal content, but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for type II IFN signaling and MHC-class II antigen presentation. In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T cells and neutrophils with enrichment of Notch and TGFβ signaling pathways at the metastatic tumor center. In summary, histological assessment can stratify outcomes in patients undergoing synchronous resection of CRLM, suggesting that it has potential as a prognostic biomarker. Furthermore, ST analysis has revealed significant intratumoral and interlesional heterogeneity and identified the underlying transcriptomic programs driving each phenotype. Significance: Spatial transcriptomics uncovers heterogeneity between patients, between matched lesions in the same patient, and within individual lesions and identifies drivers of metastatic progression in colorectal cancer with reactive and suppressed immune microenvironments.

Alzheimer’s disease (AD) is the most common form of dementia. Currently, there is no effective treatment for AD, as its etiology remains poorly understood. Mounting evidence suggests that the accumulation and aggregation of amyloid-β peptides (Aβ), which constitute amyloid plaques in the brain, is critical for initiating and accelerating AD pathogenesis. Considerable efforts have been dedicated to shedding light on the molecular basis and fundamental origins of the impaired Aβ metabolism in AD. Heparan sulfate (HS), a linear polysaccharide of the glycosaminoglycan family, co-deposits with Aβ in plaques in the AD brain, directly binds and accelerates Aβ aggregation, and mediates Aβ internalization and cytotoxicity. Mouse model studies demonstrate that HS regulates Aβ clearance and neuroinflammation in vivo. Previous reviews have extensively explored these discoveries. Here, this review focuses on the recent advancements in understanding abnormal HS expression in the AD brain, the structural aspects of HS-Aβ interaction, and the molecules involved in modulating Aβ metabolism through HS interaction. Furthermore, this review presents a perspective on the potential effects of abnormal HS expression on Aβ metabolism and AD pathogenesis. In addition, the review highlights the importance of conducting further research to differentiate the spatiotemporal components of HS structure and function in the brain and AD pathogenesis.

Chronic subdural hematoma (cSDH) can be treated with conventional surgery or middle meningeal artery embolization (MMAE). The cost profiles of open surgery versus MMAE have never been studied.Comparing costs of surgical and MMAE treatment of cSDH.Patients treated with open surgery (2006-2019) and MMAE (2018-2020) were identified from the institutional database. Propensity score-matching analysis was used to assemble a balanced group of subjects. Detailed hospitalization costs in each group were collected and compared.A total of 341 conventionally treated and 52 MMAE cases were identified. After propensity score matching, 33 patients in each group, in total 66 patients were included for analysis. Direct procedural cost was significantly higher in MMAE group compared with open surgery group ($38255±$11859 vs $11206±$7888; P0.001). Medication cost was also higher in the MMAE group ($6888±$6525 vs $4291±$3547; P=0.048). No significant difference was found in costs for ICU care, pharmacy, therapy, labs and emergency unit. Imaging costs and other miscellaneous costs (e.g. wound care, pre-op and PACU) were higher in the open surgery group (P0.05). Total hospitalization cost was not significantly different between the two groups ($60598±$61315 vs $71569±$37813 for open surgery and MMAE respectively, P=0.385). No significant differences in number of follow ups or total costs for follow up were found (P0.05).Open surgery and MMAE offer an overall equivalent cost-profile for cSDH treatment when matching for potential cost confounders. Direct procedural costs are higher in MMAE; however, total hospitalization costs and follow up costs are not significantly different.

Increasing employment outcomes for individuals with intellectual and developmental disabilities (IDD) remains an enduring emphasis of research, policy, and practice. Parents are often primary partners in the pursuit of meaningful work for their family members with IDD. This qualitative study examined the views of 55 parents regarding the importance of this pursuit and the features of employment that matter most to them. Participants discussed a range of reasons they valued employment for their family members with IDD, including factors that extended beyond a paycheck. Likewise, they described an array of features that they considered to be important to their family member thriving in the workplace (e.g., inclusivity, match with interests, opportunities for growth). We offer recommendations for promoting integrated employment among families and conceptualizing employment outcomes within future research.

Quantifying synchrony in species population fluctuations and determining its driving factors can inform multiple aspects of ecological and epidemiological research and policy decisions. We examined seasonal mosquito and arbovirus surveillance data collected in Connecticut, United States from 2001 to 2020 to quantify spatial relationships in 19 mosquito species and 7 arboviruses timeseries accounting for environmental factors such as climate and land cover characteristics. We determined that mosquito collections, on average, were significantly correlated up to 10 km though highly variable among the examined species. Few arboviruses displayed any synchrony and significant maximum correlated distances never exceeded 5 km. After accounting for distance, mixed effects models showed that mosquito or arbovirus identity explained more variance in synchrony estimates than climate or land cover factors. Correlated mosquito collections up to 10–20 km suggest that mosquito control operations for nuisance and disease vectors alike must expand treatment zones to regional scales for operations to have population-level impacts. Species identity matters as well, and some mosquito species will require much larger treatment zones than others. The much shorter correlated detection distances for arboviruses reinforce the notion that focal-level processes drive vector-borne pathogen transmission dynamics and risk of spillover into human populations.

Little is known about the extent to which species use homologous regulatory architectures to achieve phenotypic convergence. By characterizing chromatin accessibility and gene expression in developing wing tissues, we compared the regulatory architecture of convergence between a pair of mimetic butterfly species. Although a handful of color pattern genes are known to be involved in their convergence, our data suggest that different mutational paths underlie the integration of these genes into wing pattern development. This is supported by a large fraction of accessible chromatin being exclusive to each species, including the de novo lineage-specific evolution of a modular optix enhancer. These findings may be explained by a high level of developmental drift and evolutionary contingency that occurs during the independent evolution of mimicry.

Background: Newborn screening (NBS) identifies infants with severe, early-onset diseases, enabling early diagnosis and treatment. In Canada, decisions regarding disease inclusion in NBS programs occur at the provincial level, which leads to variability in patient care. We aimed to determine whether important differences exist in NBS programs across provinces and territories. Given that spinal muscular atrophy (SMA) is the most recent disease added to NBS programs, we hypothesized that its inclusion would show interprovincial variability and be more likely in provinces already screening for a greater number of diseases. Methods: We conducted a cross-sectional survey of all NBS labs in Canada to understand: 1) what conditions were included in their program; 2) what genetic-based testing was performed and; 3) if SMA was included. Results: All NBS programs (N = 8) responded to this survey by June 2022. There was a 2.5-fold difference in the number of conditions screened (N = 14 vs N = 36) and a 9-fold difference in the number of conditions screened by gene-based testing. Only nine conditions were common to all provincial NBS programs. NBS for SMA was performed in four provinces at the time of our survey, with BC recently becoming the fifth province to add SMA to their NBS on October 1, 2022. Currently, 72% of Canadian newborns are screened for SMA at birth. Conclusion: Although healthcare in Canada is universal, its decentralization gives rise to regional differences in NBS programs which creates inequity in the treatment, care, and potential outcomes of affected children across provincial jurisdictions.

Pathologies that are causative for neurodegenerative disease (ND) are also frequently present in unimpaired, older individuals. In this retrospective study of 1647 autopsied individuals, we report the incidence of 10 pathologies across ND and normal ageing in attempt to clarify which pathological combinations are disease-associated and which are ageing-related. Eight clinically defined groups were examined including unimpaired individuals and those with clinical Alzheimer’s disease, mixed dementia, amyotrophic lateral sclerosis, frontotemporal degeneration, multiple system atrophy, probable Lewy body disease or probable tauopathies. Up to seven pathologies were observed concurrently resulting in a heterogeneous mix of 161 pathological combinations. The presence of multiple additive pathologies associated with older age, increasing disease duration, APOE e4 allele and presence of dementia across the clinical groups. Fifteen to 67 combinations occurred in each group, with the unimpaired group defined by 35 combinations. Most combinations occurred at a

Vascular insulin resistance, a major characteristic of obesity and type 2 diabetes (T2D), manifests with blunting of insulin-induced vasodilation. Although there is evidence that females are more whole body insulin sensitive than males in the healthy state, whether sex differences exist in vascular insulin sensitivity is unclear. Also uncertain is whether weight loss can reestablish vascular insulin sensitivity in T2D. The purpose of this investigation was to 1) establish if sex differences in vasodilatory responses to insulin exist in absence of disease, 2) determine whether female sex affords protection against the development of vascular insulin resistance with long-term overnutrition and obesity, and 3) examine if diet-induced weight loss can restore vascular insulin sensitivity in men and women with T2D. First, we show in healthy mice and humans that sex does not influence insulin-induced femoral artery dilation and insulin-stimulated leg blood flow, respectively. Second, we provide evidence that female mice are protected against impairments in insulin-induced dilation caused by overnutrition-induced obesity. Third, we show that men and women exhibit comparable levels of vascular insulin resistance when T2D develops but that diet-induced weight loss is effective at improving insulin-stimulated leg blood flow, particularly in women. Finally, we provide indirect evidence that these beneficial effects of weight loss may be mediated by a reduction in endothelin-1. In aggregate, the present data indicate that female sex confers protection against obesity-induced vascular insulin resistance and provide supportive evidence that, in women with T2D, vascular insulin resistance can be remediated with diet-induced weight loss.

Soil water repellency inhibits seed germination and emergence, whereas soil surfactants improve the wettability of water-repellent or hydrophobic soils. An improvement in seed germination and emergence can occur when a soil surfactant is applied directly to the seed and/or to the water repellent soil at sowing. Therefore, a coating process was developed to utilize seed as a soil surfactant carrier. Greenhouse experiments were conducted to evaluate establishment of perennial ryegrass (Lolium perenne L.) seed coated with a soil surfactant (SCS = surfactant- coated seed), as compared to uncoated seed (CHK). Both SCS and CHK were sown in two hydrophilic substrates (100% sand [WSAND], 90:10% v/v sand:peat [WSP], and in two severely hydrophobic sands (100% hydrophobic stearic acid-treated sand [HSS], and hydrophobic 90:10% v/v sand:peat [HSP]). Due to the weight of the coating, SCS was sown at half the amount as compared to CHK; however, final turfgrass establishment in all rootzones with SCS was similar or better than CHK. In WSAND, WSP, and HSP, the volumetric water content was consistently higher in rootzones of SCS treatments versus CHK. SCS represents an opportunity to improve stand establishment and rootzone soil-water dynamics in challenging environmental conditions such as limited precipitation.Species used in this study: Perennial ryegrass, Lolium perenne L.

The electronic drive requirements for producing nanosecond optical pulses from blue light emitting diodes are considered. Simple circuits are used to generate the fast current pulses necessary to switch on and assist with the turn off of these devices. The intensity of the emitted radiation can be controlled by the magnitude of the drive current. Optical pulses in the nanosecond range are suitable for, but not limited to, the calibration of scintillation counters. The circuits described can be either free running or externally triggered. Typically, the optical pulse full width half maximum (FWHM) is below 1 ns. The presented techniques are not limited to blue LEDs and should be applicable to devices of longer wavelengths.

Background: E-learning has become commonplace in medical education. Incorporation of multimedia, clinical cases, and interactive elements has increased its attractiveness over textbooks. Although there has been an expansion of e-learning in medicine, the feasibility of e-learning in pediatric neurology is unclear. This study evaluates knowledge acquisition and satisfaction using pediatric neurology e-learning compared to conventional learning. Methods: Residents of Canadian pediatrics, neurology, and pediatric neurology programs and medical students from Queens University, Western University, and the University of Ottawa were invited to participate. Learners were randomly assigned two review papers and two ebrain modules in a four-topic crossover design. Participants completed pre-tests, experience surveys, and post-tests. We calculated the median change in score from pre-test to post-test and constructed a mixed-effects model to determine the effect of variables on post-test scores. Results: In total, 119 individuals participated (53 medical students; 66 residents). Ebrain had a larger positive change than review papers in post-test score from pre-test score for the pediatric stroke learning topic but a smaller positive change for Duchenne muscular dystrophy, childhood absence epilepsy, and acute disseminated encephalomyelitis. Learning topics showed statistical relationship to post-test scores (p = 0.04). Depending on topic, 57–92% (N = 59–66) of respondents favored e-learning over review article learning. Conclusions: Ebrain users scored higher on post-tests than review paper users. However, the effect is small and it is unclear if it is educationally meaningful. Although the difference in scores may not be substantially different, most learners preferred e-learning. Future projects should focus on improving the quality and efficacy of e-learning modules.

We perform simulations of star cluster formation to investigate the morphological evolution of embedded star clusters in the earliest stages of their evolution. We conduct our simulations with Torch, which uses the Amuse framework to couple state-of-the-art stellar dynamics to star formation, radiation, stellar winds, and hydrodynamics in Flash. We simulate a suite of 104 M⊙ clouds at 0.0683 pc resolution for ∼2 Myr after the onset of star formation, with virial parameters α = 0.8, 2.0, 4.0 and different random samplings of the stellar initial mass function and prescriptions for primordial binaries. Our simulations result in a population of embedded clusters with realistic morphologies (sizes, densities, and ellipticities) that reproduce the known trend of clouds with higher initial α having lower star formation efficiencies. Our key results are as follows: (1) Cluster mass growth is not monotonic, and clusters can lose up to half of their mass while they are embedded. (2) Cluster morphology is not correlated with cluster mass and changes over ∼0.01 Myr time-scales. (3) The morphology of an embedded cluster is not indicative of its long-term evolution but only of its recent history: radius and ellipticity increase sharply when a cluster accretes stars. (4) The dynamical evolution of very young embedded clusters with masses ≲1000 M⊙ is dominated by the overall gravitational potential of the star-forming region rather than by internal dynamical processes such as two- or few-body relaxation.

In this paper, we present the view that an ontological shift to complexity thinking will be significant in the future of physical education (PE). Complexity thinking not only moves PE beyond long dominant modernist approaches but also offers the opportunity to integrate many of the postmodern perspectives that currently seek to frame PE. Four interconnected complexity commonalities, becoming, lived time, self-organisation and boundaries, are presented in an overarching frame to guide future PE developments in ways that are coherent, connected and emergent. PE is subsequently viewed as a complex phenomenon that is always in a non-linear, messy and never-ending process of becoming. Students, teachers and other stakeholders are also complex as their past, present and future experiences constantly merge in a lived time unity to create lifelong and life-wide PE journeys that are both personalised and holistic. Central to these personalised journeys is each stakeholder’s ability to self-organise and influence the trajectory of their pathways. Self-organisation, however, is not a relativist ‘anything goes’ phenomenon but a process that takes place within a multiplicity of boundaries. While boundaries may traditionally be viewed as divisive features, complexity thinking recognises that many boundaries are flexible and enable the creation of ‘boundary spaces’ in which ‘rich’ discussions can take place to develop more coherent, connected and emergent forms of PE. Transdisciplinary Inquiry (TDI) and Ecologically Informed Practice (EIP) are presented as perspectives that can help teachers, and others, create the ‘boundary spaces’ in which ways to plan and introduce complexity-informed forms of PE can be explored. The paper concludes by proposing that the challenge for PE in the future will be for practitioners to develop the adaptability, openness, confidence and self-organising skills that will be needed to make the most effective use of the ‘rich interactions’ that these ‘boundary spaces’ offer.

Contraceptives are vital healthcare for women and people with wombs. Recently, there has been a rise in the use of ‘digital contraceptives’, a type of ‘femtech’ software available for download on app stores which require data input in order to make predictions about users’ fertility. Digital contraceptives, when marketed as such, fall within the definition of a ‘medical device’ and under the authority of the Medical Devices Regulations 2002 are a ‘medium-risk’ device. However, not all femtech which may be used as contraception is captured by this framework. In this article it is argued that the regulatory category into which digital contraceptives have been placed by the medical devices regime is (a) unduly limited in scope, (b) insufficiently stringent to protect users, considering the grave and life-changing effects this technology can have if things go wrong, and (c) ill-conceived as a regulatory response to a technology that affects large sections of the population. It is suggested here that the broader context in which software as a contraceptive sits (i.e. within the general contraceptive market) is key to understanding the regulatory blindness that is occurring when it comes to digital contraceptives and some other forms of fertility-related femtech. As such, software which can be used as a contraceptive is in fact ‘high risk’ and should be reclassified as such.

In the eastern North Pacific Ocean, common minke whales (Balaenoptera acutorostrata) are widespread but encountered relatively infrequently. It is generally believed that they make annual migrations between higher latitudes in the summer and lower latitudes in the winter; however, in some temperate coastal regions where common minke whales have been sighted year-round they have been referred to as resident. To determine movement patterns of common minke whales found in coastal waters of British Columbia and Washington we examined photo-identification data that were collected opportunistically from 2005–12. These data were from four non-overlapping areas between 48°N and 53°N. Despite year-round search efforts, common minke whales were only encountered between April and October. Most of the 44 unique individuals identified in 405 encounters displayed fidelity to areas both within and among years. Five of these whales made relatively large-scale intra-annual movements between areas on six occasions. They were documented to move up to 424km in a northerly direction in spring and up to 398km in a southerly direction in autumn. The seasonal patterns of these movements provide new insights into the foraging ranges and migrations of the individuals. Ecological markers provide evidence that the common minke whales photographed undertake annual long distance migrations. Scars believed to be from cookiecutter shark (Isistius brasiliensis) bites were observed on 43 individuals and the majority of whales documented with good quality images each year had acquired new scars since the previous year. Furthermore, the commensal barnacle Xenobalanus globicipitis was observed on three individuals. Since these sharks and barnacles are from relatively warm waters, it can be inferred that they interacted with the common minke whales at lower latitudes. These findings may have important implications for the definition and management of common minke whale stocks and/or populations in the eastern North Pacific.