Microglia protect against age-associated brain pathologies.

Microglia are brain-resident macrophages that contribute to central nervous system (CNS) development, maturation, and preservation. Here, we examine the consequences of permanent microglial deficiencies on brain aging using the Csf1rΔFIRE/ΔFIRE mouse model. In juvenile Csf1rΔFIRE/ΔFIRE mice, we show that microglia are dispensable for the transcriptomic maturation of other brain cell types. By contrast, with advancing age, pathologies accumulate in Csf1rΔFIRE/ΔFIRE brains, macroglia become increasingly dysregulated, and white matter integrity declines, mimicking many pathological features of human CSF1R-related leukoencephalopathy. The thalamus is particularly vulnerable to neuropathological changes in the absence of microglia, with atrophy, neuron loss, vascular alterations, macroglial dysregulation, and severe tissue calcification. We show that populating Csf1rΔFIRE/ΔFIRE brains with wild-type microglia protects against many of these pathological changes. Together with the accompanying study by Chadarevian and colleagues1, our results indicate that the lifelong absence of microglia results in an age-related neurodegenerative condition that can be counteracted via transplantation of healthy microglia.

Lifelong absence of microglia alters hippocampal glutamatergic networks but not synapse and spine density.

Microglia sculpt developing neural circuits by eliminating excess synapses in a process called synaptic pruning, by removing apoptotic neurons, and by promoting neuronal survival. To elucidate the role of microglia during embryonic and postnatal brain development, we used a mouse model deficient in microglia throughout life by deletion of the fms-intronic regulatory element (FIRE) in the Csf1r locus. Surprisingly, young adult Csf1rΔFIRE/ΔFIRE mice display no changes in excitatory and inhibitory synapse number and spine density of CA1 hippocampal neurons compared with Csf1r+/+ littermates. However, CA1 neurons are less excitable, receive less CA3 excitatory input and show altered synaptic properties, but this does not affect novel object recognition. Cytokine profiling indicates an anti-inflammatory state along with increases in ApoE levels and reactive astrocytes containing synaptic markers in Csf1rΔFIRE/ΔFIRE mice. Notably, these changes in Csf1rΔFIRE/ΔFIRE mice closely resemble the effects of acute microglial depletion in adult mice after normal development. Our findings suggest that microglia are not mandatory for synaptic pruning, and that in their absence pruning can be achieved by other mechanisms.

Microglia maintain structural integrity during fetal brain morphogenesis.

Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.

Search and reallocation in the COVID-19 pandemic: Evidence from the UK.

The impact of the pandemic on the UK labour market has been extremely heterogeneous across occupations and industries. Using novel data on job search, we document how individuals adjust their job search in response to changing employment patterns across occupations and industries in the UK. We observe that workers changed their search direction in favour of expanding occupations and industries as the pandemic developed. However, non-employed workers are more attached to their previous occupations and workers with low education are more likely to target declining occupations. We also observe workers from declining occupations making fewer transitions to expanding occupations than those who start in expanding occupations, despite targeting these jobs relatively frequently. This suggests those at the margins of the labour market may be least able to escape occupations that declined during the pandemic.

Microglia regulate central nervous system myelin growth and integrity.

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFß1-TGFßR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.

Circus-specific extension of the International Olympic Committee 2020 consensus statement: methods for recording and reporting of epidemiological data on injury and illness in sport.

Indepth knowledge of injury and illness epidemiology in circus arts is lacking. Comparing results across studies is difficult due to inconsistent methods and definitions. In 2020, the International Olympic Committee (IOC) consensus group proposed a standard method for recording and reporting epidemiological data on injuries and illnesses in sports and stated that sport-specific extension statements are needed to capture the context of each sport. This is the circus-specific extension to be used with the IOC consensus statement. International circus arts researchers in injury and illness epidemiology and performing arts medicine formed a consensus working group. Consensus statement development included a review of literature, creation of an initial draft by the working group, feedback from external reviewers, integration of feedback into the second draft and a consensus on the final document. This consensus statement contains circus-specific information on (1) injury definitions and characteristics; (2) measures of severity and exposure, with recommendations for calculating the incidence and prevalence; (3) a healthcare practitioner report form; (4) a self-report form capturing health complaints with training and performance exposure; and (5) a demographic, health history and circus experience intake questionnaire. This guideline facilitates comparing results across studies and enables combining data sets on injuries in circus arts. This guideline informs circus-specific injury prevention, rehabilitation, and risk management to improve the performance and health of circus artists.

Are there lane advantages in track and field?

Shorter distance events in track and field are replete with folk tales about which lane assignments on the track are advantageous. Estimating the causal effect of lane assignments on race times is a difficult task as lane assignments are typically non-random. To estimate these effects I exploit a random assignment rule for the first round of races in short distance events. Using twenty years of data from the IAAF world athletic championships and U20 world championships, there is no evidence of lane advantages in the 100m. Contrary to popular belief, the data suggest that outside lanes in the 200m and 400m produce faster race times. In the 800m, which is unique in having a lane break, there is some weak evidence that outside lanes producer slower race times, possibly reflecting the advantage of inside lanes having an established position on the track at the lane break. Given that these results do not support common convictions on lane advantages, they also serve as an interesting case study on false beliefs.

Macrophage compartmentalization in the brain and cerebrospinal fluid system.

Macrophages reside within the diverse anatomical compartments of the central nervous system (CNS). Within each compartment, these phagocytes are exposed to unique combinations of niche signals and mechanical stimuli that instruct their tissue-specific identities. Whereas most CNS macrophages are tissue-embedded, the macrophages of the cerebrospinal fluid (CSF) system are bathed in an oscillating liquid. Studies using multiomics technologies have recently uncovered the transcriptomic and proteomic profiles of CSF macrophages, enhancing our understanding of their cellular characteristics in both rodents and humans. Here, we review the relationships between CNS macrophage populations, with a focus on the origins, phenotypes, and functions of CSF macrophages in health and disease.

Rehabilitation for atraumatic shoulder instability in circus arts performers: delivery via telehealth.

BACKGROUND: The Watson Instability Program (WIP1) is current best evidence for conservative management of atraumatic shoulder instability, but it is unknown if this program can be effectively delivered via tele-consultation. The purpose of this longitudinal pre-post intervention study was to determine the effects of the WIP1 on patient-reported outcome measures, scapular position, shoulder strength, and handstand stability in student circus performers with atraumatic shoulder instability when delivered via tele-consultation. METHODS: Student circus performers aged between 15 and 35 years from the National Institute of Circus Arts were recruited. A 12-week shoulder exercise program was delivered via tele-consultation during the Melbourne, Australia COVID-19 (coronavirus disease 2019) lockdown. The primary outcome measures were the Western Ontario Shoulder Instability Index score and the Melbourne Instability Shoulder Scale score. Secondary outcomes measures included the Orebro Musculoskeletal Pain Questionnaire, the Tampa Scale for Kinesiophobia, and physical assessment measures including strength via handheld dynamometry, scapular position using an inclinometer, and handstand stability via center-of-pressure fluctuation. Patient-reported outcomes were collected at baseline and 6-week, 12-week, 6-month, and 9-month time points, and physical outcomes were measured at baseline and 9-month time points. A repeated-measures mixed model (with effect sizes [ESs] and 95% confidence intervals [CIs]) was used to analyze patient-reported outcomes, handstand data, strength, and scapular measures. Significance was set at P < .05. RESULTS: Twenty-three student circus arts performers completed the study. Significant improvements were found in both Western Ontario Shoulder Instability Index scores (effect size [ES], 0.79 [95% CI, 0.31-1.33] at 6 weeks; ES, 1.08 [95% CI, 0.55-1.6] at 12 weeks; ES, 1.17 [95% CI, 0.62-1.78] at 6 months; and ES, 1.31 [95% CI, 0.74-1.95] at 9 months; P < .001) and Melbourne Instability Shoulder Scale scores (ES, 0.70 [95% CI, 0.22-1.22] at 6 weeks; ES, 0.83 [95% CI, 0.34-1.37] at 3 months; ES, 0.98 [95% CI, 0.46-1.54] at 6 months; and ES, 0.98 [95% CI, 0.43-1.50] at 9 months; P < .001), as well as Orebro Musculoskeletal Pain Questionnaire scores at all follow-up time points. The Tampa Scale for Kinesiophobia scores reached significance at 6 weeks and 12 weeks. Following rehabilitation, we found statistically significant increases in shoulder strength in all positions tested and increased scapular upward rotation measured at end-of-range abduction, as well as during loaded external rotation. The affected arm showed greater instability than the unaffected arm with a significant intervention effect on the affected arm showing a greater consistent anterior-posterior movement pattern. CONCLUSION: In a group of circus performers with atraumatic shoulder instability, treatment with the WIP1 via telehealth resulted in clinically and statistically significant improvements in shoulder symptoms and function.

Strong Southern Ocean carbon uptake evident in airborne observations.

The Southern Ocean plays an important role in determining atmospheric carbon dioxide (CO2), yet estimates of air-sea CO2 flux for the region diverge widely. In this study, we constrained Southern Ocean air-sea CO2 exchange by relating fluxes to horizontal and vertical CO2 gradients in atmospheric transport models and applying atmospheric observations of these gradients to estimate fluxes. Aircraft-based measurements of the vertical atmospheric CO2 gradient provide robust flux constraints. We found an annual mean flux of ­0.53 ± 0.23 petagrams of carbon per year (net uptake) south of 45°S during the period 2009­2018. This is consistent with the mean of atmospheric inversion estimates and surface-ocean partial pressure of CO2 (Pco2)­based products, but our data indicate stronger annual mean uptake than suggested by recent interpretations of profiling float observations.

Intra-Rater and Inter-Rater Reliability of Hand-Held Dynamometry for Shoulder Strength Assessment in Circus Arts Students.

The purpose of this study was to establish the intra-rater and inter-rater reliability of isometric shoulder strength assessment using a hand-held dynamometer (HHD) in functional joint positions in student circus artists with symptomatic atraumatic shoulder instability. METHODS: Over two testing sessions, two experienced physiotherapists assessed the shoulder strength of 24 student circus artists with clinically diagnosed atraumatic shoulder instability. Both the symptomatic and asymptomatic shoulder was assessed using a HHD in 10 functional positions. Intra-class correlation coefficients (ICCs) were calculated to determine the reliability of strength measurements. RESULTS: All examined positions showed moderate-high intra-rater and inter-rater reliability. External rotation at 0° and internal rotation in horizontal flexion at 45° revealed the most reliable results, and the shrug position the least reliable. Inter-rater and intra-rater reliability was high and demonstrated similar results in symptomatic and asymptomatic shoulders by both raters. DISCUSSION: This study demonstrated clinical applicability in reliably measuring functional strength in symptomatic atraumatic instability or asymptomatic shoulders when assessed by experienced therapists using an HHD.

CNS macrophages differentially rely on an intronic Csf1r enhancer for their development.

The central nervous system hosts parenchymal macrophages, known as microglia, and non-parenchymal macrophages, collectively termed border-associated macrophages (BAMs). Microglia, but not BAMs, were reported to be absent in mice lacking a conserved Csf1r enhancer: the fms-intronic regulatory element (FIRE). However, it is unknown whether FIRE deficiency also impacts BAM arrival and/or maintenance. Here, we show that macrophages in the ventricular system of the brain, including Kolmer's epiplexus macrophages, are absent in Csf1rΔFIRE/ΔFIRE mice. Stromal choroid plexus BAMs are also considerably reduced. During normal development, we demonstrate that intracerebroventricular macrophages arrive from embryonic day 10.5, and can traverse ventricular walls in embryonic slice cultures. In Csf1rΔFIRE/ΔFIRE embryos, the arrival of both primitive microglia and intracerebroventricular macrophages was eliminated, whereas the arrival of cephalic mesenchyme and stromal choroid plexus BAMs was only partially restricted. Our results provide new insights into the development and regulation of different CNS macrophage populations.

Lentiviral delivery of human erythropoietin attenuates hippocampal atrophy and improves cognition in the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is an incurable neurodegenerative disorder caused by a trinucleotide (CAG) repeat expansion in the huntingtin gene (HTT). The R6/2 transgenic mouse model of HD expresses exon 1 of the human HTT gene with approximately 150 CAG repeats. R6/2 mice develop progressive behavioural abnormalities, impaired neurogenesis, and atrophy of several brain regions. In recent years, erythropoietin (EPO) has been shown to confer neuroprotection and enhance neurogenesis, rendering it a promising molecule to attenuate HD symptoms. In this study, the therapeutic potential of EPO was evaluated in female R6/2 transgenic mice. A single bilateral injection of a lentivirus encoding human EPO (LV-hEPO) was performed into the lateral ventricles of R6/2 mice at disease onset (8 weeks of age). Control groups were either untreated or injected with a lentivirus encoding green fluorescent protein (LV-GFP). Thirty days after virus administration, hEPO mRNA and protein were present in injected R6/2 brains. Compared to control R6/2 mice, LV-hEPO-treated R6/2 mice exhibited reduced hippocampal atrophy, increased neuroblast branching towards the dentate granular cell layer, and improved spatial cognition. Our results suggest that LV-hEPO administration may be a promising strategy to reduce cognitive impairment in HD.

Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations.

The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r-/- rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.

Macrophages restrict the nephrogenic field and promote endothelial connections during kidney development.

The origins and functions of kidney macrophages in the adult have been explored, but their roles during development remain largely unknown. Here we characterise macrophage arrival, localisation, heterogeneity, and functions during kidney organogenesis. Using genetic approaches to ablate macrophages, we identify a role for macrophages in nephron progenitor cell clearance as mouse kidney development begins. Throughout renal organogenesis, most kidney macrophages are perivascular and express F4/80 and CD206. These macrophages are enriched for mRNAs linked to developmental processes, such as blood vessel morphogenesis. Using antibody-mediated macrophage-depletion, we show macrophages support vascular anastomoses in cultured kidney explants. We also characterise a subpopulation of galectin-3+ (Gal3+) myeloid cells within the developing kidney. Our findings may stimulate research into macrophage-based therapies for renal developmental abnormalities and have implications for the generation of bioengineered kidney tissues.

On allegations of invasive species denialism.

Science denialism retards evidenced-based policy and practice and should be challenged. It has been a particular concern for mitigating global environmental issues, such as anthropogenic climate change. But allegations of science denialism must also be well founded and evidential or they risk eroding public trust in science and scientists. Recently, 77 published works by scholars, scientists, and science writers were identified as containing invasive species denialism (ISD; i.e., rejection of well-supported facts about invasive species, particularly the global scientific consensus about their negative impacts). We reevaluated 75 of these works but could find no examples of refutation of scientific facts and only 5 articles with text perhaps consistent with one of the 5 characteristics of science denialism. We found, therefore, that allegations of ISD were misplaced. These accusations of science denialism may have arisen because invasion biology defines its subjects-invasive species-based on multiple subjective and normative judgments. Thus, more than other applied sciences its consensus is one of shared values as much as agreed knowledge. Criticisms of invasion biology have largely targeted those subjective and normative judgments and their global imposition, not the knowledge on which the discipline is based. Regrettably, a few invasion biologists have misinterpreted the critique of their values-based consensus as a denial of their science when it is not. To make invasion biology a more robust and widely accepted science and to avoid unnecessary misunderstandings and conflicts, invasion biologists could be more accepting of perspectives originating from other disciplines and more open to values-based critique from scholars and scientists outside their field. This recommendation applies to all conservation sciences, especially those addressing global challenges, because these sciences must serve and be relevant to communities with an extraordinary diversity of cultures and values.

Sobre Argumentos de la Negación de Especies Invasoras Resumen La negación de la ciencia retrasa las prácticas y políticas basadas en evidencias, por lo que debería ser cuestionada. Esta negación ha sido una preocupación particular para la mitigación de los temas ambientales a nivel mundial, como el cambio climático antropogénico. Las argumentos en contra de la negación de la ciencia deben estar bien fundamentados y basados en evidencias o se corre el riesgo de mermar la confianza del público en la ciencia y en los científicos. Recientemente, se identificó que 77 trabajos publicados por académicos, científicos y escritores de ciencia contenían negaciones sobre las especies invasoras (ISD, en inglés) (es decir, el rechazo de datos bien respaldados sobre las especies invasoras, particularmente el consenso científico mundial sobre sus impactos negativos). Reevaluamos 75 de estos trabajos pero no pudimos encontrar ejemplos de refutación de datos científicos y sólo cinco de los artículos tuvieron texto quizás consistente con una de las cinco características de la negación de la ciencia. Por esto encontramos que las acusaciones de ISD eran inapropiadas. Estas imputaciones de negación de la ciencia podrían haber surgido a razón de que la biología de la invasión define a sus sujetos - las especies invasoras - con base en múltiples juicios subjetivos y normativos. Así, más que en otras ciencias aplicadas, el consenso de la biología de la invasión consiste tanto de valores compartidos como de conocimiento compartido. Las críticas hacia la biología de la invasión se han enfocado principalmente en esos juicios normativos y subjetivos y en su imposición global, no hacia el conocimiento sobre el que se basa la disciplina. Lamentablemente, unos cuantos biólogos de la invasión han malinterpretado las críticas a su consenso basado en valores como la negación de su ciencia, cuando no lo es. Para hacer de la biología de la invasión una ciencia más fuerte y con mayor aceptación y para evitar malentendidos innecesarios y conflictos, los biólogos de la invasión podrían estar más dispuestos a aceptar las perspectivas que se originan en otras disciplinas y más abiertos a las críticas basadas en valores dadas por los académicos y los científicos que están fuera de su campo de investigación. Esta recomendación aplica para todas las ciencias de la conservación, especialmente para aquellas que tratan las dificultades globales, ya que estas ciencias deben servir y ser relevantes para las comunidades con una diversidad extraordinaria de culturas y valores.

The transition to adulthood of young adults with IDD: Parents' joint projects.

INTRODUCTION: Parents have found the transition to adulthood for their sons or daughters with intellectual and/or developmental disabilities (IDD) particularly challenging. The literature has not examined how parents work together and with others in face of this transition nor has it highlighted parental goals in this process. This study used a perspective based on joint, goal-direct action to describe the projects that Canadian parents engaged in together and with others relative to this transition. METHODS: Using the qualitative action-project method, joint projects between parents and with others were identified from their conversations and followed for 6 months. FINDINGS: Three groups of projects were described: equipping the young adult for adult life, connecting for personal support and managing day-to-day while planning for the future. CONCLUSIONS: Parents act together and with others relative to the transition to adulthood of their young adult children with IDD. These projects are complex and differ in goals, steps, resources and emotional regulation and motivation.