TAK1 is an essential regulator of BMP signalling in cartilage

TGFβ activated kinase 1 (TAK1), a member of the MAPKKK family, controls diverse functions ranging from innate and adaptive immune system activation to vascular development and apoptosis. To analyse the in vivo function of TAK1 in cartilage, we generated mice with a conditional deletion of Tak1 driven by the collagen 2 promoter. Tak1col2 mice displayed severe chondrodysplasia with runting, impaired formation of secondary centres of ossification, and joint abnormalities including elbow dislocation and tarsal fusion. This phenotype resembled that of bone morphogenetic protein receptor (BMPR)1 and Gdf5-deficient mice. BMPR signalling was markedly impaired in TAK1-deficient chondrocytes as evidenced by reduced expression of known BMP target genes as well as reduced phosphorylation of Smad1/5/8 and p38/Jnk/Erk MAP kinases. TAK1 mediates Smad1 phosphorylation at C-terminal serine residues. These findings provide the first in vivo evidence in a mammalian system that TAK1 is required for BMP signalling and functions as an upstream activating kinase for Smad1/5/8 in addition to its known role in regulating MAP kinase pathways. Our experiments reveal an essential role for TAK1 in the morphogenesis, growth, and maintenance of cartilage

Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage.

Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models and are associated with several advantages, including high fecundity, optical translucency and non-protected status prior to 5 days post-fertilisation. Furthermore, other groups have shown that zebrafish larvae can exhibit spontaneous ICH. The aim of this study was to investigate whether such models can be utilised to study the pathological consequences of bleeding in the brain, in the context of pre-clinical ICH research. Here, we compared existing genetic (bubblehead) and chemically inducible (atorvastatin) zebrafish larval models of spontaneous ICH and studied the subsequent disease processes. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we quantified brain injury, locomotor function and neuroinflammation following ICH. We show that ICH in both zebrafish larval models is comparable in timing, frequency and location. ICH results in increased brain cell death and a persistent locomotor deficit. Additionally, in haemorrhaged larvae we observed a significant increase in macrophage recruitment to the site of injury. Live in vivo imaging allowed us to track active macrophage-based phagocytosis of dying brain cells 24 hours after haemorrhage. Morphological analyses and quantification indicated that an increase in overall macrophage activation occurs in the haemorrhaged brain. Our study shows that in zebrafish larvae, bleeding in the brain induces quantifiable phenotypic outcomes that mimic key features of human ICH. We hope that this methodology will enable the pre-clinical ICH community to adopt the zebrafish larval model as an alternative to rodents, supporting future high throughput drug screening and as a complementary approach to elucidating crucial mechanisms associated with ICH pathophysiology

Grooming coercion and the post-conflict trading of social services in wild Barbary macaques

In animal and human societies, social services such as protection from predators are often exchanged between group members. The tactics that individuals display to obtain a service depend on its value and on differences between individuals in their capacity to aggressively obtain it. Here we analysed the exchange of valuable social services (i.e. grooming and relationship repair) in the aftermath of a conflict, in wild Barbary macaques (Macaca sylvanus). The relationship repair function of post-conflict affiliation (i.e. reconciliation) was apparent in the victim but not in the aggressor. Conversely, we found evidence for grooming coercion by the aggressor; when the victim failed to give grooming soon after a conflict they received renewed aggression from the aggressor. We argue that post-conflict affiliation between former opponents can be better described as a trading of social services rather than coercion alone, as both animals obtain some benefits (i.e. grooming for the aggressor and relationship repair for the victim). Our study is the first to test the importance of social coercion in the aftermath of a conflict. Differences in competitive abilities can affect the exchange of services and the occurrence of social coercion in animal societies. This may also help explain the variance between populations and species in their social behaviour and conflict management strategies

Comparative safety of mRNA COVID-19 vaccines to influenza vaccines: A pharmacovigilance analysis using WHO international database.

Funder: New faculty research seed money grant of Yonsei University College of Medicine for 2021 (2021-32-0049).Two messenger RNA (mRNA) vaccines developed by Pfizer-BioNTech and Moderna are being rolled out. Despite the high volume of emerging evidence regarding adverse events (AEs) associated with the COVID-19 mRNA vaccines, previous studies have thus far been largely based on the comparison between vaccinated and unvaccinated control, possibly highlighting the AE risks with COVID-19 mRNA vaccination. Comparing the safety profile of mRNA vaccinated individuals with otherwise vaccinated individuals would enable a more relevant assessment for the safety of mRNA vaccination. We designed a comparative safety study between 18 755 and 27 895 individuals who reported to VigiBase for adverse events following immunization (AEFI) with mRNA COVID-19 and influenza vaccines, respectively, from January 1, 2020, to January 17, 2021. We employed disproportionality analysis to rapidly detect relevant safety signals and compared comparative risks of a diverse span of AEFIs for the vaccines. The safety profile of novel mRNA vaccines was divergent from that of influenza vaccines. The overall pattern suggested that systematic reactions like chill, myalgia, fatigue were more noticeable with the mRNA COVID-19 vaccine, while injection site reactogenicity events were more prevalent with the influenza vaccine. Compared to the influenza vaccine, mRNA COVID-19 vaccines demonstrated a significantly higher risk for a few manageable cardiovascular complications, such as hypertensive crisis (adjusted reporting odds ratio [ROR], 12.72; 95% confidence interval [CI], 2.47-65.54), and supraventricular tachycardia (adjusted ROR, 7.94; 95% CI, 2.62-24.00), but lower risk of neurological complications such as syncope, neuralgia, loss of consciousness, Guillain-Barre syndrome, gait disturbance, visual impairment, and dyskinesia. This study has not identified significant safety concerns regarding mRNA vaccination in real-world settings. The overall safety profile patterned a lower risk of serious AEFI following mRNA vaccines compared to influenza vaccines

Obesity and disease activity in juvenile idiopathic arthritis

<p>Abstract</p> <p>Background</p> <p>Children with physical disabilities may have an increased risk for obesity and obesity might be a risk factor for inflammatory arthritis. The aims of this study were: to determine the prevalence of obesity in children and adolescents with juvenile idiopathic arthritis (JIA), and to examine the association between obesity and disease activity in this population.</p> <p>Findings</p> <p>A cross-sectional analysis of all patients with JIA attending a pediatric rheumatology clinic, between October 2009 and September 2010, was performed. A linear regression model was used to explore the association between obesity and disease activity in patients with JIA. A total of 154 subjects were included in the analysis; median age was 10.6 years, 61% were female, and 88% were white. Obesity was found in 18%, 12% were overweight, and 3% were underweight. There was no association between obesity and JADAS-27 (Juvenile Arthritis Disease Activity Score 27), physician's assessment of disease activity, parent's assessment of child's well-being, erythrocyte sedimentation rate, number of active joints, or C-reactive protein (p-value range 0.10 to 0.95).</p> <p>Conclusions</p> <p>Although 18% of patients with JIA were obese, we did not find an association between obesity and disease activity. As obesity confers an additional health risk in children with arthritis, addressing this co-morbidity should be a health priority in patients with JIA. Future studies are necessary to further explore potential associations between obesity, development of JIA, and disease activity.</p

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Effects of the agility boot camp with cognitive challenge (ABC-C) exercise program for Parkinson’s disease

Few exercise interventions practice both gait and balance tasks with cognitive tasks to improve functional mobility in people with PD. We aimed to investigate whether the Agility Boot Camp with Cognitive Challenge (ABC-C), that simultaneously targets both mobility and cognitive function, improves dynamic balance and dual-task gait in individuals with Parkinson's disease (PD). We used a cross-over, single-blind, randomized controlled trial to determine efficacy of the exercise intervention. Eighty-six people with idiopathic PD were randomized into either an exercise (ABC-C)-first or an active, placebo, education-first intervention and then crossed over to the other intervention. Both interventions were carried out in small groups led by a certified exercise trainer (90-min sessions, 3 times a week, for 6 weeks). Outcome measures were assessed Off levodopa at baseline and after the first and second interventions. A linear mixed-effects model tested the treatment effects on the Mini-BESTest for balance, dual-task cost on gait speed, SCOPA-COG, the UPDRS Parts II and III and the PDQ-39. Although no significant treatment effects were observed for the Mini-BESTest, SCOPA-COG or MDS-UPDRS Part III, the ABC-C intervention significantly improved the following outcomes: anticipatory postural adjustment sub-score of the Mini-BESTest (p = 0.004), dual-task cost on gait speed (p = 0.001), MDS-UPDRS Part II score (p = 0.01), PIGD sub-score of MDS-UPDRS Part III (p = 0.02), and the activities of daily living domain of the PDQ-39 (p = 0.003). Participants with more severe motor impairment or more severe cognitive dysfunction improved their total Mini-BESTest scores after exercise. The ABC-C exercise intervention can improve specific balance deficits, cognitive-gait interference, and perceived functional independence and quality of life, especially in participants with more severe PD, but a longer period of intervention may be required to improve global cognitive and motor function

The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline

QUESTION: What evidence is available regarding the use of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), surgical resection or chemotherapy for the treatment of recurrent/progressive brain metastases? TARGET POPULATION: This recommendation applies to adults with recurrent/progressive brain metastases who have previously been treated with WBRT, surgical resection and/or radiosurgery. Recurrent/progressive brain metastases are defined as metastases that recur/progress anywhere in the brain (original and/or non-original sites) after initial therapy. RECOMMENDATION: Level 3 Since there is insufficient evidence to make definitive treatment recommendations in patients with recurrent/progressive brain metastases, treatment should be individualized based on a patient\u27s functional status, extent of disease, volume/number of metastases, recurrence or progression at original versus non-original site, previous treatment and type of primary cancer, and enrollment in clinical trials is encouraged. In this context, the following can be recommended depending on a patient\u27s specific condition: no further treatment (supportive care), re-irradiation (either WBRT and/or SRS), surgical excision or, to a lesser extent, chemotherapy. Question If WBRT is used in the setting of recurrent/progressive brain metastases, what impact does tumor histopathology have on treatment outcomes? No studies were identified that met the eligibility criteria for this question

The 24-h Energy Intake of Obese Adolescents Is Spontaneously Reduced after Intensive Exercise: A Randomized Controlled Trial in Calorimetric Chambers

Background: Physical exercise can modify subsequent energy intake and appetite and may thus be of particular interest in terms of obesity treatment. However, it is still unclear whether an intensive bout of exercise can affect the energy consumption of obese children and adolescents. [br/] Objective: To compare the impact of high vs. moderate intensity exercises on subsequent 24-h energy intake, macronutrient preferences, appetite sensations, energy expenditure and balance in obese adolescent. [br/] Design: This randomized cross-over trial involves 15 obese adolescent boys who were asked to randomly complete three 24-h sessions in a metabolic chamber, each separated by at least 7 days: (1) sedentary (SED); (2) Low-Intensity Exercise (LIE) (40% maximal oxygen uptake, VO(2)max); (3) High-Intensity Exercise (HIE) (75% VO(2)max). Results: Despite unchanged appetite sensations, 24-h total energy intake following HIE was 6-11% lower compared to LIE and SED (p<0.05), whereas no differences appeared between SED and LIE. Energy intake at lunch was 9.4% and 8.4% lower after HIE compared to SED and LIE, respectively (p<0.05). At dinner time, it was 20.5% and 19.7% lower after HIE compared to SED and LIE, respectively (p<0.01). 24-h energy expenditure was not significantly altered. Thus, the 24-h energy balance was significantly reduced during HIE compared to SED and LIE (p<0.01), whereas those of SED and LIE did not differ. [br/] Conclusions: In obese adolescent boys, HIE has a beneficial impact on 24-h energy balance, mainly due to the spontaneous decrease in energy intake during lunch and dinner following the exercise bout. Prescribing high-intensity exercises to promote weight loss may therefore provide effective results without affecting appetite sensations and, as a result, food frustrations

Preference Transitivity and Symbolic Representation in Capuchin Monkeys (Cebus apella)

BACKGROUND: Can non-human animals comprehend and employ symbols? The most convincing empirical evidence comes from language-trained apes, but little is known about this ability in monkeys. Tokens can be regarded as symbols since they are inherently non-valuable objects that acquire an arbitrarily assigned value upon exchange with an experimenter. Recent evidence suggested that capuchin monkeys, which diverged from the human lineage 35 million years ago, can estimate, represent and combine token quantities. A fundamental and open question is whether monkeys can reason about symbols in ways similar to how they reason about real objects. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined this broad question in the context of economic choice behavior. Specifically, we assessed whether, in a symbolic context, capuchins' preferences satisfy transitivity--a fundamental trait of rational decision-making. Given three options A, B and C, transitivity holds true if A > or = B, B > or = C and A > or = C (where > or = indicates preference). In this study, we trained monkeys to exchange three types of tokens for three different foods. We then compared choices monkeys made between different types of tokens with choices monkeys made between the foods. Qualitatively, capuchins' preferences revealed by the way of tokens were similar to those measured with the actual foods. In particular, when choosing between tokens, monkeys displayed strict economic preferences and their choices satisfied transitivity. Quantitatively, however, values measured by the way of tokens differed systematically from those measured with the actual foods. In particular, for any pair of foods, the relative value of the preferred food increased when monkeys chose between the corresponding tokens. CONCLUSIONS/SIGNIFICANCE: These results indicate that indeed capuchins are capable of treating tokens as symbols. However, as they do so, capuchins experience the cognitive burdens imposed by symbolic representation