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Transcranial direct current stimulation (tDCS) is a popular brain stimulation method that is used to modulate cortical excitability, producing facilitatory or inhibitory effects upon a variety of behaviors. There is, however, a current lack of consensus between studies, with many results suggesting that polarity-specific effects are difficult to obtain. This article explores some of these differences and highlights the experimental parameters that may underlie their occurrence. We provide a general, practical snapshot of tDCS methodology, including what it is used for, how to use it, and considerations for designing an effective and safe experiment. Our aim is to equip researchers who are new to tDCS with the essential knowledge so that they can make informed and well-rounded decisions when designing and running successful experiments. By summarizing the varied approaches, stimulation parameters, and outcomes, this article should help inform future tDCS research in a variety of fields.

Therapeutic options for the treatment of an increasing variety of cancers have been expanded by the introduction of a new class of drugs, commonly referred to as checkpoint blocking agents, that target the host immune system to positively modulate anti-tumor immune response. Although efficacy of these agents has been linked to a pre-existing level of tumor immune infiltrate, it remains unclear why some patients exhibit deep and durable responses to these agents while others do not benefit. To examine the influence of tumor genetics on tumor immune state, we interrogated the relationship between somatic mutation and copy number alteration with infiltration levels of 7 immune cell types across 40 tumor cohorts in The Cancer Genome Atlas. Levels of cytotoxic T, regulatory T, total T, natural killer, and B cells, as well as monocytes and M2 macrophages, were estimated using a novel set of transcriptional signatures that were designed to resist interference from the cellular heterogeneity of tumors. Tumor mutational load and estimates of tumor purity were included in our association models to adjust for biases in multi-modal genomic data. Copy number alterations, mutations summarized at the gene level, and position-specific mutations were evaluated for association with tumor immune infiltration. We observed a strong relationship between copy number loss of a large region of chromosome 9p and decreased lymphocyte estimates in melanoma, pancreatic, and head/neck cancers. Mutations in the oncogenes PIK3CA, FGFR3, and RAS/RAF family members, as well as the tumor suppressor TP53, were linked to changes in immune infiltration, usually in restricted tumor types. Associations of specific WNT/beta-catenin pathway genetic changes with immune state were limited, but we noted a link between 9p loss and the expression of the WNT receptor FZD3, suggesting that there are interactions between 9p alteration and WNT pathways. Finally, two different cell death regulators, CASP8 and DIDO1, were often mutated in head/neck tumors that had higher lymphocyte infiltrates. In summary, our study supports the relevance of tumor genetics to questions of efficacy and resistance in checkpoint blockade therapies. It also highlights the need to assess genome-wide influences during exploration of any specific tumor pathway hypothesized to be relevant to therapeutic response. Some of the observed genetic links to immune state, like 9p loss, may influence response to cancer immune therapies. Others, like mutations in cell death pathways, may help guide combination therapeutic approaches.

Dense connective tissue injuries have limited repair, due to the paucity of cells at the wound site. We hypothesize that decreasing the density of the local extracellular matrix (ECM) in conjunction with releasing chemoattractive signals increases cellularity and tissue formation after injury. Using the knee meniscus as a model system, we query interstitial cell migration in the context of migratory barriers using a novel tissue Boyden chamber and show that a gradient of platelet-derived growth factor-AB (PDGF-AB) expedites migration through native tissue. To implement these signals in situ, we develop nanofibrous scaffolds with distinct fiber fractions that sequentially release active collagenase (to increase ECM porosity) and PDGF-AB (to attract endogenous cells) in a localized and coordinated manner. We show that, when placed into a meniscal defect, the controlled release of collagenase and PDGF-AB increases cellularity at the interface and within the scaffold, as well as integration with the surrounding tissue. Dense connective tissues do not easily heal, in part due to a low supply of reparative cells. Here, the authors develop a fibrous scaffold for meniscal repair that sequentially releases collagenase and a growth factor at the injury site, breaking down the extracellular matrix and recruiting endogenous cells.

Geographical research on children, youth, and families has done much to highlight the ways in which children's lives have changed over the last twenty-five years. A key strand of research concerns children's play and traces, in the Global North, a decline in children's independent access to, and mobility through, public space. This article shifts the terrain of that debate from an analysis of what has been lost to an exploration of what has replaced it. Specifically, it focuses on children's participation in enrichment activities, including both individual and collective extracurricular sporting, cultural, and leisure opportunities in England. The research reveals that middle-class children have much higher participation rates in enrichment activities than their working-class counterparts. Parents value enrichment activities in very similar ways across the class spectrum-seeing them as fun, healthy, and social opportunities. The ability to pay for enrichment, however, means that it is incorporated into, and transforms, middle-class family life in ways not open to working-class families. Nevertheless, support across the class spectrum for these instrumental forms of play that institutionalize childhood in school, community, and commercial spaces leads to calls for subsidized provision for low-income children through schools. The article thus traces the \"enrichment\" and \"institutionalization\" of childhood and draws out the implications of this for how we think about play, education, parenting, and class in geography.

Blackbody radiation sources are calculable radiation sources that are frequently used in radiometry, temperature dissemination, and remote sensing. Despite their ubiquity, blackbody sources and radiometers have a plethora of systematics. We envision a new, primary route to measuring blackbody radiation using ensembles of polarizable quantum systems, such as Rydberg atoms and diatomic molecules. Quantum measurements with these exquisite electric field sensors could enable active feedback, improved design, and, ultimately, lower radiometric and thermal uncertainties of blackbody standards. A portable, calibration-free Rydberg-atom physics package could also complement a variety of classical radiation detector and thermometers. The successful merger of quantum and blackbody-based measurements provides a new, fundamental paradigm for blackbody physics.

Sarcopenia is the loss of skeletal muscle mass and function with advancing age. It involves both complex genetic and modifiable risk factors, such as lack of exercise, malnutrition and reduced neurological drive. Cognitive decline refers to diminished or impaired mental and/or intellectual functioning. Contracting skeletal muscle is a major source of neurotrophic factors, including brain-derived neurotrophic factor, which regulate synapses in the brain. Furthermore, skeletal muscle activity has important immune and redox effects that modify brain function and reduce muscle catabolism. The identification of common risk factors and underlying mechanisms for sarcopenia and cognition may allow the development of targeted interventions that slow or reverse sarcopenia and also certain forms of cognitive decline. However, the links between cognition and skeletal muscle have not been elucidated fully. This review provides a critical appraisal of the literature on the relationship between skeletal muscle health and cognition. The literature suggests that sarcopenia and cognitive decline share pathophysiological pathways. Ageing plays a role in both skeletal muscle deterioration and cognitive decline. Furthermore, lifestyle risk factors, such as physical inactivity, poor diet and smoking, are common to both disorders, so their potential role in the muscle–brain relationship warrants investigation.

Background Falls are a major public health issue, largely driven by age‐related declines in hip and lower limb muscle strength. Hip muscle strength plays a critical role in postural stability and falls prevention. Lower balance confidence increases fall risk by restricting activity participation, which may contribute to muscle weakness over time. This study examined the association between hip abductor and flexor strength and the incidence of injurious falls in older adults and investigated whether hip abductor and flexor strength mediate the relationship between balance confidence and incident injurious falls. Methods Participants (n = 952; aged ≥ 65 years) were drawn from the Geelong Osteoporosis Study (GOS). The outcome was the time to first emergency department presentation for an incident injurious fall. Hip abductor and flexor strength were assessed using a handheld dynamometer to measure hip abduction and flexion force, with strength values adjusted for leg lean mass measured by dual‐energy X‐ray absorptiometry. Balance confidence was assessed using the 14‐item Modified Falls Efficacy Scale (MFES). Associations between hip muscle strength and incident injurious falls were evaluated using a competing risk regression model, which accounted for death as a competing event. The results are expressed as adjusted sub‐distribution hazard ratios (aSHR) and 95% confidence intervals. Mediation analysis was conducted to assess whether hip abductor and flexor strength mediated the relationship between balance confidence and the incidence of injurious falls. Results Among the 952 participants, 38% were women (mean age 76.1 ± 7.3 years), and 62% were men (mean age 76.9 ± 7.0 years). The median follow‐up time was 11.5 years (IQR 5.9–19.0). During follow‐up, 219 participants (23.0%) experienced at least one injurious fall, corresponding to an incidence rate of 19.3 per 1000 person‐years (95% CI: 16.9–22.0). Greater hip abductor strength was associated with a lower risk of incident injurious falls (aSHR = 0.835, 95% CI: 0.724–0.963; p = 0.013), with each 1‐N/kg increase in hip abductor strength reducing the sub‐distribution hazard by 16.5%. Hip flexor strength was not significantly associated with incident injurious falls. Hip abductor strength accounted for 23.7% of the association between balance confidence and incident injurious falls. Conclusions Greater hip abductor strength is protective against incident injurious falls in older adults and partially mediates the relationship between balance confidence and injurious falls. Fall prevention strategies should integrate hip abductor strengthening with interventions targeting cognitive and psychological factors, such as improving balance confidence.

Hyaluronic acid (HA) is a primary component of the brain extracellular matrix and functions through cellular receptors to regulate cell behavior within the central nervous system (CNS). These behaviors, such as migration, proliferation, differentiation, and inflammation contribute to maintenance and homeostasis of the CNS. However, such equilibrium is disrupted following injury or disease leading to significantly altered extracellular matrix milieu and cell functions. This imbalance thereby inhibits inherent homeostatic processes that support critical tissue health and functionality in the CNS. To mitigate the damage sustained by injury/disease, HA-based tissue engineering constructs have been investigated for CNS regenerative medicine applications. HA’s effectiveness in tissue healing and regeneration is primarily attributed to its impact on cell signaling and the ease of customizing chemical and mechanical properties. This review focuses on recent findings to highlight the applications of HA-based materials in CNS regenerative medicine.

Epithelial-to-mesenchymal transition (EMT) is associated with tumor initiation, metastasis, and drug resistance. However, the mechanisms underlying these associations are largely unknown. We studied several tumor types to identify the source of EMT gene expression signals and a potential mechanism of resistance to immuno-oncology treatment. Across tumor types, EMT-related gene expression was strongly associated with expression of stroma-related genes. Based on RNA sequencing of multiple patient-derived xenograft models, EMT-related gene expression was enriched in the stroma versus parenchyma. EMT-related markers were predominantly expressed by cancer-associated fibroblasts (CAFs), cells of mesenchymal origin which produce a variety of matrix proteins and growth factors. Scores derived from a 3-gene CAF transcriptional signature ( COL1A1 , COL1A2 , COL3A1 ) were sufficient to reproduce association between EMT-related markers and disease prognosis. Our results suggest that CAFs are the primary source of EMT signaling and have potential roles as biomarkers and targets for immuno-oncology therapies.

We aimed to examine muscle strength, function and mass in relation to cognition in older men. This cross-sectional data-set included 292 men aged ≥60 yr. Handgrip strength (kg) was measured by dynamometry, gait speed by 4-metre walk (m/s) and appendicular lean mass (kg) by dual-energy x-ray absorptiometry. Cognition was assessed across four domains: psychomotor function, attention, visual learning and working memory. Composite scores for overall cognition were calculated. Bivariate analyses indicated that handgrip strength and gait speed were positively associated with cognitive function. After accounting for confounders, positive associations between individual muscle (or physical) measures and cognitive performance were sustained for handgrip strength and psychomotor function, gait speed and psychomotor function, gait speed and attention, handgrip strength and overall cognition, and gait speed and overall cognition. In multivariable models, handgrip strength and gait speed independently predicted psychomotor function and overall cognition. No associations were detected between lean mass and cognition after adjusting for confounders. Thus, low muscle strength and slower gait speed, rather than low lean mass, were associated with poor cognition in older men.