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The goal of this Review is to highlight advances in the development and application of gene-based therapies for neurodegenerative diseases and offer a prospective look into this emerging arena.Anxiety is a negative emotional state that is overly displayed in anxiety disorders and depression. Although anxiety is known to be controlled by distributed brain networks, key components for its initiation, maintenance and coordination with behavioral state remain poorly understood. Here, we report that anxiogenic stressors elicit acute and prolonged responses in glutamatergic neurons of the mouse medial preoptic area (mPOA). These neurons encode extremely negative valence and mediate the induction and expression of anxiety-like behaviors. Conversely, mPOA GABA-containing neurons encode positive valence and produce anxiolytic effects. Such opposing roles are mediated by competing local interactions and long-range projections of neurons to the periaqueductal gray. The two neuronal populations antagonistically regulate anxiety-like and parental behaviors anxiety is reduced, while parenting is enhanced and vice versa. Thus, by evaluating negative and positive valences through distinct but interacting circuits, the mPOA coordinates emotional state and social behavior.The application of artificial intelligence (AI) to the electrocardiogram (ECG), a ubiquitous and standardized test, is an example of the ongoing transformative effect of AI on cardiovascular medicine. Although the ECG has long offered valuable insights into cardiac and non-cardiac health and disease, its interpretation requires considerable human expertise. Advanced AI methods, such as deep-learning convolutional neural networks, have enabled rapid, human-like interpretation of the ECG, while signals and patterns largely unrecognizable to human interpreters can be detected by multilayer AI networks with precision, making the ECG a powerful, non-invasive biomarker. Large sets of digital ECGs linked to rich clinical data have been used to develop AI models for the detection of left ventricular dysfunction, silent (previously undocumented and asymptomatic) atrial fibrillation and hypertrophic cardiomyopathy, as well as the determination of a person's age, sex and race, among other phenotypes. The clinical and population-level implications of AI-based ECG phenotyping continue to emerge, particularly with the rapid rise in the availability of mobile and wearable ECG technologies. In this Review, we summarize the current and future state of the AI-enhanced ECG in the detection of cardiovascular disease in at-risk populations, discuss its implications for clinical decision-making in patients with cardiovascular disease and critically appraise potential limitations and unknowns.Moiré superlattices1,2 have recently emerged as a platform upon which correlated physics and superconductivity can be studied with unprecedented tunability3-6. Although correlated effects have been observed in several other moiré systems7-17, magic-angle twisted bilayer graphene remains the only one in which robust superconductivity has been reproducibly measured4-6. Here we realize a moiré superconductor in magic-angle twisted trilayer graphene (MATTG)18, which has better tunability of its electronic structure and superconducting properties than magic-angle twisted bilayer graphene. Measurements of the Hall effect and quantum oscillations as a function of density and electric field enable us to determine the tunable phase boundaries of the system in the normal metallic state. Zero-magnetic-field resistivity measurements reveal that the existence of superconductivity is intimately connected to the broken-symmetry phase that emerges from two carriers per moiré unit cell. We find that the superconducting phase is suppressed and bounded at the Van Hove singularities that partially surround the broken-symmetry phase, which is difficult to reconcile with weak-coupling Bardeen-Cooper-Schrieffer theory. Moreover, the extensive in situ tunability of our system allows us to reach the ultrastrong-coupling regime, characterized by a Ginzburg-Landau coherence length that reaches the average inter-particle distance, and very large TBKT/TF values, in excess of 0.1 (where TBKT and TF are the Berezinskii-Kosterlitz-Thouless transition and Fermi temperatures, respectively). These observations suggest that MATTG can be electrically tuned close to the crossover to a two-dimensional Bose-Einstein condensate. Our results establish a family of tunable moiré superconductors that have the potential to revolutionize our fundamental understanding of and the applications for strongly coupled superconductivity.Current treatments for rheumatoid arthritis (RA) do not work well for a large proportion of patients, or at all in some individuals, and cannot cure or prevent this disease. One major obstacle to developing better drugs is a lack of complete understanding of how inflammatory joint disease arises and progresses. Emerging evidence indicates an important role for the tissue microenvironment in the pathogenesis of RA. Each tissue is made up of cells surrounded and supported by a unique extracellular matrix (ECM). These complex molecular networks define tissue architecture and provide environmental signals that programme site-specific cell behaviour. In the synovium, a main site of disease activity in RA, positional and disease stage-specific cellular diversity exist. Improved understanding of the architecture of the synovium from gross anatomy to the single-cell level, in parallel with evidence demonstrating how the synovial ECM is vital for synovial homeostasis and how dysregulated signals from the ECM promote chronic inflammation and tissue destruction in the RA joint, has opened up new ways of thinking about the pathogenesis of RA. These new ideas provide novel therapeutic approaches for patients with difficult-to-treat disease and could also be used in disease prevention.Intervertebral disc (IVD) degeneration is a major cause of low back pain, a prevalent and chronic condition that has a striking effect on quality of life. EMD638683 manufacturer Currently, no approved pharmacological interventions or therapies are available that prevent the progressive destruction of the IVD; however, regenerative strategies are emerging that aim to modify the disease. Progress has been made in defining promising new treatments for disc disease, but considerable challenges remain along the entire translational spectrum, from understanding disease mechanism to useful interpretation of clinical trials, which make it difficult to achieve a unified understanding. These challenges include an incomplete appreciation of the mechanisms of disc degeneration; a lack of standardized approaches in preclinical testing; in the context of cell therapy, a distinct lack of cohesion regarding the cell types being tested, the tissue source, expansion conditions and dose; the absence of guidelines regarding disease classification and patient stratification for clinical trial inclusion; and an incomplete understanding of the mechanisms underpinning therapeutic responses to cell delivery.