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Human induced pluripotent stem cells (iPSC) hold promise for modeling diseases in individual human genetic backgrounds and thus for developing precision medicine. Here, we generate sensorimotor organoids containing physiologically functional neuromuscular junctions (NMJs) and apply the model to different subgroups of amyotrophic lateral sclerosis (ALS). Using a range of molecular, genomic, and physiological techniques, we identify and characterize motor neurons and skeletal muscle, along with sensory neurons, astrocytes, microglia, and vasculature. Organoid cultures derived from multiple human iPSC lines generated from individuals with ALS and isogenic lines edited to harbor familial ALS mutations show impairment at the level of the NMJ, as detected by both contraction and immunocytochemical measurements. The physiological resolution of the human NMJ synapse, combined with the generation of major cellular cohorts exerting autonomous and non-cell autonomous effects in motor and sensory diseases, may prove valuable to understand the pathophysiological mechanisms of ALS. Organoids have improved disease modeling. Here, the authors generate human sensorimotor organoids derived from hiPSCs of individuals with ALS. These organoids contain skeletal muscle, sensory and motor neurons as well as astrocytes, microglia, and vasculature and form neuromuscular junctions.

A bstract Asymptotic Safety provides an elegant mechanism for obtaining a consistent high-energy completion of gravity and gravity-matter systems. Following the initial idea by Steven Weinberg, the construction builds on an interacting fixed point of the theories renormalization group (RG) flow. In this work we use the Wetterich equation for the effective average action to investigate the RG flow of gravity supplemented by a real scalar field. We give a non-perturbative proof that the subspace of interactions respecting the global shift-symmetry of the scalar kinetic term is closed under RG transformations. Subsequently, we compute the beta functions in an approximation comprising the Einstein-Hilbert action supplemented by the shift-symmetric quartic scalar self-interaction and the two lowest order shift-symmetric interactions coupling scalar-bilinears to the spacetime curvature. The computation utilizes the background field method with an arbitrary background, demonstrating that the results are manifestly background independent. Our beta functions exhibit an interacting fixed point suitable for Asymptotic Safety, where all matter interactions are non-vanishing. The presence of this fixed point is rooted in the interplay of the matter couplings which our work tracks for the first time. The relation of our findings with previous results in the literature is discussed in detail and we conclude with a brief outlook on potential phenomenological applications.

We compute the one-loop divergences in a higher-derivative theory of gravity including Ricci tensor squared and Ricci scalar squared terms, in addition to the Hilbert and cosmological terms, on an (generally off-shell) Einstein background. We work with a two-parameter family of parametrizations of the graviton field, and a two-parameter family of gauges. We find that there are some choices of gauge or parametrization that reduce the dependence on the remaining parameters. The results are invariant under a recently discovered “duality” that involves the replacement of the densitized metric by a densitized inverse metric as the fundamental quantum variable.

Multipotent progenitor cells of the cerebral cortex balance self-renewal and differentiation to produce complex neural lineages in a fixed temporal order in a cell-autonomous manner. We studied the role of the polycomb epigenetic system, a chromatin-based repressive mechanism, in controlling cortical progenitor cell self-renewal and differentiation. We found that the histone methyltransferase of polycomb repressive complex 2 (PCR2), enhancer of Zeste homolog 2 (Ezh2), is essential for controlling the rate at which development progresses within cortical progenitor cell lineages. Loss of function of Ezh2 removes the repressive mark of trimethylated histone H3 at lysine 27 (H3K27me3) in cortical progenitor cells and also prevents its establishment in postmitotic neurons. Removal of this repressive chromatin modification results in marked up-regulation in gene expression, the consequence of which is a shift in the balance between self-renewal and differentiation toward differentiation, both directly to neurons and indirectly via basal progenitor cell genesis. Although the temporal order of neurogenesis and gliogenesis are broadly conserved under these conditions, the timing of neurogenesis, the relative numbers of different cell types, and the switch to gliogenesis are all altered, narrowing the neurogenic period for progenitor cells and reducing their neuronal output. As a consequence, the timing of cortical development is altered significantly after loss of PRC2 function.

In the lower solar atmosphere, the chromosphere is permeated by jets known as spicules, in which plasma is propelled at speeds of 50 to 150 kilometers per second into the corona. The origin of the spicules is poorly understood, although they are expected to play a role in heating the million-degree corona and are associated with Alfvénic waves that help drive the solar wind. We compare magnetohydrodynamic simulations of spicules with observations from the Interface Region Imaging Spectrograph and the Swedish 1-m Solar Telescope. Spicules are shown to occur when magnetic tension is amplified and transported upward through interactions between ions and neutrals or ambipolar diffusion. The tension is impulsively released to drive flows, heat plasma (through ambipolar diffusion), and generate Alfvénic waves.

The desire to understand how the brain generates and patterns behavior has driven rapid methodological innovation in tools to quantify natural animal behavior. While advances in deep learning and computer vision have enabled markerless pose estimation in individual animals, extending these to multiple animals presents unique challenges for studies of social behaviors or animals in their natural environments. Here we present Social LEAP Estimates Animal Poses (SLEAP), a machine learning system for multi-animal pose tracking. This system enables versatile workflows for data labeling, model training and inference on previously unseen data. SLEAP features an accessible graphical user interface, a standardized data model, a reproducible configuration system, over 30 model architectures, two approaches to part grouping and two approaches to identity tracking. We applied SLEAP to seven datasets across flies, bees, mice and gerbils to systematically evaluate each approach and architecture, and we compare it with other existing approaches. SLEAP achieves greater accuracy and speeds of more than 800 frames per second, with latencies of less than 3.5 ms at full 1,024 × 1,024 image resolution. This makes SLEAP usable for real-time applications, which we demonstrate by controlling the behavior of one animal on the basis of the tracking and detection of social interactions with another animal. SLEAP is a versatile deep learning-based multi-animal pose-tracking tool designed to work on videos of diverse animals, including during social behavior.

The nuclear envelope (NE) is the central organizing unit of the eukaryotic cell serving as a genome protective barrier and mechanotransduction interface between the cytoplasm and the nucleus. The NE is mainly composed of a nuclear lamina and a double membrane connected at specific points where the nuclear pore complexes (NPCs) form. Physiological aging might be generically defined as a functional decline across lifespan observed from the cellular to organismal level. Therefore, during aging and premature aging, several cellular alterations occur, including nuclear‐specific changes, particularly, altered nuclear transport, increased genomic instability induced by DNA damage, and telomere attrition. Here, we highlight and discuss proteins associated with nuclear transport dysfunction induced by aging, particularly nucleoporins, nuclear transport factors, and lamins. Moreover, changes in the structure of chromatin and consequent heterochromatin rearrangement upon aging are discussed. These alterations correlate with NE dysfunction, particularly lamins’ alterations. Finally, telomere attrition is addressed and correlated with altered levels of nuclear lamins and nuclear lamina‐associated proteins. Overall, the identification of molecular mechanisms underlying NE dysfunction, including upstream and downstream events, which have yet to be unraveled, will be determinant not only to our understanding of several pathologies, but as here discussed, in the aging process. Growing evidence has drawn attention to the nuclear envelope dysfunction as a hallmark of the aging process. Indeed, during aging and premature aging, several cellular alterations occur, including nuclear‐specific changes, particularly alterations in nuclear transport, chromatin organization, and telomere maintenance. Therefore, nuclear protein alterations are essential determinants of physiological and premature aging and may provide biomarkers for aging status and other pathologies like cancer.

A bstract Constraining quantum gravity from observations is a challenge. We expand on the idea that the interplay of quantum gravity with matter could be key to meeting this challenge. Thus, we set out to confront different potential candidates for quantum gravity — unimodular asymptotic safety, Weyl-squared gravity and asymptotically safe gravity — with constraints arising from demanding an ultraviolet complete Standard Model. Specifically, we show that within approximations, demanding that quantum gravity solves the Landau-pole problems in Abelian gauge couplings and Yukawa couplings strongly constrains the viable gravitational parameter space. In the case of Weyl-squared gravity with a dimensionless gravitational coupling, we also investigate whether the gravitational contribution to beta functions in the matter sector calculated from functional Renormalization Group techniques is universal, by studying the dependence on the regulator, metric field parameterization and choice of gauge.

This article reviews the origin and evolution of high throughput screening (HTS) through the experience of an individual pharmaceutical company, revealing some of the mysteries of the early stages of drug discovery to the wider pharmacology audience. HTS in this company (Pfizer, Groton, USA) had its origin in natural products screening in 1986, by substituting fermentation broths with dimethyl sulphoxide solutions of synthetic compounds, using 96‐well plates and reduced assay volumes of 50‐100μl. A nominal 30mM source compound concentration provided high μM assay concentrations. Starting at 800 compounds each week, the process reached a steady state of 7200 compounds per week by 1989. Screening in the Applied Biotechnology and Screening Group was centralized with screens operating in lock‐step to maximize efficiency. Initial screens were full files run in triplicate. Autoradiography and image analysis were introduced for 125I receptor ligand screens. Reverse transcriptase (RT) coupled with quantitative PCR and multiplexing addressed several targets in a single assay. By 1992 HTS produced ‘hits’ as starting matter for approximately 40% of the Discovery portfolio. In 1995, the HTS methodology was expanded to include ADMET targets. ADME targets required each compound to be physically detected leading to the development of automated high throughput LC‐MS. In 1996, 90 compounds/week were screened in microsomal, protein binding and serum stability assays. Subsequently, the mutagenic Ames assay was adapted to a 96‐well plate liquid assay and novel algorithms permitted automated image analysis of the micronucleus assay. By 1999 ADME HTS was fully integrated into the discovery cycle. British Journal of Pharmacology (2007) 152, 53–61; doi:10.1038/sj.bjp.0707373

Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies.