13273 research outputs found
Sort by
Single-cell analysis opens a goldmine for plant functional studies
No full textFunctional studies in biology require the identification of genes, regulatory elements, and networks, followed by a deep understanding of how they orchestrate to specify cell types, mediate signaling, and respond to internal and external cues over evolutionary timescales. Advances in single-cell analysis have enabled biologists to tackle these questions at the resolution of the individual cell. Here, we highlight recent studies in plants that have embraced single-cell analyses to facilitate functional studies. This review will provide guidance and perspectives for incorporating these advanced approaches in plant research for the coming decades
Metabolism in acute myeloid leukemia: mechanistic insights and therapeutic targets
No full textMetabolic rewiring and cellular reprogramming are trademarks of neoplastic initiation and progression in acute myeloid leukemia (AML). Metabolic alteration in leukemia cells is often genotype-specific, with associated changes in epigenetic and functional factors resulting in the downstream upregulation or facilitation of oncogenic pathways. Targeting abnormal or disease-sustaining metabolic activities in AML provides a wide range of therapeutic opportunities, ideally with enhanced therapeutic windows and robust clinical efficacy. This review highlights the dysregulation of amino acid, nucleotide, lipid, and carbohydrate metabolism in AML, explores the role of key vitamins and enzymes that regulate these processes, and provides an overview of metabolism-directed therapies currently in use or development
A reinforcement learning algorithm shapes maternal care in mice
Get PDFThe neural substrates for processing classical rewards such as food or drugs of abuse are well-understood. In contrast, the mechanisms by which organisms perceive social contact as rewarding and subsequently modify their interactions are unclear. Here we tracked the gradual emergence of a repetitive and highly-stereotyped parental behavior and show that trial-by-trial performance correlates with the history of midbrain dopamine (DA) neuron activity. We used a novel behavior paradigm to manipulate the subject’s expectation of imminent pup contact and show that DA signals conform to reward prediction error, a fundamental component of reinforcement learning (RL). Finally, closed-loop optogenetic inactivation of DA neurons at the onset of pup contact dramatically slowed emergence of parental care. We conclude that this prosocial behavior is shaped by an RL mechanism in which social contact itself is the primary reward
Statistical correction of input gradients for black box models trained with categorical input features
Get PDFGradients of a deep neural network’s predictions with respect to the inputs are used in a variety of downstream analyses, notably in post hoc explanations with feature attribution methods. For data with input features that live on a lower-dimensional manifold, we observe that the learned function can exhibit arbitrary behaviors off the manifold, where no data exists to anchor the function during training. This leads to a random component in the gradients which manifests as noise. We introduce a simple correction for this off-manifold gradient noise for the case of categorical input features, where input values are subject to a probabilistic simplex constraint, and demonstrate its effectiveness on regulatory genomics data. We find that our correction consistently leads to a significant improvement in gradient-based attribution scores
Structural insights into binding of therapeutic channel blockers in NMDA receptors
No full textExcitatory signaling mediated by N-methyl-D-aspartate receptor (NMDAR) is critical for brain development and function, as well as for neurological diseases and disorders. Channel blockers of NMDARs are of medical interest owing to their potential for treating depression, Alzheimer's disease, and epilepsy. However, precise mechanisms underlying binding and channel blockade have remained limited owing to challenges in obtaining high-resolution structures at the binding site within the transmembrane domains. Here, we monitor the binding of three clinically important channel blockers: phencyclidine, ketamine, and memantine in GluN1-2B NMDARs at local resolutions of 2.5-3.5 Å around the binding site using single-particle electron cryo-microscopy, molecular dynamics simulations, and electrophysiology. The channel blockers form different extents of interactions with the pore-lining residues, which control mostly off-speeds but not on-speeds. Our comparative analyses of the three unique NMDAR channel blockers provide a blueprint for developing therapeutic compounds with minimal side effects
Training the host organism to enhance anti-cancer immunity
No full textIn this issue of Cancer Cell, Kurz et al. demonstrate in an orthotopic pancreatic cancer model that low-intensity exercise improves tumor control and response to immunotherapy in an IL-15-dependent manner. Combination therapy, IL-15 super-agonist, anti-PD-1 antibody and chemotherapy, strongly reduces tumor growth. Therefore, the study opens rich translational avenues
Target binding triggers hierarchical phosphorylation of human Argonaute-2 to promote target release
Get PDFThe application of artificial intelligence to biology and neuroscience
No full textOver the last decade, the artificial intelligence (AI) has undergone a revolution that is poised to transform the economy, society, and science. The pace of progress is staggering, and problems that seemed intractable just a few years ago have now been solved. The intersection between neuroscience and AI is particularly exciting
PTP1B inhibitors protect against acute lung injury and regulate CXCR4 signaling in neutrophils
Get PDFAcute lung injury (ALI) can cause acute respiratory distress syndrome (ARDS), a lethal condition with limited treatment options and currently a common global cause of death due to COVID-19. ARDS secondary to transfusion-related ALI (TRALI) has been recapitulated preclinically by anti-MHC-I antibody administration to LPS-primed mice. In this model, we demonstrate that inhibitors of PTP1B, a protein tyrosine phosphatase that regulates signaling pathways of fundamental importance to homeostasis and inflammation, prevented lung injury and increased survival. Treatment with PTP1B inhibitors attenuated the aberrant neutrophil function that drives ALI and was associated with release of myeloperoxidase, suppression of neutrophil extracellular trap (NET) formation, and inhibition of neutrophil migration. Mechanistically, reduced signaling through the CXCR4 chemokine receptor, particularly to the activation of PI3Kγ/AKT/mTOR, was essential for these effects, linking PTP1B inhibition to promoting an aged-neutrophil phenotype. Considering that dysregulated activation of neutrophils has been implicated in sepsis and causes collateral tissue damage, we demonstrate that PTP1B inhibitors improved survival and ameliorated lung injury in an LPS-induced sepsis model and improved survival in the cecal ligation and puncture-induced (CLP-induced) sepsis model. Our data highlight the potential for PTP1B inhibition to prevent ALI and ARDS from multiple etiologies
Transcriptomic diversity in human medullary thymic epithelial cells
Get PDFThe induction of central T cell tolerance in the thymus depends on the presentation of peripheral self-epitopes by medullary thymic epithelial cells (mTECs). This promiscuous gene expression (pGE) drives mTEC transcriptomic diversity, with non-canonical transcript initiation, alternative splicing, and expression of endogenous retroelements (EREs) representing important but incompletely understood contributors. Here we map the expression of genome-wide transcripts in immature and mature human mTECs using high-throughput 5' cap and RNA sequencing. Both mTEC populations show high splicing entropy, potentially driven by the expression of peripheral splicing factors. During mTEC maturation, rates of global transcript mis-initiation increase and EREs enriched in long terminal repeat retrotransposons are up-regulated, the latter often found in proximity to differentially expressed genes. As a resource, we provide an interactive public interface for exploring mTEC transcriptomic diversity. Our findings therefore help construct a map of transcriptomic diversity in the healthy human thymus and may ultimately facilitate the identification of those epitopes which contribute to autoimmunity and immune recognition of tumor antigens