Classification and genetic targeting of cell types in the primary taste and premotor center of the adult < i > Drosophila < /i > brain
This study provides insight into the anatomical organization of the SEZ and generates resources that will facilitate further study of SEZ neurons and their contributions to sensory processing and behavior. (Source: eLife)
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Modelling spinal locomotor circuits for movements in developing zebrafish
In this study, we iteratively built models of developing zebrafish spinal circuits coupled to simplified musculoskeletal models that reproduce coiling and swimming movements. The neurons of the models were based upon morphologically or genetically identified populations in the developing zebrafish spinal cord. We simulated intact spinal circuits as well as circuits with silenced neurons or altered synaptic transmission to better understand the role of specific spinal neurons. Analysis of firing patterns and phase relationships helped identify possible mechanisms underlying the locomotor movements of developing zebrafish. N...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Single-cell and single-nucleus RNA-seq uncovers shared and distinct axes of variation in dorsal LGN neurons in mice, non-human primates, and humans
Abundant evidence supports the presence of at least three distinct types of thalamocortical (TC) neurons in the primate dorsal lateral geniculate nucleus (dLGN) of the thalamus, the brain region that conveys visual information from the retina to the primary visual cortex (V1). Different types of TC neurons in mice, humans, and macaques have distinct morphologies, distinct connectivity patterns, and convey different aspects of visual information to the cortex. To investigate the molecular underpinnings of these cell types, and how these relate to differences in dLGN between human, macaque, and mice, we profiled gene express...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
A framework for studying behavioral evolution by reconstructing ancestral repertoires
Although different animal species often exhibit extensive variation in many behaviors, typically scientists examine one or a small number of behaviors in any single study. Here, we propose a new framework to simultaneously study the evolution of many behaviors. We measured the behavioral repertoire of individuals from six species of fruit flies using unsupervised techniques and identified all stereotyped movements exhibited by each species. We then fit a Generalized Linear Mixed Model to estimate the intra- and inter-species behavioral covariances, and, by using the known phylogenetic relationships among species, we estima...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Evolutionary Biology Physics of Living Systems Source Type: research
Ascorbic acid supports ex vivo generation of plasmacytoid dendritic cells from circulating hematopoietic stem cells
Plasmacytoid dendritic cells (pDCs) constitute a rare type of immune cell with multifaceted functions, but their potential use as a cell-based immunotherapy is challenged by the scarce cell numbers that can be extracted from blood. Here, we systematically investigate culture parameters for generating pDCs from hematopoietic stem and progenitor cells (HSPCs). Using optimized conditions combined with implementation of HSPC pre-expansion, we generate an average of 465 million HSPC-derived pDCs (HSPC-pDCs) starting from 100,000 cord blood-derived HSPCs. Furthermore, we demonstrate that such protocol allows HSPC-pDC generation ...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research
DeepEthogram, a machine learning pipeline for supervised behavior classification from raw pixels
Videos of animal behavior are used to quantify researcher-defined behaviors-of-interest to study neural function, gene mutations, and pharmacological therapies. Behaviors-of-interest are often scored manually, which is time-consuming, limited to few behaviors, and variable across researchers. We created DeepEthogram: software that uses supervised machine learning to convert raw video pixels into an ethogram, the behaviors-of-interest present in each video frame. DeepEthogram is designed to be general-purpose and applicable across species, behaviors, and video-recording hardware. It uses convolutional neural networks to com...
Source: eLife - September 2, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
Skeleton interoception regulates bone and fat metabolism through hypothalamic neuroendocrine NPY
The central nervous system regulates activity of peripheral organs through interoception. In our previous study, we have demonstrated that PGE2/EP4 skeleton interception regulate bone homeostasis. Here we show that ascending skeleton interoceptive signaling downregulates expression of hypothalamic neuropeptide Y (NPY) and induce lipolysis of adipose tissue for osteoblastic bone formation. Specifically, the ascending skeleton interoceptive signaling induces expression of small heterodimer partner-interacting leucine zipper protein (SMILE) in the hypothalamus. SMILE binds to pCREB as a transcriptional heterodimer on Npy prom...
Source: eLife - September 1, 2021 Category: Biomedical Science Tags: Medicine Neuroscience Source Type: research
< i > In situ < /i > imaging of bacterial outer membrane projections and associated protein complexes using electron cryo-tomography
The ability to produce outer membrane projections in the form of tubular membrane extensions (MEs) and membrane vesicles (MVs) is a widespread phenomenon among diderm bacteria. Despite this, our knowledge of the ultrastructure of these extensions and their associated protein complexes remains limited. Here, we surveyed the ultrastructure and formation of MEs and MVs, and their associated protein complexes, in tens of thousands of electron cryo-tomograms of ~ 90 bacterial species that we have collected for various projects over the past 15 years (Jensen lab database), in addition to data generated in the Briegel lab. We ide...
Source: eLife - September 1, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research
Structural insights into the activation of human calcium-sensing receptor
Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca2+ homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in addition to the full inactive and active states, there are multiple intermediate states during the activation of CaSR. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca2+ ion that acts as a composite agonist with L-amino acid to stabilize the closure of ...
Source: eLife - September 1, 2021 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research
Human genetic analyses of organelles highlight the nucleus in age-related trait heritability
Most age-related human diseases are accompanied by a decline in cellular organelle integrity, including impaired lysosomal proteostasis and defective mitochondrial oxidative phosphorylation. An open question, however, is the degree to which inherited variation in or near genes encoding each organelle contributes to age-related disease pathogenesis. Here, we evaluate if genetic loci encoding organelle proteomes confer greater-than-expected age-related disease risk. As mitochondrial dysfunction is a 'hallmark' of aging, we begin by assessing nuclear and mitochondrial DNA loci near genes encoding the mitochondrial proteome an...
Source: eLife - September 1, 2021 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research
The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging
Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial membrane thought to be composed of the F-ATP synthase (complex V). OSCP, a subunit of F-ATP synthase, helps protect against mPTP formation. How the destabilization of OSCP may contribute to aging, however, is unclear. We have found that loss OSCP in the nematodeCaenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood, in part via initiation of the mitochondrial unfolded protein response (UPRmt). Pharmacolo...
Source: eLife - September 1, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research
Endoplasmic reticulum tubules limit the size of misfolded protein condensates
The endoplasmic reticulum (ER) is composed of sheets and tubules. Here we report that the COPII coat subunit, SEC24C, works with the long form of the tubular ER-phagy receptor, RTN3, to target dominant-interfering mutant proinsulin Akita puncta to lysosomes. When the delivery ofAkita puncta to lysosomes was disrupted, large puncta accumulated in the ER. Unexpectedly, photobleach analysis indicated thatAkita puncta behaved as condensates and not aggregates, as previously suggested.Akita puncta enlarged when either RTN3 or SEC24C were depleted, or when ER sheets were proliferated by either knocking out Lunapark or overexpres...
Source: eLife - September 1, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research
The dual role of amyloid β-sheet interaction sequences in the cell surface properties of < i > FLO11 < /i > -encoded flocculins in the yeast < i > Saccharomyces cerevisiae < /i >
In this report, we show that flocculins encoded byFLO11 inSaccharomyces cerevisiae behave like adhesins inC. albicans. To do so, we show that the formation of nanodomains under an external physical force requires a threshold number of amyloid-forming sequences in the Flo11 protein. Then, using a genome editing approach, we constructed strains expressing variants of the Flo11 protein under the endogenous FLO11 promoter, leading to the demonstration that the loss of amyloid-forming sequences strongly reduces cell-cell interaction but has no effect on either plastic adherence or invasive growth in agar, both phenotypes being ...
Source: eLife - September 1, 2021 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research
Deciphering the triad of infection, immunity and pathology
The factors which drive and control disease progression can be inferred from mathematical models that integrate measures of immune responses, data from tissue sampling and markers of infection dynamics. (Source: eLife)
Source: eLife - September 1, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Immunology and Inflammation Source Type: research
Dorsal premammillary projection to periaqueductal gray controls escape vigor from innate and conditioned threats
Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats....
Source: eLife - September 1, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research
