Interrogating the recognition landscape of a conserved HIV-specific TCR reveals distinct bacterial peptide cross-reactivity
T cell cross-reactivity ensures that diverse pathogen-derived epitopes encountered during a lifetime are recognized by the available TCR repertoire. A feature of cross-reactivity where previous exposure to one microbe can alter immunity to subsequent, non-related pathogens has been mainly explored for viruses. Yet cross-reactivity to additional microbes is important to consider, especially in HIV infection where gut-intestinal barrier dysfunction could facilitate T cell exposure to commensal/pathogenic microbes. Here we evaluated the cross-reactivity of a ‘public’, HIV-specific, CD8 T cell-derived TCR (AGA1 TCR...
Source: eLife - July 27, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Par protein localization during the early development of < i > Mnemiopsis leidyi < /i > suggests different modes of epithelial organization in the Metazoa
In bilaterians and cnidarians, epithelial cell-polarity is regulated by the interactions between Par proteins, Wnt/PCP signalling pathway, and cell-cell adhesion. Par proteins are highly conserved across Metazoa, including ctenophores. But strikingly, ctenophore genomes lack components of the Wnt/PCP pathway and cell-cell adhesion complexes raising the question if ctenophore cells are polarized by mechanisms involving Par proteins. Here, by using immunohistochemistry and live-cell imaging of specific mRNAs, we describe for the first time the subcellular localization of selected Par proteins in blastomeres and epithelial ce...
Source: eLife - July 27, 2020 Category: Biomedical Science Tags: Developmental Biology Evolutionary Biology Source Type: research

A quantitative modelling approach to zebrafish pigment pattern formation
Pattern formation is a key aspect of development. Adult zebrafish exhibit a striking striped pattern generated through the self-organisation of three different chromatophores. Numerous investigations have revealed a multitude of individual cell-cell interactions important for this self-organisation, but it has remained unclear whether these known biological rules were sufficient to explain pattern formation. To test this, we present an individual-based mathematical model incorporating all the important cell-types and known interactions. The model qualitatively and quantitatively reproduces wild type and mutant pigment patt...
Source: eLife - July 27, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Developmental Biology Source Type: research

Microglial calcium signaling is attuned to neuronal activity in awake mice
Microglial calcium signaling underlies a number of key physiological processes in situ, but has not been studiedin vivo in awake mice. Using multiple GCaMP6 variants targeted to microglia, we assessed how microglial calcium signaling responds to alterations in neuronal activity across a wide physiological range. We find that only a small subset of microglial somata and processes exhibited spontaneous calcium transients in a chronic window preparation. However, hyperactive shifts in neuronal activity (kainate status epilepticus and CaMKIIa Gq DREADD activation) trigger increased microglial process calcium signaling, often c...
Source: eLife - July 27, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Dissecting transcriptional amplification by MYC
SupraphysiologicalMYC levels are oncogenic. Originally considered a typical transcription factor recruited to E-boxes (CACGTG), another theory posits MYC a global amplifier increasing output at all active promoters. Both models rest on large-scale genome-wide ”-omics’. Because the assumptions, statistical parameter and model choice dictates the ‘-omic’ results, whether MYC is a general or specific transcription factor remains controversial. Therefore, an orthogonal series of experiments interrogated MYC’s effect on the expression of synthetic r eporters. Dose-dependently, MYC increased output ...
Source: eLife - July 27, 2020 Category: Biomedical Science Tags: Cancer Biology Computational and Systems Biology Source Type: research

Intrinsic control of muscle attachment sites matching
Myogenesis is an evolutionarily conserved process. Little known, however, is how the morphology of each muscle is determined, such that movements relying upon contraction of many muscles are both precise and coordinated. EachDrosophila larval muscle is a single multinucleated fiber whose morphology reflects expression of distinctive identity Transcription Factors (iTFs). By deleting transcription cis-regulatory modules of one iTF, Collier, we generated viable muscle identity mutants, allowing live imaging and locomotion assays. We show that both selection of muscle attachment sites and muscle/muscle matching is intrinsic t...
Source: eLife - July 24, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Periodic propagating waves coordinate RhoGTPase network dynamics at the leading and trailing edges during cell migration
Migrating cells need to coordinate distinct leading and trailing edge dynamics but the underlying mechanisms are unclear. Here, we combine experiments and mathematical modeling to elaborate the minimal autonomous biochemical machinery necessary and sufficient for this dynamic coordination and cell movement. RhoA activates Rac1 via DIA and inhibits Rac1 via ROCK, while Rac1 inhibits RhoA through PAK. Our data suggest that in motile, polarized cells, RhoA –ROCK interactions prevail at the rear, whereas RhoA-DIA interactions dominate at the front where Rac1/Rho oscillations drive protrusions and retractions. At the rear...
Source: eLife - July 24, 2020 Category: Biomedical Science Tags: Cell Biology Computational and Systems Biology Source Type: research

Dynamics of gaze control during prey capture in freely moving mice
Many studies of visual processing are conducted in constrained conditions such as head- and gaze-fixation, and therefore less is known about how animals actively acquire visual information in natural contexts. To determine how mice target their gaze during natural behavior, we measured head and bilateral eye movements in mice performing prey capture, an ethological behavior that engages vision. We found that the majority of eye movements are compensatory for head movements, thereby serving to stabilize the visual scene. During movement, however, periods of stabilization are interspersed with non-compensatory saccades that ...
Source: eLife - July 24, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Estrogen exacerbates mammary involution through neutrophil dependent and independent mechanism
There is strong evidence that the pro-inflammatory microenvironment during post-partum mammary involution promotes parity-associated breast cancer. Estrogen exposure during mammary involution drives tumour growth through neutrophils' activity. However, how estrogen and neutrophils influence mammary involution are unknown. Combined analysis of transcriptomic, protein, and immunohistochemical data in BALB/c mice showed that estrogen promotes involution by exacerbating inflammation, cell death and adipocytes repopulation. Remarkably, 88% of estrogen-regulated genes in mammary tissue were mediated through neutrophils, which we...
Source: eLife - July 24, 2020 Category: Biomedical Science Tags: Developmental Biology Immunology and Inflammation Source Type: research

Odd-paired is a pioneer-like factor that coordinates with Zelda to control gene expression in embryos
Pioneer factors such as Zelda (Zld) help initiate zygotic transcription in Drosophila early embryos, but whether other factors support this dynamic process is unclear. Odd-paired (Opa), a zinc-finger transcription factor expressed at cellularization, controls the transition of genes from pair-rule to segmental patterns along the anterior-posterior axis. Finding that Opa also regulates expression through enhancer sog_Distal along the dorso-ventral axis, we hypothesized Opa ’s role is more general. Chromatin-immunoprecipitation (ChIP-seq) confirmed its in vivo binding to sog_Distal but also identified widespread bindin...
Source: eLife - July 23, 2020 Category: Biomedical Science Tags: Developmental Biology Genetics and Genomics Source Type: research

Chronic ethanol consumption compromises neutrophil function in acute pulmonary < i > Aspergillus fumigatus < /i > infection
This study establishes a new paradigm in innate immune response in chronic ethanol consumers. (Source: eLife)
Source: eLife - July 23, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

Antagonistic control of DDK binding to licensed replication origins by Mcm2 and Rad53
Eukaryotic replication origins are licensed by the loading of the replicative DNA helicase, Mcm2-7, in inactive double hexameric form around DNA. Subsequent origin activation is under control of multiple protein kinases that either promote or inhibit origin activation, which is important for genome maintenance. Using the reconstituted budding yeast DNA replication system, we find that the flexible N-terminal extension (NTE) of Mcm2 promotes the stable recruitment of Dbf4-dependent kinase (DDK) to Mcm2-7 double hexamers, which in turn promotes DDK phosphorylation of Mcm4 and -6 and subsequent origin activation. Conversely, ...
Source: eLife - July 23, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Chromosomes and Gene Expression Source Type: research

Altered expression of a quality control protease in < i > E. coli < /i > reshapes the in vivo mutational landscape of a model enzyme
Protein mutational landscapes are shaped by the cellular environment, but key factors and their quantitative effects are often unknown. Here we show that Lon, a quality control protease naturally absent in commonE. coli expression strains, drastically reshapes the mutational landscape of the metabolic enzyme dihydrofolate reductase (DHFR). Selection under conditions that resolve highly active mutants reveals that 23.3% of all single point mutations in DHFR are advantageous in the absence of Lon, but advantageous mutations are largely suppressed when Lon is reintroduced. Protein stability measurements demonstrate extensive ...
Source: eLife - July 23, 2020 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Synaptic and intrinsic mechanisms underlying development of cortical direction selectivity
Modifications of synaptic inputs and cell-intrinsic properties both contribute to neuronal plasticity and development. To better understand these mechanisms, we undertook an intracellular analysis of the development of direction selectivity in the ferret visual cortex, which occurs rapidly over a few days after eye opening. We found strong evidence of developmental changes in linear spatiotemporal receptive fields of simple cells, implying alterations in circuit inputs. Further, this receptive field plasticity was accompanied by increases in near-spike-threshold excitability and input-output gain that resulted in dramatica...
Source: eLife - July 23, 2020 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Private –public mappings in human prefrontal cortex
A core feature of human cognition is an ability to separate private states of mind – what we think or believe – from public actions – what we say or do. This ability is central to successful social interaction – with different social contexts often requiring different mappings between private states and public actions in order to minimise conflict and facilitate communicat ion. Here we investigated how the human brain supports private-public mappings, using an interactive task which required subjects to adapt how they communicated their confidence about a perceptual decision to the social context. U...
Source: eLife - July 23, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Combining agent-based, trait-based and demographic approaches to model coral-community dynamics
The complexity of coral-reef ecosystems makes it challenging to predict their dynamics and resilience under future disturbance regimes. Models for coral-reef dynamics do not adequately account for the high functional diversity exhibited by corals. Models that are ecologically and mechanistically detailed are therefore required to simulate the ecological processes driving coral reef dynamics. Here we describe a novel model that includes processes at different spatial scales, and the contribution of species ’ functional diversity to benthic-community dynamics. We calibrated and validated the model to reproduce observed...
Source: eLife - July 23, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Ecology Source Type: research

The growth of acronyms in the scientific literature
Some acronyms are useful and are widely understood, but many of the acronyms used in scientific papers hinder understanding and contribute to the increasing fragmentation of science. Here we report the results of an analysis of more than 24 million article titles and 18 million article abstracts published between 1950 and 2019. There was at least one acronym in 19% of the titles and 73% of the abstracts. Acronym use has also increased over time, but the re-use of acronyms has declined. We found that from more than one million unique acronyms in our data, just over 2,000 (0.2%) were used regularly, and most acronyms (79%) a...
Source: eLife - July 23, 2020 Category: Biomedical Science Source Type: research

Transposase assisted tagmentation of RNA/DNA hybrid duplexes
Tn5-mediated transposition of double-strand DNA has been widely utilized in various high-throughput sequencing applications. Here, we report that the Tn5 transposase is also capable of direct tagmentation of RNA/DNA hybrids in vitro. As a proof-of-concept application, we utilized this activity to replace the traditional library construction procedure of RNA sequencing, which contains many laborious and time-consuming processes. Results ofTransposase assistedRNA/DNA hybridsCo-tagmEntation (termed 'TRACE-seq') are compared to traditional RNA-seq methods in terms of detected gene number, gene body coverage, gene expression me...
Source: eLife - July 23, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Genetics and Genomics Source Type: research

Controlling protein function by fine-tuning conformational flexibility
In a living cell, protein function is regulated in several ways, including post-translational modifications (PTMs), protein-protein interaction, or by the global environment (e.g. crowding or phase separation). While site-specific PTMs act very locally on the protein, specific protein interactions typically affect larger (sub-)domains, and global changes affect the whole protein non-specifically. Herein, we directly observe protein regulation under three different degrees of localization, and present the effects on the Hsp90 chaperone system at the levels of conformational steady states, kinetics and protein function. Inte...
Source: eLife - July 22, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Host Sirtuin 2 as an immunotherapeutic target against tuberculosis
Mycobacterium tuberculosis (Mtb) employs plethora of mechanisms to hijack the host defence machinery for its successful survival, proliferation and persistence. Here we show thatMtb upregulates one of the key epigenetic modulators, NAD+ dependent histone deacetylase Sirtuin 2 (SIRT2), which upon infection translocate to the nucleus and deacetylates histone H3K18, thus modulating the host transcriptome leading to enhanced macrophage activation. Furthermore, inMtb specific T cells, SIRT2 deacetylates NF κB-p65 at K310 to modulate T helper cell differentiation. Pharmacological inhibition of SIRT2 restricts the intracell...
Source: eLife - July 22, 2020 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Electron tomography visualization of HIV-1 fusion with target cells using inhibitors to trap the prehairpin intermediate
Fusion of HIV-1 with the membrane of its target cell, an obligate first step in virus infectivity, is mediated by binding of the viral envelope (Env) spike protein to its receptors, CD4 and CCR5/CXCR4, on the cell surface. The process of viral fusion appears to be fast compared with viral egress and has not been visualized by EM. To capture fusion events, the process must be curtailed by trapping Env-receptor binding at an intermediate stage. We have used fusion inhibitors to trap HIV-1 virions attached to target cells by Envs in an extended pre-hairpin intermediate state. Electron tomography revealed HIV-1 virions bound t...
Source: eLife - July 22, 2020 Category: Biomedical Science Tags: Cell Biology Microbiology and Infectious Disease Source Type: research

Inhibition of post-termination ribosome recycling at premature termination codons in UPF1 ATPase mutants
Recognition and rapid degradation of mRNA harboring premature translation termination codons (PTCs) serves to protect cells from accumulating non-functional and potentially toxic truncated polypeptides. Targeting of PTC-containing transcripts is mediated by the nonsense-mediated mRNA decay (NMD) pathway and requires a conserved set of proteins including UPF1, an RNA helicase whose ATPase activity is essential for NMD. Previously, we identified a functional interaction between the NMD machinery and terminating ribosomes based on 3 ’ RNA decay fragments that accrue in UPF1 ATPase mutants. Herein, we show that those dec...
Source: eLife - July 22, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

Studying the biology of cytotoxic T lymphocytes in vivo with a fluorescent granzyme B-mTFP knock-in mouse
Understanding T cell function in vivo is of key importance for basic and translational immunology alike. To study T cells in vivo, we developed a new knock-in mouse line, which expresses a fusion protein of granzyme B, a key component of cytotoxic granules involved in T cell-mediated target cell-killing, and monomeric teal fluorescent protein from the endogenousGzmb locus. Homozygous knock-ins, which are viable and fertile, have cytotoxic T lymphocytes with endogeneously fluorescent cytotoxic granules but wild-type-like killing capacity. Expression of the fluorescent fusion protein allows quantitative analyses of cytotoxic...
Source: eLife - July 22, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome
Abnormal α-synuclein aggregation has been implicated in several diseases and is known to spread in a prion-like manner. There is a relationship between protein aggregate structure (strain) and clinical phenotype in prion diseases, however, whether differences in the strains of α‑synuclein aggregates acco unt for the different pathologies remained unclear. Here, we generated two types of α-synuclein fibrils from identical monomer and investigated their seeding and propagation ability in mice and primary-cultured neurons. One α-synuclein fibril induced marked accumulation of phosphorylated α-s...
Source: eLife - July 22, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Genetic and environmental determinants of variation in the plasma lipidome of older Australian twins
We examined heritability of the plasma lipidome among healthy older-aged twins (75 monozygotic/55 dizygotic pairs) enrolled in the Older Australian Twins Study (OATS) and explored corresponding gene expression and DNA methylation associations. 27/209 lipids (13.3%) detected by liquid chromatography-coupled mass spectrometry (LC-MS) were significantly heritable under the classical ACE twin model (h2=0.28-0.59), which included ceramides (Cer) and triglycerides (TG). Relative to non-significantly heritable TGs, heritable TGs had a greater number of associations with gene transcripts, not directly associated with lipid metabol...
Source: eLife - July 22, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research

High glucose levels increase influenza-associated damage to the pulmonary epithelial-endothelial barrier
This study provides the first evidence that hyperglycaemia may increase influenza severity by damaging the pulmonary epithelial-endothelial barrier and increasing pulmonary oedema. These data suggest that maintaining long-term glucose control in individuals with diabetes is paramount in reducing the morbidity and mortality associated with influenza virus infections. (Source: eLife)
Source: eLife - July 22, 2020 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

Sensory restoration by epidural stimulation of the lateral spinal cord in upper-limb amputees
Restoring somatosensory feedback to people with limb amputations is crucial to improve prosthetic control. Multiple studies have demonstrated that peripheral nerve stimulation and targeted reinnervation can provide somatotopically relevant sensory feedback. While effective, the surgical procedures required for these techniques remain a major barrier to translatability. Here, we demonstrate in four people with upper-limb amputation that epidural spinal cord stimulation (SCS), a common clinical technique to treat pain, evoked somatosensory percepts that were perceived as emanating from the missing arm and hand. Over up to 29...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Neuroscience Source Type: research

Early life adversity decreases pre-adolescent fear expression by accelerating amygdala PV cell development
Early life adversity (ELA) is associated with increased risk for stress-related disorders later in life. The link between ELA and risk for psychopathology is well established but the developmental mechanisms remain unclear. Using a mouse model of resource insecurity, limited bedding (LB), we tested the effects of LB on the development of fear learning and neuronal structures involved in emotional regulation, the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). LB delayed the ability of peri-weanling (21 days old) mice to express, but not form, an auditory conditioned fear memory. LB accelerated the developme...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Molecular determinants of large cargo transport into the nucleus
Nucleocytoplasmic transport is tightly regulated by the nuclear pore complex (NPC). Among the thousands of molecules that cross the NPC, even very large (>15 nm) cargoes such as pathogens, mRNAs and pre-ribosomes can pass the NPC intact. For these cargoes, there is little quantitative understanding of the requirements for their nuclear import, especially the role of multivalent binding to transport receptors via nuclear localisation sequences (NLSs) and the effect of size on import efficiency. Here, we assayed nuclear import kinetics of 30 large cargo models based on four capsid-like particles in the size range of 17 &n...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Cell Biology Structural Biology and Molecular Biophysics Source Type: research

Alcohol drinking alters stress response to predator odor via BNST kappa opioid receptor signaling in male mice
Maladaptive responses to stress are a hallmark of alcohol use disorder, but the mechanisms that underlie this are not well characterized. Here we show that kappa opioid receptor signaling in the bed nucleus of the stria terminalis (BNST) is a critical molecular substrate underlying abnormal stress responses to predator odor following heavy alcohol drinking. Exposure to predator odor during protracted withdrawal from intermittent alcohol drinking resulted in enhanced prefrontal cortex (PFC)-driven excitation of prodynorphin-containing neurons in the BNST. Furthermore, deletion of prodynorphin in the BNST and chemogenetic in...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

New insights into the mechanism of dynein motor regulation by lissencephaly-1
Lissencephaly ( ‘smooth brain’) is a severe brain disease associated with numerous symptoms, including cognitive impairment, and shortened lifespan. The main causative gene of this disease – lissencephaly-1 (LIS1) – has been a focus of intense scrutiny since its first identification almost 30 years ago. LIS 1 is a critical regulator of the microtubule motor cytoplasmic dynein, which transports numerous cargoes throughout the cell, and is a key effector of nuclear and neuronal transport during brain development. Here, we review the role of LIS1 in cellular dynein function and discuss recent key findi...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Stem cell niche exit in < i > C. elegans < /i > via orientation and segregation of daughter cells by a cryptic cell outside the niche
Stem cells reside in and rely upon their niche to maintain stemness but must balance self-renewal with the production of daughters that leave the niche to differentiate. We discovered a mechanism of stem cell niche exit in the canonicalC. elegans distal tip cell (DTC) germ stem cell niche mediated by previously unobserved, thin, membranous protrusions of the adjacent somatic gonad cell pair (Sh1). A disproportionate number of germ cell divisions were observed at the DTC-Sh1 interface. Stem-like and differentiating cell fates segregated across this boundary. Spindles polarized, pairs of daughter cells oriented between the D...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

A taxonomy of seizure dynamotypes
Seizures are a disruption of normal brain activity present across a vast range of species and conditions. We introduce an organizing principle that leads to the first objective Taxonomy of Seizure Dynamics (TSD) based on bifurcation theory. The ‘dynamotype’ of a seizure is the dynamic composition that defines its observable characteristics, including how it starts, evolves and ends. Analyzing over 2000 focal-onset seizures from multiple centers, we find evidence of all 16 dynamotypes predicted in TSD. We demonstrate that patients’ dy namotypes evolve during their lifetime and display complex but systemati...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Neuroscience Source Type: research

Turning away from danger
The flexible escape behavior exhibited byC. elegans in response to threats relies on a combination of feedback and feedforward circuits. (Source: eLife)
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging < i > Caenorhabditis elegans < /i >
All eukaryotes require iron. Replication, detoxification, and a cancer-protective form of regulated cell death termedferroptosis, all depend on iron metabolism. Ferrous iron accumulates over adult lifetime inCaenorhabditis elegans. Here, we show that glutathione depletion is coupled to ferrous iron elevation in these animals, and that both occur in late life to prime cells for ferroptosis. We demonstrate that blocking ferroptosis, either by inhibition of lipid peroxidation or by limiting iron retention, mitigates age-related cell death and markedly increases lifespan and healthspan. Temporal scaling of lifespan is not evid...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Emergence and diversification of a host-parasite RNA ecosystem through Darwinian evolution
In prebiotic evolution, molecular self-replicators are considered to develop into diverse, complex living organisms. The appearance of parasitic replicators is believed inevitable in this process. However, the role of parasitic replicators in prebiotic evolution remains elusive. Here, we demonstrated experimental coevolution of RNA self-replicators (host RNAs) and emerging parasitic replicators (parasitic RNAs) using an RNA-protein replication system we developed. During a long-term replication experiment, a clonal population of the host RNA turned into an evolving host-parasite ecosystem through the continuous emergence o...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Evolutionary Biology Source Type: research

Phylogenetic variation in cortical layer II immature neuron reservoir of mammals
The adult mammalian brain is mainly composed of mature neurons. A limited amount of stem cell-driven neurogenesis persists in postnatal life and is reduced in large-brained species. Another source of immature neurons in adult brains is cortical layer II. These cortical immature neurons (cINs) retain developmentally undifferentiated states in adulthood, though they are generated before birth. Here, the occurrence, distribution and cellular features of cINs were systematically studied in 12 diverse mammalian species spanning from small-lissencephalic to large-gyrencephalic brains. In spite of well-preserved morphological and...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Tracking cells in epithelial acini by light sheet microscopy reveals proximity effects in breast cancer initiation
Cancer clone evolution takes place within tissue ecosystem habitats. But, how exactly tumors arise from a few malignant cells within an intact epithelium is a central, yet unanswered question. This is mainly due to the inaccessibility of this process to longitudinal imaging together with a lack of systems that model the progression of a fraction of transformed cells within a tissue. Here, we developed a new methodology based on primary mouse mammary epithelial acini, where oncogenes can be switched on in single cells within an otherwise normal epithelial cell layer. We combine this stochastic breast tumor induction model w...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Cancer Biology Cell Biology Source Type: research

Three-dimensional synaptic organization of the human hippocampal CA1 field
The hippocampal CA1 field integrates a wide variety of subcortical and cortical inputs, but its synaptic organization in humans is still unknown due to the difficulties involved studying the human brain via electron microscope techniques. However, we have shown that the 3D reconstruction method using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) can be applied to study in detail the synaptic organization of the human brain obtained from autopsies, yielding excellent results. Using this technology, 24,752 synapses were fully reconstructed in CA1, revealing that most of them were excitatory, targeting dendritic spi...
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Delayed gratification in the adult brain
Some immature neurons in the cerebral cortex of mammals might wait for years before they become activated and finish their development. (Source: eLife)
Source: eLife - July 21, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Expandable and reversible copy number amplification drives rapid adaptation to antifungal drugs
Previously, we identified long repeat sequences that are frequently associated with genome rearrangements, including copy number variation (CNV), in many diverse isolates of the human fungal pathogenCandida albicans (Todd et al., 2019). Here, we describe the rapid acquisition of novel, high copy number CNVs during adaptation to azole antifungal drugs. Single-cell karyotype analysis indicates that these CNVs appear to arise via a dicentric chromosome intermediate and breakage-fusion-bridge cycles that are repaired using multiple distinct long inverted repeat sequences. Subsequent removal of the antifungal drug can lead to a...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Genetics and Genomics Microbiology and Infectious Disease Source Type: research

Protective role of neuronal and lymphoid cannabinoid CB < sub > 2 < /sub > receptors in neuropathic pain
Cannabinoid CB2 receptor (CB2) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB2, however the involvement of CB2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2 agonist JWH133 in wild-type and knockout mice lacking CB2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2 disrupted JWH133-taking behavior, t...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Human Biology and Medicine Neuroscience Source Type: research

Persistent firing in LEC III neurons is differentially modulated by learning and aging
In this study, persistent firing was evoked in vitro from LEC III neurons from young and aged rats that were behaviorally naive or trained on trace eyeblink conditioning. Persistent firing ability from neurons from behaviorally naive aged rats was lower compared to neurons from young rats. Neurons from learning impaired aged animals also exhibited reduced persistent firing capacity, which may contribute to aging-related learning impairments. Successful acquisition of the trace eyeblink task, however, increased persistent firing ability in both young and aged rats. These changes in persistent firing ability are due to chang...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Neural dynamics of perceptual inference and its reversal during imagery
After the presentation of a visual stimulus, neural processing cascades from low-level sensory areas to increasingly abstract representations in higher-level areas. It is often hypothesised that a reversal in neural processing underlies the generation of mental images as abstract representations are used to construct sensory representations in the absence of sensory input. According to predictive processing theories, such reversed processing also plays a central role in later stages of perception. Direct experimental evidence of reversals in neural information flow has been missing. Here, we used a combination of machine l...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Different theta frameworks coexist in the rat hippocampus and are coordinated during memory-guided and novelty tasks
Hippocampal firing is organized in theta sequences controlled by internal memory processes and by external sensory cues, but how these computations are coordinated is not fully understood. Although theta activity is commonly studied as a unique coherent oscillation, it is the result of complex interactions between different rhythm generators. Here, by separating hippocampal theta activity in three different current generators, we found epochs with variable theta frequency and phase coupling, suggesting flexible interactions between theta generators. We found that epochs of highly synchronized theta rhythmicity preferential...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Neuroscience Source Type: research

Stochastic logistic models reproduce experimental time series of microbial communities
We analyze properties of experimental microbial time series, from plankton and the human microbiome, and investigate whether stochastic generalized Lotka-Volterra models could reproduce those properties. We show that this is the case when the noise term is large and a linear function of the species abundance, while the strength of the self-interactions varies over multiple orders of magnitude. We stress the fact that all the observed stochastic properties can be obtained from a logistic model, i.e. without interactions, even the niche character of the experimental time series. Linear noise is associated with growth rate st...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research

S-phase-independent silencing establishment in < i > Saccharomyces cerevisiae < /i >
The establishment of silent chromatin, a heterochromatin-like structure atHMLandHMR inSaccharomyces cerevisiae, depends on progression through S phase of the cell cycle, but the molecular nature of this requirement has remained elusive despite intensive study. Using high-resolution chromatin immunoprecipitation and single-molecule RNA analysis, we found that silencing establishment proceeded via gradual repression of transcription in individual cells over several cell cycles, and that the cell-cycle-regulated step was downstream of Sir protein recruitment. In contrast to prior results,HML andHMR had identical cell-cycle re...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis
Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors culturedex vivo,and identify DECR1,encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival.DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selective...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Cancer Biology Source Type: research

DAZL mediates a broad translational program regulating expansion and differentiation of spermatogonial progenitors
Fertility across metazoa requires the germline-specific DAZ family of RNA-binding proteins. Here we examine whether DAZL directly regulates progenitor spermatogonia using a conditional genetic mouse model andin vivo biochemical approaches combined with chemical synchronization of spermatogenesis. We find that the absence ofDazlimpairs both expansion and differentiation of the spermatogonial progenitor population. In undifferentiated spermatogonia, DAZL binds the 3' UTRs of ~2,500 protein-coding genes. Some targets are known regulators of spermatogonial proliferation and differentiation while others are broadly expressed, d...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Universality of clonal dynamics poses fundamental limits to identify stem cell self-renewal strategies
How adult stem cells maintain self-renewing tissues is in vivo commonly assessed by analysing clonal data from cell lineage tracing assays. To identify strategies of stem cell self-renewal requires that different models of stem cell fate choice predict sufficiently different clonal statistics. Here we show that models of cell fate choice can, in homeostatic tissues, be categorized by exactly two 'universality classes', whereby models of the same class predict, under asymptotic conditions, the same clonal statistics. Those classes relate to generalizations of the canonical asymmetric vs. symmetric stem cell self-renewal str...
Source: eLife - July 20, 2020 Category: Biomedical Science Tags: Computational and Systems Biology Developmental Biology Source Type: research