Post-transcriptional repression of circadian component CLOCK regulates cancer-stemness in murine breast cancer cells
In this study, we demonstrated the negative regulation of ALDH activity by the major circadian component CLOCK in murine breast cancer 4T1 cells. The expression of CLOCK was repressed in high-ALDH-activity 4T1, and enhancement of CLOCK expression abrogated their stemness properties, such as tumorigenicity and invasive potential. Furthermore, reduced expression of CLOCK in high-ALDH-activity 4T1 was post-transcriptionally regulated by microRNA: miR-182. Knockout of miR-182 restored the expression of CLOCK, resulted in preventing tumor growth. Our findings suggest that increased expression of CLOCK in BCSCs by targeting post...
Source: eLife - April 23, 2021 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Ongoing repair of migration-coupled DNA damage allows planarian adult stem cells to reach wound sites
Mechanical stress during cell migration may be a previously unappreciated source of genome instability, but the extent to which this happens in any animalin vivo remains unknown. We consider anin vivo system where the adult stem cells of planarian flatworms are required to migrate to a distal wound site. We observe a relationship between adult stem cell migration and ongoing DNA damage and repair during tissue regeneration. Migrating planarian stem cells undergo changes in nuclear shape and exhibit increased levels of DNA damage. Increased DNA damage levels reduce once stem cells reach the wound site. Stem cells in which D...
Source: eLife - April 23, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Co-regulation and function of < i > FOXM1 < /i > / < i > RHNO1 < /i > bidirectional genes in cancer
The FOXM1 transcription factor is an oncoprotein and a top biomarker of poor prognosis in human cancer. Overexpression and activation of FOXM1 is frequent in high-grade serous carcinoma (HGSC), the most common and lethal form of human ovarian cancer, and is linked to copy number gains at chromosome 12p13.33. We show thatFOXM1 is co-amplified and co-expressed withRHNO1, a gene involved in the ATR-Chk1 signaling pathway that functions in the DNA replication stress (RS) response. We demonstrate thatFOXM1 andRHNO1 are head-to-head (i.e. bidirectional) genes (BDG) regulated by a bidirectional promoter (BDP) (named F/R-BDP). FOX...
Source: eLife - April 23, 2021 Category: Biomedical Science Tags: Cancer Biology Chromosomes and Gene Expression Source Type: research

Cells under pressure
A new method for applying solid stress to aggregates of cells is shedding light on the impact of mechanical forces on cancer cells. (Source: eLife)
Source: eLife - April 23, 2021 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation
Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell ...
Source: eLife - April 23, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research

High-resolution imaging of skin deformation shows that afferents from human fingertips signal slip onset
Human tactile afferents provide essential feedback for grasp stability during dexterous object manipulation. Interacting forces between an object and the fingers induce slip events that are thought to provide information about grasp stability. To gain insight into this phenomenon, we made a transparent surface slip against a fixed fingerpad while monitoring skin deformation at the contact. Using microneurography, we simultaneously recorded the activity of single tactile afferents innervating the fingertips. This unique combination allowed us to describe how afferents respond to slip events and to relate their responses to ...
Source: eLife - April 22, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Identification of functionally distinct macrophage subpopulations in < i > Drosophila < /i >
Vertebrate macrophages are a highly heterogeneous cell population, but whileDrosophila blood is dominated by a macrophage-like lineage (plasmatocytes), until very recently these cells were considered to represent a homogeneous population. Here, we present our identification of enhancer elements labelling plasmatocyte subpopulations, which vary in abundance across development. These subpopulations exhibit functional differences compared to the overall population, including more potent injury responses and differential localisation and dynamics in pupae and adults. Our enhancer analysis identified candidate genes regulating ...
Source: eLife - April 22, 2021 Category: Biomedical Science Tags: Developmental Biology Immunology and Inflammation Source Type: research

UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling
To adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that UBTD1 (Ubiquitin domain-containing protein 1) plays a crucial role in both the EGFR (Epidermal Growth Factor Receptor) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through ASAH1 (N-Acylsphingosine Amidohydrolase 1) ubiquitination, UBTD1 controls the ligand-independent phosphoryla...
Source: eLife - April 22, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research

Confinement discerns swarmers from planktonic bacteria
Powered by flagella, many bacterial species exhibit collective motion on a solid surface commonly known as swarming. As a natural example of active matter, swarming is also an essential biological phenotype associated with virulence, chemotaxis, and host pathogenesis. Physical changes like cell elongation and hyper flagellation have been shown to accompany the swarming phenotype. Less studied, however, are the contrasts of collective motion between the swarming cells and their counterpart planktonic cells of comparable cell density. Here, we show that confining bacterial movement in circular microwells allows distinguishin...
Source: eLife - April 22, 2021 Category: Biomedical Science Tags: Physics of Living Systems Source Type: research

T cell self-reactivity during thymic development dictates the timing of positive selection
Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced TCR sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells wi...
Source: eLife - April 22, 2021 Category: Biomedical Science Tags: Developmental Biology Immunology and Inflammation Source Type: research

The < i > cis < /i > -regulatory effects of modern human-specific variants
The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells, and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1791 (13%) of sequences containing these variants showed active regulatory activ...
Source: eLife - April 22, 2021 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Anticipation of temporally structured events in the brain
We examined how the brain uses experience in structured environments to anticipate upcoming events. During fMRI, individuals watched a 90-second movie clip six times. Using a Hidden Markov Model applied to searchlights across the whole brain, we identified temporal shifts between activity patterns evoked by the first vs. repeated viewings of the movie clip. In many regions throughout the cortex, neural activity patterns for repeated viewings shifted to precede those of initial viewing by up to 15 seconds. This anticipation varied hierarchically in a posterior (less anticipation) to anterior (more anticipation) fashion. We ...
Source: eLife - April 22, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Creating and controlling visual environments using BonVision
Real-time rendering of closed-loop visual environments is important for next-generation understanding of brain function and behaviour, but is often prohibitively difficult for non-experts to implement and is limited to few laboratories worldwide. We developed BonVision as an easy-to-use open-source software for the display of virtual or augmented reality, as well as standard visual stimuli. BonVision has been tested on humans and mice, and is capable of supporting new experimental designs in other animal models of vision. As the architecture is based on the open-source Bonsai graphical programming language, BonVision benef...
Source: eLife - April 21, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Correction: Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer
(Source: eLife)
Source: eLife - April 21, 2021 Category: Biomedical Science Tags: Cancer Biology Chromosomes and Gene Expression Source Type: research

Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors
The metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G protein-coupled receptors that contain both a seven-helix transmembrane domain (TMD) and a large extracellular ligand-binding domain (LBD) which enables stable dimerization. While numerous studies have revealed variability across subtypes in the initial activation steps at the level of LBD dimers, an understanding of inter-TMD interaction and rearrangement remains limited. Here we use a combination of single molecule fluorescence, molecular dynamics, functional assays, and conformational sensors to reveal that distinct TMD assembly properties ...
Source: eLife - April 21, 2021 Category: Biomedical Science Tags: Neuroscience Structural Biology and Molecular Biophysics Source Type: research

Tissue-specific modulation of gene expression in response to lowered insulin signalling in < i > Drosophila < /i >
Reduced activity of the insulin/IGF signalling network increases health during ageing in multiple species. Diverse and tissue-specific mechanisms drive the health improvement. Here, we performed tissue-specific transcriptional and proteomic profiling of long-livedDrosophila dilp2-3,5 mutants, and identified tissue-specific regulation of>3600 transcripts and>3700 proteins. Most expression changes were regulated post-transcriptionally in the fat body, and only in mutants infected with the endosymbiotic bacteria,Wolbachia pipientis, which increases their lifespan. Bioinformatic analysis identified reduced co-translation...
Source: eLife - April 21, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Computational and Systems Biology Source Type: research

Corollary discharge promotes a sustained motor state in a neural circuit for navigation
Animals exhibit behavioral and neural responses that persist on longer time scales than transient or fluctuating stimulus inputs. Here, we report thatC. elegans uses feedback from the motor circuit to a sensory processing interneuron to sustain its motor state during thermotactic navigation. By imaging circuit activity in behaving animals, we show that a principal postsynaptic partner of the AFD thermosensory neuron, the AIY interneuron, encodes both temperature and motor state information. By optogenetic and genetic manipulation of this circuit, we demonstrate that the motor state representation in AIY is a corollary disc...
Source: eLife - April 21, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Nutrient dominance governs the assembly of microbial communities in mixed nutrient environments
A major open question in microbial community ecology is whether we can predict how the components of a diet collectively determine the taxonomic composition of microbial communities. Motivated by this challenge, we investigate whether communities assembled in pairs of nutrients can be predicted from those assembled in every single nutrient alone. We find that although the null, naturally additive model generally predicts well the family-level community composition, there exist systematic deviations from the additive predictions that reflect generic patterns of nutrient dominance at the family level. Pairs of more-similar n...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Ecology Source Type: research

Insights from a Pan India Sero-Epidemiological survey (Phenome-India Cohort) for SARS-CoV2
To understand the spread of SARS-CoV2, in August and September 2020, the Council of Scientific and Industrial Research (India), conducted a sero-survey across its constituent laboratories and centers across India. Of 10,427 volunteers, 1058 (10.14%) tested positive for SARS CoV2 anti-nucleocapsid (anti-NC) antibodies; 95% of which had surrogate neutralization activity. Three-fourth of these recalled no symptoms. Repeat serology tests at 3 (n=607) and 6 (n=175) months showed stable anti-NC antibodies but declining neutralization activity. Local sero-positivity was higher in densely populated cities and was inversely correla...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Medicine Source Type: research

Sensitivity of ID NOW and RT-PCR for detection of SARS-CoV-2 in an ambulatory population
Diagnosis of SARS-CoV-2 (COVID-19) requires confirmation by Reverse-Transcription Polymerase Chain Reaction (RT-PCR). Abbott ID NOW provides fast results but has been criticized for low sensitivity. Here we determine the sensitivity of ID NOW in an ambulatory population presenting for testing. The study enrolled 785 symptomatic patients, 21 of whom were positive by both ID NOW and RT-PCR, and 2 only by RT-PCR. All 189 asymptomatic patients tested negative. The positive percent agreement between the ID NOW assay and the RT-PCR assay was 91.3%, and negative percent agreement was 100%. The results from the current study were ...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Medicine Source Type: research

Robust and distributed neural representation of action values
Studies in rats, monkeys, and humans have found action-value signals in multiple regions of the brain. These findings suggest that action-value signals encoded in these brain structures bias choices toward higher expected rewards. However, previous estimates of action-value signals might have been inflated by serial correlations in neural activity and also by activity related to other decision variables. Here, we applied several statistical tests based on permutation and surrogate data to analyze neural activity recorded from the striatum, frontal cortex, and hippocampus. The results show that previously identified action-...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

< i > In vitro < /i > proteasome processing of neo-splicetopes does not predict their presentation < i > in vivo < /i >
Proteasome catalyzed peptide splicing (PCPS) of cancer-driving antigens could generate attractive neoepitopes to be targeted by TCR-based adoptive T cell therapy. Based on a spliced peptide prediction algorithm TCRs were generated against putative KRASG12V and RAC2P29L derived neo-splicetopes with high HLA-A*02:01 binding affinity. TCRs generated in mice with a diverse human TCR repertoire specifically recognized the respective target peptides with high efficacy. However, we failed to detect any neo-splicetope specific T cell response when testing thein vivo neo-splicetope generation and obtained no experimental evidence t...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Immunology and Inflammation Source Type: research

A cross-sectional study of functional and metabolic changes during aging through the lifespan in male mice.
In this study, we conducted physiologic and functional tests cross-sectionally throughout the entire lifespan of male C57BL/6N mice. In parallel, metabolomics analyses in serum, brain, liver, heart, and skeletal muscle were also performed to identify signatures associated with frailty and age-dependent functional decline. Our findings indicate that declines in gait speed as a function of age and frailty are associated with a dramatic increase in the energetic cost of physical activity and decreases in working capacity. Aging and functional decline prompt organs to rewire their metabolism and substrate selection and towards...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research

The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle function
Aging is accompanied by disrupted information flow, resulting from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders including skeletal muscle wasting, or sarcopenia. To derive a global metric of growing 'disorderliness' of aging muscle, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Escalating network entropy reached an inflection point at old age, while structural and functional alterations progressed into oldest-old age. To probe the potential for restoration of molecular 'orde...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Stem Cells and Regenerative Medicine Source Type: research

Plant-associated CO < sub > 2 < /sub > mediates long-distance host location and foraging behaviour of a root herbivore
Insect herbivores use different cues to locate host plants. The importance of CO2 in this context is not well understood. We manipulated CO2 perception in western corn rootworm (WCR) larvae through RNAi and studied how CO2 perception impacts their interaction with their host plant. The expression of a carbon dioxide receptor,DvvGr2, is specifically required for dose-dependent larval responses to CO2. Silencing CO2 perception or scrubbing plant-associated CO2 has no effect on the ability of WCR larvae to locate host plants at short distances (
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Ecology Source Type: research

Therapeutic inhibition of keratinocyte TRPV3 sensory channel by local anesthetic dyclonine
The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted Syndrome in human. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine i...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Characterization and functional analysis of cathelicidin-MH, a novel frog-derived peptide with anti-septicemic properties
Antimicrobial peptides form part of the innate immune response and play a vital role in host defense against pathogens. Here we report a new antimicrobial peptide belonging to the cathelicidin family, cathelicidin-MH (cath-MH), from the skin ofMicrohyla heymonsivogt frog. Cath-MH has a single α-helical structure in membrane-mimetic environments and is antimicrobial against fungi and bacteria, especially Gram-negative bacteria. In contrast to other cathelicidins, cath-MH suppresses coagulation by affecting the enzymatic activities of tissue plasminogen activator, plasmin, β-tryptase, el astase, thrombin, and chym...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Bacterial-fungal interactions in the neonatal gut influence asthma outcomes later in life
Bacterial members of the infant gut microbiota and bacterial-derived short-chain fatty acids (SCFAs) have been shown to be protective against childhood asthma, but a role for the fungal microbiota in asthma etiology remains poorly defined. We recently reported an association between overgrowth of the yeastPichia kudriavzeviiin the gut microbiota of Ecuadorian infants and increased asthma risk. In the present study, we replicated these findings in Canadian infants and investigated a causal association between early life gut fungal dysbiosis and later allergic airway disease (AAD). In a mouse model, we demonstrate that overg...
Source: eLife - April 20, 2021 Category: Biomedical Science Tags: Immunology and Inflammation Medicine Source Type: research

Repeated introductions and intensive community transmission fueled a mumps virus outbreak in Washington State
In 2016/2017, Washington State experienced a mumps outbreak despite high childhood vaccination rates, with cases more frequently detected among school-aged children and members of the Marshallese community. We sequenced 166 mumps virus genomes collected in Washington and other US states, and traced mumps introductions and transmission within Washington. We uncover that mumps was introduced into Washington approximately 13 times, primarily from Arkansas, sparking multiple co-circulating transmission chains. Although age and vaccination status may have impacted transmission, our dataset could not quantify their precise effec...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Defective apoptotic cell contractility provokes sterile inflammation leading to liver damage and tumour suppression
Apoptosis is characterized by profound morphological changes, but their physiological purpose is unknown. To characterize the role of apoptotic cell contraction, ROCK1 was rendered caspase non-cleavable (ROCK1nc) by mutating Aspartate 1113, which revealed that ROCK1 cleavage was necessary for forceful contraction and membrane blebbing. When homozygous ROCK1nc mice were treated with the liver-selective apoptotic stimulus of diethylnitrosamine, ROCK1nc mice had more profound liver damage with greater neutrophil infiltration than wild-type mice. Inhibition of the damage associated molecular pattern protein HMGB1 or signalling...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Cancer Biology Cell Biology Source Type: research

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses
Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27R α, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mut...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Immunology and Inflammation Source Type: research

Spontaneous and evoked activity patterns diverge over development
The immature brain is highly spontaneously active. Over development this activity must be integrated with emerging patterns of stimulus-evoked activity, but little is known about how this occurs. Here we investigated this question by recording spontaneous and evoked neural activity in the larval zebrafish tectum from 4 to 15 days post fertilisation. Correlations within spontaneous and evoked activity epochs were comparable over development, and their neural assemblies properties refined in similar ways. However both the similarity between evoked and spontaneous assemblies, and also the geometric distance between spontaneou...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Structure of HIV-1 gp41 with its membrane anchors targeted by neutralizing antibodies
The HIV-1 gp120/gp41 trimer undergoes a series of conformational changes in order to catalyze gp41-induced fusion of viral and cellular membranes. Here, we present the crystal structure of gp41 locked in a fusion intermediate state by an MPER-specific neutralizing antibody. The structure illustrates the conformational plasticity of the six membrane anchors arranged asymmetrically with the fusion peptides and the transmembrane regions pointing into different directions. Hinge regions located adjacent to the fusion peptide and the transmembrane region facilitate the conformational flexibility that allows high affinity bindin...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Structural Biology and Molecular Biophysics Source Type: research

Genetic determinants facilitating the evolution of resistance to carbapenem antibiotics
In this era of rising antibiotic resistance, in contrast to our increasing understanding of mechanisms that cause resistance, our understanding of mechanisms that influence the propensity to evolve resistance remains limited. Here, we identified genetic factors that facilitate the evolution of resistance to carbapenems, the antibiotic of 'last resort,' inKlebsiella pneumoniae, the major carbapenem resistant species. In clinical isolates, we found that high-level transposon insertional mutagenesis plays an important role in contributing to high-level resistance frequencies in several major and emerging carbapenem-resistant ...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Evolutionary Biology Microbiology and Infectious Disease Source Type: research

Multiscale analysis of single and double maternal-zygotic < i > Myh9 < /i > and < i > Myh10 < /i > mutants during mouse preimplantation development
During the first days of mammalian development, the embryo forms the blastocyst, the structure responsible for implanting the mammalian embryo. Consisting of an epithelium enveloping the pluripotent inner cell mass and a fluid-filled lumen, the blastocyst results from a series of cleavages divisions, morphogenetic movements and lineage specification. Recent studies identified the essential role of actomyosin contractility in driving the cytokinesis, morphogenesis and fate specification leading to the formation of the blastocyst. However, the preimplantation development of contractility mutants has not been characterized. H...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Downregulation of glial genes involved in synaptic function mitigates Huntington's Disease pathogenesis
Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations ofDrosophila expressing human mutantHuntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes invo...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Genetics and Genomics Source Type: research

DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation
The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). DCC and NTN1 are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent inDccandNtn1knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulati...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Characterizing the hum of hovering animals
The sounds of flying animals, such as the hum of a hummingbird as it hovers, are influenced by the unique forces generated by the flapping of their wings. (Source: eLife)
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Evolutionarily conserved sperm factors, DCST1 and DCST2, are required for gamete fusion
To trigger gamete fusion, spermatozoa need to activate the molecular machinery in which sperm IZUMO1 and oocyte JUNO (IZUMO1R) interaction plays a critical role in mammals. Although a set of factors involved in this process has recently been identified, no common factor that can function in both vertebrates and invertebrates has yet been reported. Here, we first demonstrate that the evolutionarily conserved factors dendrocyte expressed seven transmembrane protein domain-containing 1 (DCST1) and dendrocyte expressed seven transmembrane protein domain-containing 2 (DCST2) are essential for sperm –egg fusion in mice, as...
Source: eLife - April 19, 2021 Category: Biomedical Science Tags: Developmental Biology Source Type: research

The Nesprin-1/-2 ortholog ANC-1 regulates organelle positioning in < i > C. elegans < /i > independently from its KASH or actin-binding domains
KASH proteins in the outer nuclear membrane comprise the cytoplasmic half of LINC complexes that connect nuclei to the cytoskeleton.Caenorhabditis elegans ANC-1, an ortholog of Nesprin-1/2, contains actin-binding and KASH domains at opposite ends of a long spectrin-like region. Deletion of either the KASH or calponin homology (CH) domains does not completely disrupt nuclear positioning, suggesting neither KASH nor CH domains are essential. Deletions in the spectrin-like region of ANC-1 led to significant defects, but only recapitulated the null phenotype in combination with mutations in the trans-membrane span. Inanc-1 mut...
Source: eLife - April 16, 2021 Category: Biomedical Science Tags: Cell Biology Source Type: research

Synaptic learning rules for sequence learning
Remembering the temporal order of a sequence of events is a task easily performed by humans in everyday life, but the underlying neuronal mechanisms are unclear. This problem is particularly intriguing as human behavior often proceeds on a time scale of seconds, which is in stark contrast to the much faster millisecond time-scale of neuronal processing in our brains. One long-held hypothesis in sequence learning suggests that a particular temporal fine-structure of neuronal activity - termed 'phase precession' - enables the compression of slow behavioral sequences down to the fast time scale of the induction of synaptic pl...
Source: eLife - April 16, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Live-cell single-molecule tracking highlights requirements for stable Smc5/6 chromatin association < i > in vivo < /i >
The essential Smc5/6 complex is required in response to replication stress and is best known for ensuring the fidelity of homologous recombination. Using single-molecule tracking in live fission yeast to investigate Smc5/6 chromatin association, we show that Smc5/6 is chromatin associated in unchallenged cells and this depends on the non-SMC protein Nse6. We define a minimum of two Nse6-dependent sub-pathways, one of which requires the BRCT-domain protein Brc1. Using defined mutants in genes encoding the core Smc5/6 complex subunits we show that the Nse3 double-stranded DNA binding activity and the arginine fingers of the ...
Source: eLife - April 16, 2021 Category: Biomedical Science Tags: Chromosomes and Gene Expression Genetics and Genomics Source Type: research

Heterogeneity in transmissibility and shedding SARS-CoV-2 via droplets and aerosols
Background: Which virological factors mediate overdispersion in the transmissibility of emerging viruses remains a longstanding question in infectious disease epidemiology. (Source: eLife)
Source: eLife - April 16, 2021 Category: Biomedical Science Tags: Epidemiology and Global Health Microbiology and Infectious Disease Source Type: research

A convolutional neural network for the prediction and forward design of ribozyme-based gene-control elements
Ribozyme switches are a class of RNA-encoded genetic switch that support conditional regulation of gene expression across diverse organisms. An improved elucidation of the relationships between sequence, structure, and activity can improve our capacity forde novo rational design of ribozyme switches. Here, we generated data on the activity of hundreds of thousands of ribozyme sequences. Using automated structural analysis and machine learning, we leveraged these large datasets to develop predictive models that estimate thein vivo gene-regulatory activity of a ribozyme sequence. These models supported thede novo design of r...
Source: eLife - April 16, 2021 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research

Rapid recycling of glutamate transporters on the astroglial surface
Glutamate uptake by astroglial transporters confines excitatory transmission to the synaptic cleft. The efficiency of this mechanism depends on the transporter dynamics in the astrocyte membrane, which remains poorly understood. Here, we visualise the main glial glutamate transporter GLT1 by generating its pH-sensitive fluorescent analogue, GLT1-SEP. FRAP-based imaging shows that 70-75% of GLT1-SEP dwell on the surface of rat brain astroglia, recycling with a lifetime of ~22 s. Genetic deletion of the C-terminus accelerates GLT1-SEP membrane turnover while disrupting its surface pattern, as revealed by single-molecule loca...
Source: eLife - April 16, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

Improving oligo-conjugated antibody signal in multimodal single-cell analysis
This study provides new insight into titration response and background of oligo-conjugated antibodies and offers concrete guidelines to improve such panels. (Source: eLife)
Source: eLife - April 16, 2021 Category: Biomedical Science Tags: Genetics and Genomics Immunology and Inflammation Source Type: research

Why flies look to the skies
Fruit flies rely on an intricate neural pathway to process polarized light signals in order to inform their internal compass about the position of the Sun. (Source: eLife)
Source: eLife - April 16, 2021 Category: Biomedical Science Tags: Neuroscience Source Type: research

ORACLE reveals a bright future to fight bacteria
A new way to alter the genome of bacteriophages helps produce large libraries of variants, allowing these bacteria-killing viruses to be designed to target species harmful to human health. (Source: eLife)
Source: eLife - April 15, 2021 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly
Numerous proteins target lipid droplets (LDs) through amphipathic helices (AHs). It is generally assumed that AHs insert bulky hydrophobic residues in packing defects at the LD surface. However, this model does not explain the targeting of perilipins, the most abundant and specific amphipathic proteins of LDs, which are weakly hydrophobic. A striking example is Plin4, whose gigantic and repetitive AH lacks bulky hydrophobic residues. Using a range of complementary approaches, we show that Plin4 forms a remarkably immobile and stable protein layer at the surface of cellular or in vitro generated oil droplets, and decreases ...
Source: eLife - April 15, 2021 Category: Biomedical Science Tags: Cell Biology Physics of Living Systems Source Type: research

Inverse regulation of < i > Vibrio cholerae < /i > biofilm dispersal by polyamine signals
The global pathogenVibrio cholerae undergoes cycles of biofilm formation and dispersal in the environment and the human host. Little is understood about biofilm dispersal. Here, we show that MbaA, a periplasmic polyamine sensor, and PotD1, a polyamine importer, regulateV. cholerae biofilm dispersal. Spermidine, a commonly produced polyamine, drivesV. cholerae dispersal, whereas norspermidine, an uncommon polyamine produced by vibrios, inhibits dispersal. Spermidine and norspermidine differ by one methylene group. Both polyamines control dispersal via MbaA detection in the periplasm and subsequent signal relay. Our results ...
Source: eLife - April 15, 2021 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research