A stochastic framework of neurogenesis underlies the assembly of neocortical cytoarchitecture
The cerebral cortex contains multiple areas with distinctive cytoarchitectonical patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have investigated the neuronal output of individual progenitor cells in the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. Our experimental results indicate that progenitor cells generate pyramidal cell lineages with a wide range of sizes and laminar configurations. Mathematical modelling indicates that these outcomes are compatible with a stochastic m...
Source: eLife - November 18, 2019 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist
Immune regulation is a finely balanced process of positive and negative signals. PD-L1 and its receptor PD-1 are critical regulators of autoimmune, anti-viral and anti-tumoural T cell responses. Although the function of its predominant membrane-bound form is well-established, the source and biological activity of soluble PD-L1 (sPD-L1) remain incompletely understood. Here, we show that sPD-L1 in human healthy tissues and tumours is produced by exaptation of an intronicLINE-2A (L2A) endogenous retroelement in theCD274 gene, encoding PD-L1, which causes omission of the transmembrane domain and the regulatory sequence in the ...
Source: eLife - November 15, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Immunology and Inflammation Source Type: research

Risk factors for asthma among schoolchildren who participated in a case-control study in urban Uganda
In conclusion, asthma was associated with a strong rural-town-city risk gradient, higher parental socio-economic status and urbanicity. This work provides the basis for future studies to identify specific environmental/lifestyle factors responsible for increasing asthma risk among children in urban areas in LMICs. (Source: eLife)
Source: eLife - November 15, 2019 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

Stimulating the hippocampal posterior-medial network enhances task-dependent connectivity and memory
Successful episodic memory involves dynamic increases in activity across distributed hippocampal networks, including the posterior-medial (PMN) and the anterior-temporal (ATN) networks. We tested whether this up-regulation of functional connectivity during memory processing can be enhanced within hippocampal networks by noninvasive stimulation, and whether such task-dependent connectivity enhancement predicts memory improvement. Participants received stimulation targeting the PMN or an out-of-network control location. We compared the effects of stimulation on fMRI connectivity during an autobiographical retrieval task vers...
Source: eLife - November 14, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Formation of a β-barrel membrane protein is catalyzed by the interior surface of the assembly machine protein BamA
The β-barrel assembly machine (Bam) complex in Gram-negative bacteria and its counterparts in mitochondria and chloroplasts fold and insert outer membrane β-barrel proteins. BamA, an essential component of the complex, is itself a β-barrel and is proposed to play a central role in assembling other ba rrel substrates. Here, we map the path of substrate insertion by the Bam complex using site-specific crosslinking to understand the molecular mechanisms that control β-barrel folding and release. We find that the C-terminal strand of the substrate is stably held by BamA and that the N-terminal stra nds of t...
Source: eLife - November 14, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Microbiology and Infectious Disease Source Type: research

Direct binding of phosphatidylglycerol at specific sites modulates desensitization of a ligand-gated ion channel
Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five argin...
Source: eLife - November 14, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Shifts in myeloarchitecture characterise adolescent development of cortical gradients
We studied an accelerated longitudinal cohort of adolescents and young adults (n = 234, two time points) to investigate dynamic reconfigurations in myeloarchitecture. Intracortical profiles were generated using magnetization transfer (MT) data, a myelin-sensitive magnetic resonance imaging contrast. Mixed-effect models of depth specific intracortical profiles demonstrated two separate processes i) overall increases in MT, and ii) flattening of the MT profile related to enhanced signal in mid-to-deeper layers, especially in heteromodal and unimodal association cortices. This development was independent of morphological chan...
Source: eLife - November 14, 2019 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

How contraction has shaped evolution
Two unicellular relatives of animals reveal that coordinated contractions of groups of cells using actomyosin predated animal multicellularity during evolution. (Source: eLife)
Source: eLife - November 14, 2019 Category: Biomedical Science Tags: Cell Biology Evolutionary Biology Source Type: research

Movement of accessible plasma membrane cholesterol by GRAMD1 lipid transfer protein complex
Cholesterol is a major structural component of the plasma membrane (PM). The majority of PM cholesterol forms complexes with other PM lipids, making it inaccessible for intracellular transport. Transition of PM cholesterol between accessible and inaccessible pools maintains cellular homeostasis, but how cells monitor PM cholesterol accessibility remains unclear. We show that endoplasmic reticulum (ER)-anchored lipid transfer proteins, the GRAMD1s, sense and transport accessible PM cholesterol to the ER. GRAMD1s bind one another and populate at ER-PM contacts by sensing a transient expansion of the accessible pool of PM cho...
Source: eLife - November 14, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

The ion selectivity filter is not an activation gate in TRPV1-3 channels
Activation of TRPV1 channels in sensory neurons results in opening of a cation permeation pathway that triggers the sensation of pain. Opening of TRPV1 has been proposed to involve two gates that appear to prevent ion permeation in the absence of activators: the ion selectivity filter on the external side of the pore and the S6 helices that line the cytosolic half of the pore. Here we measured the access of thiol-reactive ions and compounds across the selectivity filters in rodent TRPV1-3 channels. Although our results are consistent with structural evidence that the selectivity filters in these channels are dynamic, they ...
Source: eLife - November 14, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Nitric oxide acts as a cotransmitter in a subset of dopaminergic neurons to diversify memory dynamics
Animals employ diverse learning rules and synaptic plasticity dynamics to record temporal and statistical information about the world. However, the molecular mechanisms underlying this diversity are poorly understood. The anatomically defined compartments of the insect mushroom body function as parallel units of associative learning, with different learning rates, memory decay dynamics and flexibility (Aso& Rubin 2016). Here we show that nitric oxide (NO) acts as a neurotransmitter in a subset of dopaminergic neurons inDrosophila. NO's effects develop more slowly than those of dopamine and depend on soluble guanylate c...
Source: eLife - November 14, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

The cerebellum shows its stripes
New studies examine how the different sub-structures in the cerebellum are organized to receive information during complex behavioral tasks (Source: eLife)
Source: eLife - November 14, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Efa6 protects axons and regulates their growth and branching by inhibiting microtubule polymerisation at the cortex
Cortical collapse factors affect microtubule (MT) dynamics at the plasma membrane. They play important roles in neurons, as suggested by inhibition of axon growth and regeneration through the Arf activator Efa6 inC. elegans, and by neurodevelopmental disorders linked to the mammalian kinesin Kif21A. How cortical collapse factors influence axon growth is little understood. Here we studied them, focussing on the function ofDrosophila Efa6 in experimentally and genetically amenable fly neurons. First, we show thatDrosophila Efa6 can inhibit MTs directly without interacting molecules via an N-terminal 18 amino acid motif (MT e...
Source: eLife - November 13, 2019 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Auto-regulation of Rab5 GEF activity in Rabex5 by allosteric structural changes, catalytic core dynamics and ubiquitin binding
Intracellular trafficking depends on the function of Rab GTPases, whose activation is regulated by guanine exchange factors (GEFs). The Rab5 GEF, Rabex5, was previously proposed to be auto-inhibited by its C-terminus. Here, we studied full-length Rabex5 and Rabaptin5 proteins as well as domain deletion Rabex5 mutants using hydrogen deuterium exchange mass spectrometry. We generated a structural model of Rabex5, using chemical cross-linking mass spectrometry and integrative modeling techniques. By correlating structural changes with nucleotide exchange activity for each construct, we uncovered new auto-regulatory roles for ...
Source: eLife - November 13, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Get online to support wellbeing of graduate students
Universities should use online resources to help graduate students who are struggling with their mental health to access appropriate support. (Source: eLife)
Source: eLife - November 13, 2019 Category: Biomedical Science Source Type: research

Reliability of an interneuron response depends on an integrated sensory state
The central nervous system transforms sensory information into representations that are salient to the animal. Here we define the logic of this transformation in aCaenorhabditis elegans integrating interneuron. AIA interneurons receive input from multiple chemosensory neurons that detect attractive odors. We show that reliable AIA responses require the coincidence of two sensory inputs: activation of AWA olfactory neurons that are activated by attractive odors, and inhibition of one or more chemosensory neurons that are inhibited by attractive odors. AWA activates AIA through an electrical synapse, while the disinhibitory ...
Source: eLife - November 13, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Motor cortex can directly drive the globus pallidus neurons in a projection neuron type-dependent manner in the rat
The basal ganglia are critical for the control of motor behaviors and for reinforcement learning. Here, we demonstrate in rats that primary and secondary motor areas (M1 and M2) make functional synaptic connections in the globus pallidus (GP), not usually thought of as an input site of the basal ganglia. Morphological observation revealed that the density of axonal boutons from motor cortices in the GP was 47% and 78% of that in the subthalamic nucleus (STN) from M1 and M2, respectively. Cortical excitation of GP neurons was comparable to that of STN neurons in slice preparations. FoxP2-expressing arkypallidal neurons were...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

DNA damage checkpoint activation impairs chromatin homeostasis and promotes mitotic catastrophe during aging
We present several lines of evidence supporting a model of antagonistic pleiotropy in the DNA damage response where histone degradation, and limited histone transcription are beneficial to respond rapidly to damage but reduce lifespan and genomic stability in th e long term. (Source: eLife)
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Cell Biology Source Type: research

Exploring structural dynamics of a membrane protein by combining bioorthogonal chemistry and cysteine mutagenesis
The functional mechanisms of membrane proteins are extensively investigated with cysteine mutagenesis. To complement cysteine-based approaches, we engineered a membrane protein with thiol-independent crosslinkable groups using azidohomoalanine (AHA), a non-canonical methionine analogue containing an azide group that can selectively react with cycloalkynes through a strain-promoted azide-alkyne cycloaddition (SPAAC) reaction. We demonstrate that AHA can be readily incorporated into the Shaker Kv channel in place of methionine residues and modified with azide-reactive alkyne probes inXenopus oocytes. Using voltage-clamp fluo...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research

The impact of light during the night
Exposing chicks to one hour of light during the night disrupts the release of a hormone that is needed by cells in the developing brain to survive. (Source: eLife)
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Motor cortex can directly drive the globus pallidus neurons in a projection neuron type- dependent manner in the rat
The basal ganglia are critical for the control of motor behaviors and for reinforcement learning. Here, we demonstrate in rats that primary and secondary motor areas (M1 and M2) make functional synaptic connections in the globus pallidus (GP), not usually thought of as an input site of the basal ganglia. Morphological observation revealed that the density of axonal boutons from motor cortices in the GP was 47% and 78% of that in the subthalamic nucleus (STN) from M1 and M2, respectively. Cortical excitation of GP neurons was comparable to that of STN neurons in slice preparations. FoxP2-expressing arkypallidal neurons were...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn
This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our result...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Cycles of autoubiquitination and deubiquitination regulate the ERAD ubiquitin ligase Hrd1
Misfolded proteins in the lumen of the endoplasmic reticulum (ER) are retrotranslocated into the cytosol and polyubiquitinated before being degraded by the proteasome. The multi-spanning ubiquitin ligase Hrd1 forms the retrotranslocation channel and associates with three other membrane proteins (Hrd3, Usa1, Der1) of poorly defined function. The Hrd1 channel is gated by autoubiquitination, but how Hrd1 escapes degradation by the proteasome and returns to its inactive ground state is unknown. Here, we show that autoubiquitination of Hrd1 is counteracted by Ubp1, a deubiquitinating enzyme that requires its N-terminal transmem...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

The effects of psychosocial stress on dopaminergic function and the acute stress response
Chronic psychosocial adversity induces vulnerability to mental illnesses. Animal studies demonstrate that this may be mediated by dopaminergic dysfunction. We therefore investigated whether long-term exposure to psychosocial adversity was associated with dopamine dysfunction and its relationship to psychological and physiological responses to acute stress. Using 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine ([18F]-DOPA) positron emission tomography (PET), we compared dopamine synthesis capacity inn = 17 human participants with high cumulative exposure to psychosocial adversity withn = 17 age- and sex-matched participants wi...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

The mother ’s risk of premature death after child loss across two centuries
While the rare occurrence of child loss is accompanied by reduced life expectancy of parents in contemporary affluent populations, its impact in developing societies with high child mortality rates is unclear. We identified all parents in Iceland born 1800 –1996 and compared the mortality rates of 47,711 parents who lost a child to those of their siblings (N = 126,342) who did not. The proportion of parents who experienced child loss decreased from 61.1% of those born 1800–1880 to 5.2% of those born after 1930. Child loss was consistently associat ed with increased rate of maternal, but not paternal, death befo...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

Atypical memory B-cells are associated with < i > Plasmodium falciparum < /i > anemia through anti-phosphatidylserine antibodies
Anemia is a common complication of malaria which is characterized by the loss of infected and uninfected erythrocytes. In mice malaria models, clearance of uninfected erythrocytes is promoted by autoimmune anti-phosphatidylserine (PS) antibodies produced by T-bet+B-cells, which bind to exposed PS in erythrocytes, but the mechanism in patients is still unclear. InP. falciparum patients with anemia, we show that atypical memory FcRL5+T-bet+B-cells are expanded and associate with higher levels of anti-PS antibodies in plasma and with the development of anemia in these patients. No association of anti-PS antibodies or anemia w...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Immunology and Inflammation Source Type: research

Insights into the evolution of social systems and species from baboon studies
This article summarizes our current knowledge of the natural history of baboons and highlights directions for future research. We suggest that baboons can serve as a valuable model for complex evolutionary processes, such as speciation and hybridization. The evolution of baboons has been heavily shaped by climatic changes and population expansion and fragmentation in the African savanna environment, similar to the processes that acted during human evolution. With accumulating long-term data, and new data from previously understudied species, baboons are ideally suited for investigating the links between sociality, health, ...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Interspecies interactions induce exploratory motility in < i > Pseudomonas aeruginosa < /i >
Microbes often live in multispecies communities where interactions among community members impact both the individual constituents and the surrounding environment. Here, we developed a system to visualize interspecies behaviors at initial encounters. By imaging two prevalent pathogens known to be coisolated from chronic illnesses,Pseudomonas aeruginosa andStaphylococcus aureus, we observedP. aeruginosa can modify surface motility in response to secreted factors fromS. aureus. Upon sensingS. aureus,P. aeruginosa transitioned from collective to single-cell motility with an associated increase in speed and directedness - a be...
Source: eLife - November 12, 2019 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Single-cell transcriptomic evidence for dense intracortical neuropeptide networks
Seeking new insights into the homeostasis, modulation and plasticity of cortical synaptic networks, we have analyzed results from a single-cell RNA-seq study of 22,439 mouse neocortical neurons. Our analysis exposes transcriptomic evidence for dozens of molecularly distinct neuropeptidergic modulatory networks that directly interconnect all cortical neurons. This evidence begins with a discovery that transcripts of one or more neuropeptide precursor (NPP) and one or more neuropeptide-selective G-protein-coupled receptor (NP-GPCR) genes are highly abundant in all, or very nearly all, cortical neurons. Individual neurons exp...
Source: eLife - November 11, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes
Targeted differentiation of pluripotent stem (PS) cells into myotubes enables in vitro disease modeling of skeletal muscle diseases. Although various protocols achieve myogenic differentiation in vitro, resulting myotubes typically display an embryonic identity. This is a major hurdle for accurately recapitulating disease phenotypes in vitro, as disease commonly manifests at later stages of development. To address this problem, we identified four factors from a small molecule screen whose combinatorial treatment resulted in myotubes with enhanced maturation, as shown by the expression profile of myosin heavy chain isoforms...
Source: eLife - November 11, 2019 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Cryo electron tomography with Volta phase plate reveals novel structural foundations of the 96-nm axonemal repeat in the pathogen < i > Trypanosoma brucei < /i >
We examined bloodstream and procyclic life cycle stages, and a knockdown lacking DRC11/CMF22 of the nexin dynein regulatory complex (NDRC). Sub-tomogram averaging yields a resolution of 21.8 Å for the 96-nm repeat. We discovered several lineage-specific structures, including novel inter-doublet linkages and microtubule inner proteins (MIPs). We establish that DRC11/CMF22 is required for the NDRC proximal lobe that binds the adjacent doublet microtubule. We propose that lineage-specific elaboration of axoneme structure inT. brucei reflects adaptations to support unique motility needs in diverse host environments. (Source: eLife)
Source: eLife - November 11, 2019 Category: Biomedical Science Tags: Cell Biology Microbiology and Infectious Disease Source Type: research

Induction of Sertoli-like cells from human fibroblasts by NR5A1 and GATA4
Sertoli cells are essential nurse cells in the testis that regulate the process of spermatogenesis and establish the immune-privileged environment of the blood-testis-barrier (BTB). Here, we report the in vitro reprogramming of fibroblasts to human induced Sertoli-like cells (hiSCs). Initially, five transcriptional factors and a gene reporter carrying the AMH promoter were utilized to obtain the hiSCs. We further reduce the number of reprogramming factors to two, NR5A1 and GATA4, and show that these hiSCs have transcriptome profiles and cellular properties that are similar to those of primary human Sertoli cells. Moreover,...
Source: eLife - November 11, 2019 Category: Biomedical Science Tags: Developmental Biology Human Biology and Medicine Source Type: research

Perinatal hormones favor CC17 Group B < i > Streptococcus < /i > intestinal translocation through M cells and hypervirulence in neonates
Group BStreptococcus (GBS) is the leading cause of invasive bacterial neonatal infections. Late-onset diseases (LOD) occur between 7 and 89 days of life and are largely due to the CC17 GBS hypervirulent clone. We studied the impact of estradiol (E2) and progesterone (P4), which impregnate the fetus during pregnancy, on GBS neonatal infection in cellular and mouse models of hormonal exposure corresponding to concentrations found at birth (E2-P4 C0) and over 7 days old (E2-P4 C7). Using representative GBS isolates, we show that E2-P4 C7 concentrations specifically favor CC17 GBS meningitis following mice oral infection. CC17...
Source: eLife - November 11, 2019 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

One-shot learning and behavioral eligibility traces in sequential decision making
In many daily tasks we make multiple decisions before reaching a goal. In order to learn such sequences of decisions, a mechanism to link earlier actions to later reward is necessary. Reinforcement learning theory suggests two classes of algorithms solving this credit assignment problem: In classic temporal-difference learning, earlier actions receive reward information only after multiple repetitions of the task, whereas models with eligibility traces reinforce entire sequences of actions from a single experience (one-shot). Here we show one-shot learning of sequences. We developed a novel paradigm to directly observe whi...
Source: eLife - November 11, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Initiation of chromosome replication controls both division and replication cycles in E. coli through a double-adder mechanism
Living cells proliferate by completing and coordinating two cycles, a division cycle controlling cell size, and a DNA replication cycle controlling the number of chromosomal copies. It remains unclear how bacteria such asE. coli tightly coordinate those two cycles across a wide range of growth conditions. Here, we used time-lapse microscopy in combination with microfluidics to measure growth, division and replication in singleE. coli cells in slow and fast growth conditions. To compare different phenomenological cell cycle models, we introduce a statistical framework assessing their ability to capture the correlation struc...
Source: eLife - November 11, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Microbiology and Infectious Disease Source Type: research

The DNA-binding protein HTa from < i > Thermoplasma acidophilum < /i > is an archaeal histone analog
Histones are a principal constituent of chromatin in eukaryotes and fundamental to our understanding of eukaryotic gene regulation. In archaea, histones are widespread but not universal: several lineages have lost histone genes. What prompted or facilitated these losses and how archaea without histones organize their chromatin remains largely unknown. Here, we elucidate primary chromatin architecture in an archaeon without histones,Thermoplasma acidophilum,which harbours a HU family protein (HTa) that protects part of the genome from micrococcal nuclease digestion. Charting HTa-based chromatin architecturein vitro, in vivo...
Source: eLife - November 11, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Evolutionary Biology Source Type: research

Lymphatic vessels help mend broken hearts
Experiments on zebrafish show that the regeneration of the heart after an injury is supported by lymphatic vessels. (Source: eLife)
Source: eLife - November 11, 2019 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Thermosensitive alternative splicing senses and mediates temperature adaptation in < i > Drosophila < /i >
Circadian rhythms are generated by cyclic transcription, translation, and degradation of clock gene products, includingtimeless(tim), but how the circadian clock senses and adapts to temperature changes is not completely understood. Here we show that temperature dramatically changes the splicing pattern oftim inDrosophila. We found that at 18 °C, TIM levels are low due to the induction of two cold-specific isoforms:tim-cold andtim-short&cold. At 29 °C, another isoform,tim-medium, is upregulated. This isoform switching regulates the levels and activity of TIM as each isoform has a specific function. We found tha...
Source: eLife - November 8, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration
The cardiac lymphatic vascular system and its potentially critical functions in heart patients have been largely underappreciated, in part due to a lack of experimentally accessible systems. We here demonstrate that cardiac lymphatic vessels develop in young adult zebrafish, using coronary arteries to guide their expansion down the ventricle. Mechanistically, we show that incxcr4a mutants with defective coronary artery development, cardiac lymphatic vessels fail to expand onto the ventricle. In regenerating adult zebrafish hearts the lymphatic vasculature undergoes extensive lymphangiogenesis in response to a cryoinjury. A...
Source: eLife - November 8, 2019 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Wedging open a catalytic site
The activation mechanism of the nitric oxide receptor has been revealed by cryo-electron microscopy. (Source: eLife)
Source: eLife - November 8, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Distinct origins and molecular mechanisms contribute to lymphatic formation during cardiac growth and regeneration
In recent years there has been increasing interest in the role of lymphatics in organ repair and regeneration, due to their importance in immune surveillance and fluid homeostasis. Experimental approaches aimed at boosting lymphangiogenesis following myocardial infarction in mice, were shown to promote healing of the heart. Yet, the mechanisms governing cardiac lymphatic growth remain unclear. Here we identify two distinct lymphatic populations in the hearts of zebrafish and mouse, one that forms through sprouting lymphangiogenesis, and the other by coalescence of isolated lymphatic cells. By tracing the development of eac...
Source: eLife - November 8, 2019 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Non-enzymatic primer extension with strand displacement
Non-enzymatic RNA self-replication is integral to the emergence of the 'RNA World'. Despite considerable progress in non-enzymatic template copying, demonstrating a full replication cycle remains challenging due to the difficulty of separating the strands of the product duplex. Here, we report a prebiotically plausible approach to strand displacement synthesis in which short 'invader' oligonucleotides unwind an RNA duplex through a toehold/branch migration mechanism, allowing non-enzymatic primer extension on a template that was previously occupied by its complementary strand. Kinetic studies of single-step reactions sugge...
Source: eLife - November 8, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

An image-computable model for the stimulus selectivity of gamma oscillations
Gamma oscillations in visual cortex have been hypothesized to be critical for perception, cognition, and information transfer. However, observations of these oscillations in visual cortex vary widely; some studies report little to no stimulus-induced narrowband gamma oscillations, others report oscillations for only some stimuli, and yet others report large oscillations for most stimuli. To better understand this signal, we developed a model that predicts gamma responses for arbitrary images and validated this model on electrocorticography (ECoG) data from human visual cortex. The model computes variance across the outputs...
Source: eLife - November 8, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

< i > Drosophila < /i > PSI controls circadian period and the phase of circadian behavior under temperature cycle via < i > tim < /i > splicing
TheDrosophila circadian pacemaker consists of transcriptional feedback loops subjected to post-transcriptional and post-translational regulation. While post-translational regulatory mechanisms have been studied in detail, much less is known about circadian post-transcriptional control. Thus, we targeted 364 RNA binding and RNA associated proteins with RNA interference. Among the 43 hits we identified was the alternative splicing regulator P-element somatic inhibitor (PSI). PSI regulates the thermosensitive alternative splicing oftimeless (tim), promoting splicing events favored at warm temperature over those increased at c...
Source: eLife - November 8, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Free circular introns with an unusual branchpoint in neuronal projections
The polarized structure of axons and dendrites in neuronal cells depends in part on RNA localization. Previous studies have looked at which polyadenylated RNAs are enriched in neuronal projections or at synapses, but less is known about the distribution of non-adenylated RNAs. By physically dissecting projections from cell bodies of primary rat hippocampal neurons and sequencing total RNA, we found an unexpected set of free circular introns with a non-canonical branchpoint enriched in neuronal projections. These introns appear to be tailless lariats that escape debranching. They lack ribosome occupancy, sequence conservati...
Source: eLife - November 7, 2019 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

Differential contributions of the two human cerebral hemispheres to action timing
Rhythmic actions benefit from synchronization with external events. Auditory-paced finger tapping studies indicate the two cerebral hemispheres preferentially control different rhythms. It is unclear whether left-lateralized processing of faster rhythms and right-lateralized processing of slower rhythms bases upon hemispheric timing differences that arise in the motor or sensory system or whether asymmetry results from lateralized sensorimotor interactions. We measured fMRI and MEG during symmetric finger tapping, in which fast tapping was defined as auditory-motor synchronization at 2.5 Hz. Slow tapping corresponded to ta...
Source: eLife - November 7, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Selection on mutators is not frequency-dependent
The evolutionary fate of mutator mutations – genetic variants that raise the genome-wide mutation rate – in asexual populations is often described as being frequency (or number) dependent. Mutators can invade a population by hitchhiking with a sweeping beneficial mutation, but motivated by earlier experiments results, it has been repeate dly suggested that mutators must be sufficiently frequent to produce such a driver mutation before non-mutators do. Here, we use stochastic, agent-based simulations to show that neither the strength nor the sign of selection on mutators depend on their initial frequency, and wh...
Source: eLife - November 7, 2019 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome
Defective mismatch repair leads to increased mutation rates, and germline loss-of-function variants in the repair component MLH1 cause the hereditary cancer predisposition disorder known as Lynch syndrome. Early diagnosis is important, but complicated by many variants being of unknown significance. Here we show that a majority of the disease-linked MLH1 variants we studied are present at reduced cellular levels. We show that destabilized MLH1 variants are targeted for chaperone-assisted proteasomal degradation, resulting also in degradation of co-factors PMS1 and PMS2. In silico saturation mutagenesis and computational pre...
Source: eLife - November 7, 2019 Category: Biomedical Science Tags: Cancer Biology Computational and Systems Biology Source Type: research

Crumbs organizes the transport machinery by regulating apical levels of PI(4,5)P < sub > 2 < /sub > in < i > Drosophila < /i >
An efficient vectorial intracellular transport machinery depends on a well-established apico-basal polarity and is a prerequisite for the function of secretory epithelia. Despite extensive knowledge on individual trafficking pathways, little is known about the mechanisms coordinating their temporal and spatial regulation. Here, we report that the polarity protein Crumbs is essential for apical plasma membrane phospholipid-homeostasis and efficient apical secretion. Through recruiting βHeavy-Spectrin and MyosinV to the apical membrane, Crumbs maintains the Rab6-, Rab11- and Rab30-dependent trafficking and regulates the...
Source: eLife - November 7, 2019 Category: Biomedical Science Tags: Cell Biology Source Type: research

Negative regulation of autophagy by UBA6-BIRC6 –mediated ubiquitination of LC3
Although the process of autophagy has been extensively studied, the mechanisms that regulate it remain insufficiently understood. To identify novel autophagy regulators, we performed a whole-genome CRISPR/Cas9 knockout screen in H4 human neuroglioma cells expressing endogenous LC3B tagged with a tandem of GFP and mCherry. Using this methodology, we identified the ubiquitin-activating enzyme UBA6 and the hybrid ubiquitin-conjugating enzyme/ubiquitin ligase BIRC6 as autophagy regulators. We found that these enzymes cooperate to monoubiquitinate LC3B, targeting it for proteasomal degradation. Knockout of UBA6 or BIRC6 increas...
Source: eLife - November 6, 2019 Category: Biomedical Science Tags: Cell Biology Source Type: research