Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses
The magnitude and duration of vertebrate viremia is a critical determinant of arbovirus transmission, geographic spread, and disease severity. We find that multiple alphaviruses, including chikungunya (CHIKV), Ross River (RRV), and o'nyong 'nyong (ONNV) viruses, are cleared from the circulation of mice by liver Kupffer cells, impeding viral dissemination. Clearance from the circulation was independent of natural antibodies or complement factor C3, and instead relied on scavenger receptor SR-A6 (MARCO). Remarkably, lysine to arginine substitutions at distinct residues within the E2 glycoproteins of CHIKV and ONNV (E2 K200R)...
Source: eLife - October 9, 2019 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Modular organization of cerebellar climbing fiber inputs during goal-directed behavior
The cerebellum has a parasagittal modular architecture characterized by precisely organized climbing fiber (CF) projections congruent with alternating aldolase C/zebrin II expression. However, behavioral relevance of CF inputs to individual modules remains poorly understood. Here, we used two-photon calcium imaging in the cerebellar hemisphere Crus II in mice performing an auditory go/no-go task to investigate the functional differences in CF inputs to modules. CF signals in medial modules show anticipatory decreases, early increases, secondary increases, and reward-related increases or decreases, which represent quick mot...
Source: eLife - October 9, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Mitochondrial fusion is required for spermatogonial differentiation and meiosis
We examined whether mitochondrial fusion is important for metabolic tailoring during spermatogenesis. Acutely after depletion of mitofusinsMfn1 andMfn2, spermatogenesis arrests due to failure to accomplish a metabolic shift during meiosis. This metabolic shift includes increased mitochondrial content, mitochondrial elongation, and upregulation of oxidative phosphorylation (OXPHOS). With long-term mitofusin loss, all differentiating germ cell types are depleted, but proliferation of stem-like undifferentiated spermatogonia remains unaffected. Thus, compared with undifferentiated spermatogonia, differentiating spermatogonia ...
Source: eLife - October 9, 2019 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Electrocorticographic dissociation of alpha and beta rhythmic activity in the human sensorimotor system
This study uses electrocorticography in humans to assess how alpha- and beta-band rhythms modulate excitability of the sensorimotor cortex during psychophysically-controlled movement imagery. Both rhythms displayed effector-specific modulations, tracked spectral markers of action potentials in the local neuronal population, and showed spatially systematic phase relationships (traveling waves). Yet, alpha- and beta-band rhythms differed in their anatomical and functional properties, were weakly correlated, and traveled along opposite directions across the sensorimotor cortex. Increased alpha-band power in the somatosensory ...
Source: eLife - October 9, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion
Cocaine is an addictive drug that acts in brain reward areas. Recent evidence suggests that cocaine stimulates synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in midbrain, increasing dopamine neuron activity via disinhibition. Although a mechanism for cocaine-stimulated 2-AG synthesis is known, our understanding of 2-AG release is limited. In NG108 cells and mouse midbrain tissue we find that 2-AG is localized in non-synaptic extracellular vesicles (EVs) that are secreted in the presence of cocaine via interaction with the chaperone protein sigma-1 receptor (Sig-1R). The release of EVs occurs when cocaine ca...
Source: eLife - October 9, 2019 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

Ten common statistical mistakes to watch out for when writing or reviewing a manuscript
Inspired by broader efforts to make the conclusions of scientific research more robust, we have compiled a list of some of the most common statistical mistakes that appear in the scientific literature. The mistakes have their origins in ineffective experimental designs, inappropriate analyses and/or flawed reasoning. We provide advice on how authors, reviewers and readers can identify and resolve these mistakes and, we hope, avoid them in the future. (Source: eLife)
Source: eLife - October 9, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

A single regulator NrtR controls bacterial NAD < sup > + < /sup > homeostasis via its acetylation
Nicotinamide adenine dinucleotide (NAD+) is an indispensable cofactor in all domains of life, the homeostasis of which requires tight regulation. Here we report that a Nudix-related transcriptional factor, designated MsNrtR (MSMEG_3198), controls thede novo pathway of NAD+ biosynthesis inM. smegmatis, a non-tuberculosisMycobacterium. The integrated evidence in vitro andin vivo confirms that MsNrtR is an auto-repressor, and negatively controls thede novo NAD+ biosynthetic pathway. Binding of MsNrtR cognate DNA is finely mapped, which can be disrupted by an ADP-ribose intermediate. Unexpectedly, we discover that the acetylat...
Source: eLife - October 9, 2019 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Embryo polarity in moth flies and mosquitoes relies on distinct old genes with localized transcript isoforms
In conclusion, flies evolved an unexpected diversity of anterior determinants, and alternative transcript isoforms with distinct expression can adopt fundamentally distinct developmental roles. (Source: eLife)
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Developmental Biology Evolutionary Biology Source Type: research

Improved characterisation of MRSA transmission using within-host bacterial sequence diversity
We examined the between-subject bottleneck, finding a wide range in the amount of diversity transmitted. Finally, we compared our approach to the simpler method of identifying transmission pairs using single nucleotide polymorphism (SNP) counts. This suggested that the optimum threshold for identifying a pair is 39 SNPs, if sensitivities and specificities are equally weighted. (Source: eLife)
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Epidemiology and Global Health Source Type: research

Looking into nerve damage in the cornea
Interactions between T helper cells and the complement system promote loss of sensory neurons in the eye. (Source: eLife)
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Immunology and Inflammation Microbiology and Infectious Disease Source Type: research

Olfactory connectivity mediates sleep-dependent food choices in humans
Sleep deprivation has marked effects on food intake, shifting food choices toward energy-dense options. Here we test the hypothesis that neural processing in central olfactory circuits, in tandem with the endocannabinoid system (ECS), plays a key role in mediating this relationship. We combined a partial sleep-deprivation protocol, pattern-based olfactory neuroimaging, andad libitum food intake to test how central olfactory mechanisms alter food intake after sleep deprivation. We found that sleep restriction increased levels of the ECS compound 2-oleoylglycerol (2-OG), enhanced encoding of food odors in piriform cortex, an...
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Pretectal neurons control hunting behaviour
For many species, hunting is an innate behaviour that is crucial for survival, yet the circuits that control predatory action sequences are poorly understood. We used larval zebrafish to identify a population of pretectal neurons that control hunting. By combining calcium imaging with a virtual hunting assay, we identified a discrete pretectal region that is selectively active when animals initiate hunting. Targeted genetic labelling allowed us to examine the function and morphology of individual cells and identify two classes of pretectal neuron that project to ipsilateral optic tectum or the contralateral tegmentum. Opto...
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

A primal role for the vestibular sense in the development of coordinated locomotion
Mature locomotion requires that animal nervous systems coordinate distinct groups of muscles. The pressures that guide the development of coordination are not well understood. To understand how and why coordination might emerge, we measured the kinematics of spontaneous vertical locomotion across early development in zebrafish (Danio rerio) . We found that zebrafish used their pectoral fins and bodies synergistically during upwards swims. As larvae developed, they changed the way they coordinated fin and body movements, allowing them to climb with increasingly stable postures. This fin-body synergy was absent in vestibular...
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Stereotyped transcriptomic transformation of somatosensory neurons in response to injury
In mice, spared nerve injury replicates symptoms of human neuropathic pain and induces upregulation of many genes in somatosensory neurons. Here we used single cell transcriptomics to probe the effects of partial infraorbital transection of the trigeminal nerve at the cellular level. Uninjured neurons were unaffected by transection of major nerve branches, segregating into many different classes. In marked contrast, axotomy rapidly transformed damaged neurons into just two new and closely-related classes where almost all original identity was lost. Remarkably, sensory neurons also adopted this transcriptomic state followin...
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Multiplex live single-cell transcriptional analysis demarcates cellular functional heterogeneity
A fundamental goal in the biological sciences is to determine how individual cells with varied gene expression profiles and diverse functional characteristics contribute to development, physiology, and disease. Here, we report a novel strategy to assess gene expression and cell physiology in single living cells. Our approach utilizes fluorescently-labeled mRNA-specific anti-sense RNA probes and dsRNA-binding protein to identify the expression of specific genes in real-time at single-cell resolution via FRET. We use this technology to identify distinct myocardial subpopulations expressing the structural proteins myosin heav...
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Structured inhibitory activity dynamics in new virtual environments
Inhibition plays a powerful role in regulating network excitation and plasticity; however, the activity of defined interneuron types during spatial exploration remain poorly understood. Using two-photon calcium imaging, we recorded hippocampal CA1 somatostatin- and parvalbumin-expressing interneurons as mice performed a goal-directed spatial navigation task in new visual virtual reality (VR) contexts. Activity in both interneuron classes was strongly suppressed but recovered as animals learned to adapt the previously learned task to the new spatial context. Surprisingly, although there was a range of activity suppression a...
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Epistasis and entrenchment of drug resistance in HIV-1 subtype B
The development of drug resistance in HIV is the result of primary mutations whose effects on viral fitness depend on the entire genetic background, a phenomenon called ‘epistasis’. Based on protein sequences derived from drug-experienced patients in the Stanford HIV database, we use a co-evolutionary (Potts) Hamiltonian model to provide direct confirmation of epistasis involving many simultaneous mutations. Building on earlier work, we show that primary mutati ons leading to drug resistance can become highly favored (or entrenched) by the complex mutation patterns arising in response to drug therapy despite be...
Source: eLife - October 8, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Physics of Living Systems Source Type: research

Stimulation of Piezo1 by mechanical signals promotes bone anabolism
We report that the ion channel Piezo1 is required for changes in gene expression induced by fluid shear stress in cultured osteocytes and stimulation of Piezo1 by a small molecule agonist is sufficient to replicate the effects of fluid flow on osteocytes. Conditional deletion ofPiezo1 in osteoblasts and osteocytes notably reduced bone mass and strength in mice. Conversely, administration of a Piezo1 agonist to adult mice increased bone mass, mimicking the effects of mechanical loading. These results demonstrate that Piezo1 is a mechanosensitive ion channel by which osteoblast lineage cells sense and respond to changes in m...
Source: eLife - October 7, 2019 Category: Biomedical Science Tags: Human Biology and Medicine Source Type: research

Sensing the load
How does the skeleton detect and adapt to changes in the mechanical load it has to carry? (Source: eLife)
Source: eLife - October 7, 2019 Category: Biomedical Science Tags: Cell Biology Human Biology and Medicine Source Type: research

Visualizing endogenous opioid receptors in living neurons using ligand-directed chemistry
Identifying neurons that have functional opioid receptors is fundamental for the understanding of the cellular, synaptic and systems actions of opioids. Current techniques are limited to post hoc analyses of fixed tissues. Here we developed a fluorescent probe, naltrexamine-acylimidazole (NAI), to label opioid receptors based on a chemical approach termed 'traceless affinity labeling'. In this approach, a high affinity antagonist naltrexamine is used as the guide molecule for a transferring reaction of acylimidazole at the receptor. This reaction generates a fluorescent dye covalently linked to the receptor while naltrexam...
Source: eLife - October 7, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Dynamic ubiquitination determines transcriptional activity of the plant immune coactivator NPR1
Activation of systemic acquired resistance in plants is associated with transcriptome reprogramming induced by the unstable coactivator NPR1. Immune-induced ubiquitination and proteasomal degradation of NPR1 are thought to facilitate continuous delivery of active NPR1 to target promoters, thereby maximising gene expression. Because of this potentially costly sacrificial process, we investigated if ubiquitination of NPR1 plays transcriptional roles prior to its proteasomal turnover. Here we show ubiquitination of NPR1 is a progressive event in which initial modification by a Cullin-RING E3 ligase promotes its chromatin asso...
Source: eLife - October 7, 2019 Category: Biomedical Science Tags: Plant Biology Source Type: research

Ctf4 organizes sister replisomes and Pol α into a replication factory
The current view is that eukaryotic replisomes are independent. Here we show that Ctf4 tightly dimerizes CMG helicase, with an extensive interface involving Psf2, Cdc45, and Sld5. Interestingly, Ctf4 binds only one Pol α-primase. Thus, Ctf4 may have evolved as a trimer to organize two helicases and one Pol α-primase into a replication factory. In the 2CMG-Ctf43-1Pol α-primase factory model, the two CMGs nearly face each other, placing the two lagging strands toward the center and two leading strands out the sides. The single Pol α-primase is centrally located and may prime both sister replisomes. Th...
Source: eLife - October 7, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Source Type: research

Building a better model of the retina
Researchers have combined organ-on-a-chip engineering with the benefits of organoids to make improved models of the human retina. (Source: eLife)
Source: eLife - October 4, 2019 Category: Biomedical Science Tags: Human Biology and Medicine Stem Cells and Regenerative Medicine Source Type: research

Correction: Activity dynamics of amygdala GABAergic neurons during cataplexy of narcolepsy
(Source: eLife)
Source: eLife - October 4, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

< i > C. elegans < /i > neurons have functional dendritic spines
Dendritic spines are specialized postsynaptic structures that transduce presynaptic signals, are regulated by neural activity and correlated with learning and memory. Most studies of spine function have focused on the mammalian nervous system. However, spine-like protrusions have been reported inC. elegans(Philbrook et al. 2018), suggesting that the experimental advantages of smaller model organisms could be exploited to study the biology of dendritic spines. Here, we used super-resolution microscopy, electron microscopy, live-cell imaging and genetics to show thatC. elegans motor neurons have functional dendritic spines t...
Source: eLife - October 4, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

DeepFly3D, a deep learning-based approach for 3D limb and appendage tracking in tethered, adult < i > Drosophila < /i >
Studying how neural circuits orchestrate limbed behaviors requires the precise measurement of the positions of each appendage in 3-dimensional (3D) space. Deep neural networks can estimate 2-dimensional (2D) pose in freely behaving and tethered animals. However, the unique challenges associated with transforming these 2D measurements into reliable and precise 3D poses have not been addressed for small animals including the fly,Drosophila melanogaster. Here we present DeepFly3D, a software that infers the 3D pose of tethered, adultDrosophila using multiple camera images. DeepFly3D does not require manual calibration, uses p...
Source: eLife - October 4, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Cryo-EM structures of the human glutamine transporter SLC1A5 (ASCT2) in the outward-facing conformation
Alanine-serine-cysteine transporter 2 (ASCT2, SLC1A5) is the primary transporter of glutamine in cancer cells and regulates the mTORC1 signaling pathway. The SLC1A5 function involves finely tuned orchestration of two domain movements that include the substrate-binding transport domain and the scaffold domain. Here, we present cryo-EM structures of human SLC1A5 and its complex with the substrate, L-glutamine in an outward-facing conformation. These structures reveal insights into the conformation of the critical ECL2a loop which connects the two domains, thus allowing rigid body movement of the transport domain throughout t...
Source: eLife - October 3, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Endothelial PKA activity regulates angiogenesis by limiting autophagy through phosphorylation of ATG16L1
The cAMP-dependent protein kinase A (PKA) regulates various cellular functions in health and disease. In endothelial cells PKA activity promotes vessel maturation and limits tip cell formation. Here, we used a chemical genetic screen to identify endothelial-specific direct substrates of PKA in human umbilical vein endothelial cells (HUVEC) that may mediate these effects. Amongst several candidates, we identified ATG16L1, a regulator of autophagy, as novel target of PKA. Biochemical validation, mass spectrometry and peptide spot arrays revealed that PKA phosphorylates ATG16L1 α at Ser268 and ATG16L1β at Ser269, d...
Source: eLife - October 3, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

In vivo functional diversity of midbrain dopamine neurons within identified axonal projections
Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinctin vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and labelling in mouse brain to create anin vivo functional topography of the midbrain DA system. We identified differences in bur...
Source: eLife - October 3, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Intracellular cholesterol trafficking is dependent upon NPC2 interaction with Lysobisphosphatidic Acid
Unesterified cholesterol accumulation in the late endosomal/lysosomal (LE/LY) compartment is the cellular hallmark of Niemann-Pick C (NPC) disease, caused by defects in the genes encoding NPC1 or NPC2. We previously reported the dramatic stimulation of NPC2 cholesterol transport rates to and from model membranes by the LE/LY phospholipid lysobisphosphatidic acid (LBPA). It had been previously shown that enrichment of NPC1-deficient cells with LBPA results in cholesterol clearance. Here we demonstrate that LBPA enrichment in human NPC2-deficient cells, either directly or via its biosynthetic precursor phosphtidylglycerol (P...
Source: eLife - October 3, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Linking spatial patterns of terrestrial herbivore community structure to trophic interactions
Large herbivores influence ecosystem functioning via their effects on vegetation at different spatial scales. It is often overlooked that the spatial distribution of large herbivores result from their responses to interacting top-down and bottom-up ecological gradients that create landscape-scale variation in the structure of the entire community. We studied the complexity of these cascading interactions using high-resolution camera trapping and remote sensing data in the best-preserved European lowland forest, Bia łowieża Forest, Poland. We showed that the variation in spatial distribution of an entire community of larg...
Source: eLife - October 2, 2019 Category: Biomedical Science Tags: Ecology Source Type: research

Differential requirements for cyclase-associated protein (CAP) in actin-dependent processes of < i > Toxoplasma gondii < /i >
Toxoplasmagondiicontains a limited subset of actin binding proteins. Here we show that the putative actin regulator cyclase-associated protein (CAP) is present in two different isoforms and its deletion leads to significant defects in some but not all actin dependent processes. We observe defects in cell-cell communication, daughter cell orientation and the juxtanuclear accumulation of actin, but only modest defects in synchronicity of division and no defect in the replication of the apicoplast. 3D electron microscopy reveals that loss of CAP results in a defect in formation of a normal central residual body, but parasites...
Source: eLife - October 2, 2019 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Balancing model-based and memory-free action selection under competitive pressure
In competitive situations, winning depends on selecting actions that surprise the opponent. Such unpredictable action can be generated based on representations of the opponent's strategy and choice history (model-based counter-prediction) or by choosing actions in a memory-free, stochastic manner. Across five different experiments using a variant of a matching-pennies game with simulated and human opponents we found that people toggle between these two strategies, using model-based selection when recent wins signal the appropriateness of the current model, but reverting to stochastic selection following losses. Also, after...
Source: eLife - October 2, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

N-cadherin-regulated FGFR ubiquitination and degradation control mammalian neocortical projection neuron migration
The functions of FGF receptors (FGFRs) in early development of the cerebral cortex are well established. Their functions in the migration of neocortical projection neurons, however, are unclear. We have found that FGFRs regulate multipolar neuron orientation and the morphological change into bipolar cells necessary to enter the cortical plate. Mechanistically, our results suggest that FGFRs are activated by N-Cadherin. N-Cadherin cell-autonomously binds FGFRs and inhibits FGFR K27- and K29-linked polyubiquitination and lysosomal degradation. Accordingly, FGFRs accumulate and stimulate prolonged Erk1/2 phosphorylation. Neur...
Source: eLife - October 2, 2019 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Regulated spindle orientation buffers tissue growth in the epidermis
Tissue homeostasis requires a balance between progenitor cell proliferation and loss. Mechanisms that maintain this robust balance are needed to avoid tissue loss or overgrowth. Here we demonstrate that regulation of spindle orientation/asymmetric cell divisions is one mechanism that is used to buffer changes in proliferation and tissue turnover in mammalian skin. Genetic and pharmacologic experiments demonstrate that asymmetric cell divisions were increased in hyperproliferative conditions and decreased under hypoproliferative conditions. Further, active K-Ras also increased the frequency of asymmetric cell divisions. Dis...
Source: eLife - October 2, 2019 Category: Biomedical Science Tags: Cell Biology Source Type: research

Matrix metalloproteinase 1 modulates invasive behavior of tracheal branches during entry into < i > Drosophila < /i > flight muscles
Tubular networks like the vasculature extend branches throughout animal bodies, but how developing vessels interact with and invade tissues is not well understood. We investigated the underlying mechanisms using the developing tracheal tube network ofDrosophila indirect flight muscles (IFMs) as a model. Live imaging revealed that tracheal sprouts invade IFMs directionally with growth-cone-like structures at branch tips. Ramification inside IFMs proceeds until tracheal branches fill the myotube. However, individual tracheal cells occupy largely separate territories, possibly mediated by cell-cell repulsion. Matrix metallopr...
Source: eLife - October 2, 2019 Category: Biomedical Science Tags: Cell Biology Developmental Biology Source Type: research

Presenilin/ γ-secretase-dependent EphA3 processing mediates axon elongation through non-muscle myosin IIA
In conclusion, PS/γ-secretase-dependent EphA3 cleavage mediates axon growth by regulating filament assembly through RhoA signaling and NMIIA, suggesting opposite roles of EphA3 on inhibiting (ligand-dependent) and promoting (receptor processing) axon growth in developing neurons. (Source: eLife)
Source: eLife - October 2, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

DeepPoseKit, a software toolkit for fast and robust animal pose estimation using deep learning
Quantitative behavioral measurements are important for answering questions across scientific disciplines-from neuroscience to ecology. State-of-the-art deep-learning methods offer major advances in data quality and detail by allowing researchers to automatically estimate locations of an animal's body parts directly from images or videos. However, currently-available animal pose estimation methods have limitations in speed and robustness. Here we introduce a new easy-to-use software toolkit,DeepPoseKit, that addresses these problems using an efficient multi-scale deep-learning model, calledStacked DenseNet, and a fast GPU-b...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Adaptive thermal plasticity enhances sperm and egg performance in a model insect
Rising and more variable global temperatures pose a challenge for biodiversity, with reproduction and fertility being especially sensitive to heat. Here, we assessed the potential for thermal adaptation in sperm and egg function usingTribolium flour beetles, a warm-temperate-tropical insect model. Following temperature increases through adult development, we found opposing gamete responses, with males producing shorter sperm and females laying larger eggs. Importantly, this gamete phenotypic plasticity was adaptive: thermal translocation experiments showed that both sperm and eggs produced in warmer conditions had superior...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Ecology Source Type: research

Power analysis
After acknowledging that power differentials exist, can scientists find inspiration to persevere anyway? (Source: eLife)
Source: eLife - October 1, 2019 Category: Biomedical Science Source Type: research

Size control of the inner ear via hydraulic feedback
Animals make organs of precise size, shape, and symmetry but how developing embryos do this is largely unknown. Here, we combine quantitative imaging, physical theory, and physiological measurement of hydrostatic pressure and fluid transport in zebrafish to study size control of the developing inner ear. We find that fluid accumulation creates hydrostatic pressure in the lumen leading to stress in the epithelium and expansion of the otic vesicle. Pressure, in turn, inhibits fluid transport into the lumen. This negative feedback loop between pressure and transport allows the otic vesicle to change growth rate to control nat...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Developmental Biology Source Type: research

The tardigrade damage suppressor protein binds to nucleosomes and protects DNA from hydroxyl radicals
Tardigrades, also known as water bears, are animals that can survive extreme conditions. The tardigradeRamazzottius varieornatus contains a unique nuclear protein termed Dsup, for damage suppressor, which can increase the resistance of human cells to DNA damage under conditions, such as ionizing radiation or hydrogen peroxide treatment, that generate hydroxyl radicals. Here we find thatR. varieornatus Dsup is a nucleosome-binding protein that protects chromatin from hydroxyl radicals. Moreover, a Dsup ortholog from the tardigradeHypsibius exemplaris similarly binds to nucleosomes and protects DNA from hydroxyl radicals. St...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Chromosomes and Gene Expression Source Type: research

H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis
Cell-type-specific 3D organization of the genome is unrecognizable during mitosis. It remains unclear how essential positional information is transmitted through cell division such that a daughter cell recapitulates the spatial genome organization of the parent. Lamina-associated domains (LADs) are regions of repressive heterochromatin positioned at the nuclear periphery that vary by cell type and contribute to cell-specific gene expression and identity. Here we show that histone 3 lysine 9 dimethylation (H3K9me2) is an evolutionarily conserved, specific mark of nuclear peripheral heterochromatin and that it is retained th...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Cell Biology Chromosomes and Gene Expression Source Type: research

Interplay of disordered and ordered regions of a human small heat shock protein yields an ensemble of 'quasi-ordered' states
Small heat shock proteins (sHPSs) are nature's 'first responders' to cellular stress, interacting with affected proteins to prevent their aggregation. Little is known about sHSP structure beyond its structured a-crystallin domain (ACD), which is flanked by disordered regions. In the human sHSP HSPB1, the disordered N-terminal region (NTR) represents nearly 50% of the sequence. Here, we present a hybrid approach involving NMR, hydrogen-deuterium exchange mass spectrometry, and modeling to provide the first residue-level characterization of the NTR. The results support a model in which multiple grooves on the ACD interact wi...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Diverse deep-sea anglerfishes share a genetically reduced luminous symbiont that is acquired from the environment
Deep-sea anglerfishes are relatively abundant and diverse, but their luminescent bacterial symbionts remain enigmatic. The genomes of two symbiont species have qualities common to vertically transmitted, host-dependent bacteria. However, a number of traits suggest that these symbionts may be environmentally acquired. To determine how anglerfish symbionts are transmitted, we analyzed bacteria-host codivergence across six diverse anglerfish genera. Most of the anglerfish species surveyed shared a common species of symbiont. Only one other symbiont species was found, which had a specific relationship with one anglerfish speci...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Ecology Evolutionary Biology Source Type: research

Adaptation to mutational inactivation of an essential gene converges to an accessible suboptimal fitness peak
The mechanisms of adaptation to inactivation of essential genes remain unknown. Here we inactivateE. coli dihydrofolate reductase (DHFR) by introducing D27G,N,F chromosomal mutations in a key catalytic residue with subsequent adaptation by an automated serial transfer protocol. The partial reversal G27->C occurred in three evolutionary trajectories. Conversely, in one trajectory for D27G and in all trajectories for D27F,N strains adapted to grow at very low metabolic supplement (folAmix) concentrations but did not escape entirely from supplement auxotrophy. Major global shifts in metabolome and proteome occurred upon DH...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Computational and Systems Biology Evolutionary Biology Source Type: research

How flies turn food into progeny
Sex-optimal diets have different effects on gene expression in female and male flies. (Source: eLife)
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Functional brain alterations following mild-to-moderate sensorineural hearing loss in children
Auditory deprivation in the form of deafness during development leads to lasting changes in central auditory system function. However, less is known about the effects of mild-to-moderate sensorineural hearing loss (MMHL) during development. Here, we used a longitudinal design to examine late auditory evoked responses and mismatch responses to nonspeech and speech sounds for children with MMHL. At Time 1, younger children with MMHL (8-12 years; n = 23) showed age-appropriate mismatch negativities (MMNs) to sounds, but older children (12-16 years; n = 23) did not. Six years later, we re-tested a subset of the younger (now ol...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Neuroscience Source Type: research

Hemozoin produced by mammals confers heme tolerance
Free heme is cytotoxic as exemplified by hemolytic diseases and genetic deficiencies in heme recycling and detoxifying pathways. Thus, intracellular accumulation of heme has not been observed in mammalian cells to date. Here we show that mice deficient for the heme transporter SLC48A1 (also known as HRG1) accumulate over ten-fold excess heme in reticuloendothelial macrophage lysosomes that are 10 to 100 times larger than normal. Macrophages tolerate these high concentrations of heme by crystallizing them into hemozoin, which heretofore has only been found in blood-feeding organisms.SLC48A1 deficiency results in impaired er...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Cell Biology Source Type: research

Taste bud formation depends on taste nerves
It has been known for more than a century that, in adult vertebrates, the maintenance of taste buds depends on their afferent nerves. However, the initial formation of taste buds is proposed to be nerve-independent in amphibians, and evidence to the contrary in mammals has been endlessly debated, mostly due to indirect and incomplete means to impede innervation during the protracted perinatal period of taste bud differentiation. Here, by genetically ablating, in mice, all somatic (i.e. touch) or visceral (i.e. taste) neurons for the oral cavity, we show that the latter but not the former are absolutely required for the pro...
Source: eLife - October 1, 2019 Category: Biomedical Science Tags: Developmental Biology Source Type: research