Gene losses did not stop the evolution of big brains
Elephants and fruit bats have evolved large brains even though they have lost a gene that is fundamental to the supply of energy to the brain when glucose is not available. (Source: eLife)
Source: eLife - October 16, 2018 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Recurrent loss of HMGCS2 shows that ketogenesis is not essential for the evolution of large mammalian brains
Apart from glucose, fatty acid-derived ketone bodies provide metabolic energy for the brain during fasting and neonatal development. We investigated the evolution ofHMGCS2, the key enzyme required for ketone body biosynthesis (ketogenesis). Unexpectedly, we found that three mammalian lineages, comprising cetaceans (dolphins and whales), elephants and mastodons, and Old World fruit bats have lost this gene. Remarkably, many of these species have exceptionally large brains and signs of intelligent behavior. While fruit bats are sensitive to starvation, cetaceans and elephants can still withstand periods of fasting. This sugg...
Source: eLife - October 16, 2018 Category: Biomedical Science Tags: Evolutionary Biology Genetics and Genomics Source Type: research

Integrated culturing, modeling and transcriptomics uncovers complex interactions and emergent behavior in a three-species synthetic gut community
Whereas the composition of the human gut microbiome is well resolved, predictive understanding is still lacking. Here, we followed a bottom-up strategy to explore human gut community dynamics: we established a synthetic community composed of three representative human gut isolates (Roseburia intestinalisL1-82,Faecalibacterium prausnitzii A2-165 andBlautia hydrogenotrophicaS5a33) and explored their interactions under well-controlled conditionsin vitro.Systematic mono- and pair-wise fermentation experiments confirmed competition for fructose and cross-feeding of formate. We quantified with a mechanistic model how well tri-cu...
Source: eLife - October 16, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Microbiology and Infectious Disease Source Type: research

Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells
In cancer cells, loss of G1/S control is often accompanied by p53 pathway inactivation, the latter usually rationalized as a necessity for suppressing cell cycle arrest and apoptosis. However, we found an unanticipated effect of p53 loss in mouse and human G1-checkpoint-deficient cells: reduction of DNA damage. We show that abrogation of the G1/S-checkpoint allowed cells to enter S-phase under growth-restricting conditions at the expense of severe replication stress manifesting as decelerated DNA replication, reduced origin firing and accumulation of DNA double-strand breaks (DSBs). In this system, loss of p53 allowed mito...
Source: eLife - October 16, 2018 Category: Biomedical Science Tags: Cancer Biology Source Type: research

Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse model of ALS
Despite being an early event in ALS, it remains unclear whether the denervation of neuromuscular junctions (NMJ) is simply the first manifestation of a globally degenerating motor neuron. Usingin vivo imaging of single axons and their NMJs over a three-month period, we identify that single motor-units are dismantled asynchronously inSOD1G37R mice. We reveal that weeks prior to complete axonal degeneration, the dismantling of axonal branches is accompanied by contemporaneous new axonal sprouting resulting in synapse formation onto nearby NMJs. Denervation events tend to propagate from the first lost NMJ, consistent with a c...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Trajectories of childhood immune development and respiratory health relevant to asthma and allergy
Events in early life contribute to subsequent risk of asthma; however, the causes and trajectories of childhood wheeze are heterogeneous and do not always result in asthma. Similarly, not all atopic individuals develop wheeze, and vice versa. The reasons for these differences are unclear. Using unsupervised model-based cluster analysis, we identified latent clusters within a prospective birth cohort with deep immunological and respiratory phenotyping. We characterised each cluster in terms of immunological profile and disease risk, and replicated our results in external cohorts from the UK and USA. We discovered three dist...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Source Type: research

Species and cell-type properties of classically defined human and rodent neurons and glia
Determination of the molecular properties of genetically targeted cell types has led to fundamental insights into mouse brain function and dysfunction. Here, we report an efficient strategy for precise exploration of gene expression and epigenetic events in specific cell types in a range of species, including postmortem human brain. We demonstrate that classically defined, homologous neuronal and glial cell types differ between rodent and human by the expression of hundreds of orthologous, cell specific genes. Confirmation that these genes are differentially active was obtained using epigenetic mapping and immunofluorescen...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Chromosomes and Gene Expression Neuroscience Source Type: research

Screening of candidate substrates and coupling ions of transporters by thermostability shift assays
Substrates of most transport proteins have not been identified, limiting our understanding of their role in physiology and disease. Traditional identification methods use transport assays with radioactive compounds, but they are technically challenging and many compounds are unavailable in radioactive form or are prohibitively expensive, precluding large-scale trials. Here, we present a high-throughput screening method that can identify candidate substrates from libraries of unlabeled compounds. The assay is based on the principle that transport proteins recognize substrates through specific interactions, which lead to enh...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Structural basis for isoform-specific kinesin-1 recognition of Y-acidic cargo adaptors
The light chains (KLCs) of the heterotetrameric microtubule motor kinesin-1, that bind to cargo adaptor proteins and regulate its activity, have a capacity to recognize short peptides via their tetratricopeptide repeat domains (KLCTPR). Here, using X-ray crystallography, we show how kinesin-1 recognizes a novel class of adaptor motifs that we call 'Y-acidic' (tyrosine flanked by acidic residues), in a KLC-isoform specific manner. Binding specificities of Y-acidic motifs (present in JIP1 and in TorsinA) to KLC1TPR are distinct from those utilized for the recognition of W-acidic motifs found in adaptors that are KLC- isoform...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Characterization of a < i > Toxoplasma < /i > effector uncovers an alternative GSK3/ β-catenin-regulatory pathway of inflammation
The intracellular parasiteToxoplasma gondii, hijacks evolutionarily conserved host processes by delivering effector proteins into the host cell that shift gene expression in a timely fashion. We identified a parasite dense granule protein as GRA18 that once released in the host cell cytoplasm forms versatile complexes with regulatory elements of the β-catenin destruction complex. By interacting with GSK3/PP2A-B56, GRA18 drives β-catenin up-regulation and the downstream effects on host cell gene expression. In the context of macrophages infection, GRA18 induces the expression of a specific set of genes commonly as...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

Dynein-2 intermediate 1 chains play crucial but distinct roles in primary cilia formation and function
The dynein-2 microtubule motor is the retrograde motor for intraflagellar transport.  Mutations in dynein-2 components cause skeletal ciliopathies, notably Jeune syndrome. Dynein-2 contains a heterodimer of two non-identical intermediate chains, WDR34 and WDR60. Here, we use knockout cell lines to demonstrate that each intermediate chain has a distinct role in cilium function. Usi ng quantitative proteomics, we show that WDR34 KO cells can assemble a dynein-2 motor complex that binds IFT proteins yet fails to extend an axoneme, indicating complex function is stalled. In contrast, WDR60 KO cells do extend axonemes but sho...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Cell Biology Source Type: research

Myosin V functions as a vesicle tether at the plasma membrane to control neurotransmitter release in central synapses
Synaptic vesicle fusion occurs at specialized release sites at the active zone. How refilling of release sites with new vesicles is regulated in central synapses remains poorly understood. Using nanoscale-resolution detection of individual release events in rat hippocampal synapses we found that inhibition of myosin V, the predominant vesicle-associated motor, strongly reduced refilling of the release sites during repetitive stimulation. Single-vesicle tracking revealed that recycling vesicles continuously shuttle between a plasma membrane pool and an inner pool. Vesicle retention at the membrane pool was regulated by neur...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Can Hamilton's rule be violated?
How generally Hamilton's rule holds is a much debated question. The answer to that question depends on how costs and benefits are defined. When using the regression method to define costs and benefits, there is no scope for violations of Hamilton's rule. We introduce a general model for assortative group compositions to show that, when using the counterfactual method for computing costs and benefits, there is room for violations. The model also shows that there are limitations to observing violations in equilibrium, as the discrepancies between Hamilton's rule and the direction of selection may imply that selection will ta...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

RalB directly triggers invasion downstream Ras by mobilizing the Wave complex
The two Ral GTPases, RalA and RalB, have crucial roles downstream Ras oncoproteins in human cancers; in particular, RalB is involved in invasion and metastasis. However, therapies targeting Ral signalling are not available yet. By a novel optogenetic approach, we found that light-controlled activation of Ral at plasma-membrane promotes the recruitment of the Wave Regulatory Complex (WRC) via its effector exocyst, with consequent induction of protrusions and invasion. We show that active Ras signals to RalB via two RalGEFs (Guanine nucleotide Exchange Factors), RGL1 and RGL2, to foster invasiveness; RalB contribution appear...
Source: eLife - October 15, 2018 Category: Biomedical Science Tags: Cell Biology Source Type: research

A biological switching valve evolved in the female of a sex-role reversed cave insect to receive multiple seminal packages
We report a functional switching valve within the female genitalia of the Brazilian cave insectNeotrogla. The valve complex is composed of two plate-like sclerites, a closure element, and in-and-outflow canals. Females have a penis-like intromittent organ to coercively anchor males and obtain voluminous semen. The semen is packed in a capsule, whose formation is initiated by seminal injection. It is not only used for fertilization but also consumed by the female as nutrition. The valve complex has two slots for insemination so thatNeotrogla can continue mating while the first slot is occupied. In conjunction with the femal...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

The fate of hippocampal synapses depends on the sequence of plasticity-inducing events
Synapses change their strength in response to specific activity patterns. This functional plasticity is assumed to be the brain's primary mechanism for information storage. We used optogenetic stimulation of rat hippocampal slice cultures to induce long-term potentiation (LTP), long-term depression (LTD), or both forms of plasticity in sequence. Two-photon imaging of spine calcium signals allowed us to identify stimulated synapses and to follow their fate for the next 7 days. We found that plasticity-inducing protocols affected the synapse's chance for survival: LTP increased synaptic stability, LTD destabilized synapses, ...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

How we see the forest and the trees
Signaling pathways in the retina help us see spatial detail in our visual world. (Source: eLife)
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

< i > Dlk1-Dio3 < /i > locus-derived LncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity
The mammalian imprintedDlk1-Dio3locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, includingMeg3 (i.e.,Gtl2) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By profiling cell types at each stage of embryonic stem cell derived motor neurons (ESC~MNs) that recapitulate spinal cord development, we uncovered that lncRNAs expressed from theDlk1-Dio3locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically,Meg3and otherDlk1-Dio3 locus-derived ...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Developmental Biology Neuroscience Source Type: research

The chloroplast 2-cysteine peroxiredoxin functions as thioredoxin oxidase in redox regulation of chloroplast metabolism
Thiol-dependent redox regulation controls central processes in plant cells including photosynthesis. Thioredoxins reductively activate e.g. Calvin-Benson cycle enzymes. However the mechanism of oxidative inactivation is unknown despite its importance for efficient regulation. Here, the abundant 2-cysteine peroxiredoxin (2-CysPrx), but not its site-directed variants, mediates rapid inactivation of reductively activated fructose-1,6-bisphosphatase and NADPH-dependent malate dehydrogenase (MDH) in the presence of the proper thioredoxins. Deactivation of phosphoribulokinase (PRK) and MDH was compromised in2cysprxAB mutant plan...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Plant Biology Source Type: research

Perceptual processing in the ventral visual stream requires area TE but not rhinal cortex
There is on-going debate over whether area TE, or the anatomically adjacent rhinal cortex, is the final stage of visual object processing. Both regions have been implicated in visual perception, but their involvement in non-perceptual functions, such as short-term memory, hinders clear-cut interpretation. Here using a two-interval forced choice task without a short-term memory demand, we find that after bilateral removal of area TE, monkeys trained to categorize images based on perceptual similarity (morphs between dogs and cats), are, on the initial viewing, badly impaired when given a new set of images. They improve mark...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect
Proper brain development relies highly on protein N-glycosylation to sustain neuronal migration, axon guidance and synaptic physiology. Impairing the N-glycosylation pathway at early steps produces broad neurological symptoms identified in congenital disorders of glycosylation. However, little is known about the molecular mechanisms underlying these defects. We generated a cerebellum specific knockout mouse forSrd5a3, a gene involved in the initiation of N-glycosylation. In addition to motor coordination defects and abnormal granule cell development,Srd5a3 deletion causes mild N-glycosylation impairment without significant...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research

Central < i > Dicer < /i > -miR-103/107 controls developmental switch of POMC progenitors into NPY neurons and impacts glucose homeostasis
Proopiomelanocortin (POMC) neurons are major negative regulators of energy balance. A distinct developmental property of POMC neurons is that they can adopt an orexigenic neuropeptide Y (NPY) phenotype. However, the mechanisms underlying the differentiation ofPomc progenitors remain unknown. Here, we show that the loss of the microRNA (miRNA)-processing enzymeDicer in POMC neurons causes metabolic defects, an age-dependent decline in the number ofPomc mRNA-expressing cells, and an increased proportion ofPomc progenitors acquiring a NPY phenotype. miRNome microarray screening further identified miR-103/107 as candidates tha...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

WNT signaling memory is required for ACTIVIN to function as a morphogen in human gastruloids
Self-organization of discrete fates in human gastruloids is mediated by a hierarchy of signaling pathways. How these pathways are integrated in time, and whether cells maintain a memory of their signaling history remains obscure. Here, we dissect the temporal integration of two key pathways, WNT and ACTIVIN, which along with BMP control gastrulation. CRISPR/Cas9-engineered live reporters of SMAD1, 2 and 4 demonstrate that in contrast to the stable signaling by SMAD1, signaling and transcriptional response by SMAD2 is transient, and while necessary for pluripotency, it is insufficient for differentiation. Pre-exposure to WN...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

Calcium-dependent electrostatic control of anion access to the pore of the calcium-activated chloride channel TMEM16A
TMEM16A is a ligand-gated anion channel that is activated by intracellular Ca2+. This channel contains two independent pores and closely apposed Ca2+ binding sites that are contained within each subunit of a homodimeric protein. Previously we characterized the influence of positively charged pore-lining residues on anion conduction (Paulino C. et. al., 2017). Here, we demonstrate the electrostatic control of permeation by the bound calcium ions in mouse TMEM16A using electrophysiology and Poisson-Boltzmann calculations. The currents of constitutively active mutants lose their outward rectification as a function of Ca2+ con...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Sensory experience inversely regulates feedforward and feedback excitation-inhibition ratio in rodent visual cortex
Brief (2-3d) monocular deprivation (MD) during the critical period induces a profound loss of responsiveness within binocular (V1b) and monocular (V1m) regions of rodent primary visual cortex. This has largely been ascribed to long-term depression (LTD) at thalamocortical synapses, while a contribution from intracortical inhibition has been controversial. Here we used optogenetics to isolate and measure feedforward thalamocortical and feedback intracortical excitation-inhibition (E-I) ratios following brief MD. Despite depression at thalamocortical synapses, thalamocortical E-I ratio was unaffected in V1b and shifted towar...
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Chromatin mapping identifies BasR, a key regulator of bacteria-triggered production of fungal secondary metabolites
The eukaryotic epigenetic machinery can be modified by bacteria to reprogram the response of eukaryotes during their interaction with microorganisms. We discovered that the bacteriumStreptomyces rapamycinicus triggered increased chromatin acetylation and thus activation of the silent secondary metabolismors gene cluster in the fungusAspergillus nidulans. Using this model we aim at understanding mechanisms of microbial communication based on bacteria-triggered chromatin modification. By genome-wide ChIP-seq analysis of acetylated histone H3 we uncovered the unique chromatin landscape inA. nidulans upon co-cultivation withS....
Source: eLife - October 12, 2018 Category: Biomedical Science Tags: Microbiology and Infectious Disease Source Type: research

A complex peripheral code for salt taste in < i > Drosophila < /i >
Each taste modality is generally encoded by a single, molecularly defined, population of sensory cells. However, salt stimulates multiple taste pathways in mammals and insects, suggesting a more complex code for salt taste. Here, we examine salt coding inDrosophila. After creating a comprehensive molecular map comprised of five discrete sensory neuron classes across the fly labellum, we find that four are activated by salt: two exhibiting characteristics of ‘low salt’ cells, and two ‘high salt’ classes. Behaviorally, low salt attraction depends primarily on ‘sweet’ neurons, with addition...
Source: eLife - October 11, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Correction: Auxiliary subunits of the CKAMP family differentially modulate AMPA receptor properties
(Source: eLife)
Source: eLife - October 11, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Effects of microcompartmentation on flux distribution and metabolic pools in < i > Chlamydomonas reinhardtii < /i > chloroplasts
Cells and organelles are not homogeneous but include microcompartments that alter the spatiotemporal characteristics of cellular processes. The effects of microcompartmentation on metabolic pathways are however difficult to study experimentally. The pyrenoid is a microcompartment that is essential for a carbon concentrating mechanism (CCM) that improves the photosynthetic performance of eukaryotic algae. UsingChlamydomonas reinhardtii, we obtained experimental data on photosynthesis, metabolites, and proteins in CCM-induced and CCM-suppressed cells. We then employed a computational strategy to estimate how fluxes through t...
Source: eLife - October 11, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Plant Biology Source Type: research

Adrb2 controls glucose homeostasis by developmental regulation of pancreatic islet vasculature
A better understanding of processes controlling the development and function of pancreatic islets is critical for diabetes prevention and treatment. Here, we reveal a previously unappreciated function for pancreatic β2-adrenergic receptors (Adrb2) in controlling glucose homeostasis by restricting islet vascular growth during development. Pancreas-specific deletion ofAdrb2 results in glucose intolerance and impaired insulin secretion in mice, and unexpectedly, specifically in females. The metabolic phenotypes were recapitulated byAdrb2 deletion from neonatal, but not adult, b-cells. Mechanistically,Adrb2 loss increases...
Source: eLife - October 10, 2018 Category: Biomedical Science Tags: Developmental Biology Source Type: research

Ongoing, rational calibration of reward-driven perceptual biases
Decision-making is often interpreted in terms of normative computations that maximize a particular reward function for stable, average behaviors. Aberrations from the reward-maximizing solutions, either across subjects or across different sessions for the same subject, are often interpreted as reflecting poor learning or physical limitations. Here we show that such aberrations may instead reflect the involvement of additional satisficing and heuristic principles. For an asymmetric-reward perceptual decision-making task, three monkeys produced adaptive biases in response to changes in reward asymmetries and perceptual sensi...
Source: eLife - October 10, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Context-enriched interactome powered by proteomics helps the identification of novel regulators of macrophage activation
The role of pro-inflammatory macrophage activation in cardiovascular disease (CVD) is a complex one amenable to network approaches. While an indispensible tool for elucidating the molecular underpinnings of complex diseases including CVD, the interactome is limited in its utility as it is not specific to any cell type, experimental condition or disease state. We introduced context-specificity to the interactome by combining it with co-abundance networks derived from unbiased proteomics measurements from activated macrophage-like cells. Each macrophage phenotype contributed to certain regions of the interactome. Using a net...
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Immunology and Inflammation Source Type: research

Mitochondria reorganization upon proliferation arrest predicts individual yeast cell fate
Most cells spend the majority of their life in a non-proliferating state. When proliferation cessation is irreversible, cells are senescent. By contrast, if the arrest is only temporary, cells are defined as quiescent. These cellular states are hardly distinguishable without triggering proliferation resumption, hampering thus the study of quiescent cells properties. Here we show that quiescent and senescent yeast cells are recognizable based on their mitochondrial network morphology. Indeed, while quiescent yeast cells display numerous small vesicular mitochondria, senescent cells exhibit few globular mitochondria. This al...
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Cell Biology Source Type: research

Ancient mechanisms for the evolution of the bicoid homeodomain's function in fly development
The ancient mechanisms that caused developmental gene regulatory networks to diversify among distantly related taxa are not well understood. Here we use ancestral protein reconstruction, biochemical experiments, and developmental assays of transgenic animals carrying reconstructed ancestral genes to investigate how the transcription factor Bicoid (Bcd) evolved its central role in anterior-posterior patterning in flies. We show that most of Bcd ’s derived functions are attributable to evolutionary changes within its homeodomain (HD) during a phylogenetic interval>140 million years ago. A single substitution from th...
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

Range, routing and kinetics of rod signaling in primate retina
Stimulus- or context-dependent routing of neural signals through parallel pathways can permit flexible processing of diverse inputs. For example, work in mouse shows that rod photoreceptor signals are routed through several retinal pathways, each specialized for different light levels. This light-level-dependent routing of rod signals has been invoked to explain several human perceptual results, but it has not been tested in primate retina. Here we show, surprisingly, that rod signals traverse the primate retina almost exclusively through a single pathway - the dedicated rod bipolar pathway. Identical experiments in mouse ...
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Oldest skeleton of a fossil flying squirrel casts new light on the phylogeny of the group
Flying squirrels are the only group of gliding mammals with a remarkable diversity and wide geographical range. However, their evolutionary story is not well known. Thus far, identification of extinct flying squirrels has been exclusively based on dental features, which, contrary to certain postcranial characters, are not unique to them. Therefore, fossils attributed to this clade may indeed belong to other squirrel groups. Here we report the oldest fossil skeleton of a flying squirrel (11.6 Ma) that displays the gliding-related diagnostic features shared by extant forms and allows for a recalibration of the divergence tim...
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Evolutionary Biology Source Type: research

Personality links with lifespan in chimpanzees
Life history strategies for optimizing individual fitness fall on a spectrum between maximizing reproductive efforts and maintaining physical health over time. Strategies across this spectrum are viable and different suites of personality traits evolved to support these strategies. Using data from 538 captive chimpanzees (Pan troglodytes) we tested whether any of the dimensions of chimpanzee personality – agreeableness, conscientiousness, dominance, extraversion, neuroticism, and openness – were associated with longevity, an attribute of slow life history strategies that is especially important in primates give...
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Ecology Epidemiology and Global Health Source Type: research

Transition between fermentation and respiration determines history-dependent behavior in fluctuating carbon sources
Cells constantly adapt to environmental fluctuations. These physiological changes require time and therefore cause a lag phase during which the cells do not function optimally. Interestingly, past exposure to an environmental condition can shorten the time needed to adapt when the condition re-occurs, even in daughter cells that never directly encountered the initial condition. Here, we use the molecular toolbox ofSaccharomyces cerevisiae to systematically unravel the molecular mechanism underlying such history-dependent behavior in transitions between glucose and maltose. In contrast to previous hypotheses, the behavior d...
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Microbiology and Infectious Disease Source Type: research

Spatiotemporal mosaic self-patterning of pluripotent stem cells using CRISPR interference
We examined effects of induced mosaic knockdown of molecular regulators of cortical tension (ROCK1) and cell-cell adhesion (CDH1) with CRISPR interference. Mosaic knockdown of ROCK1 or CDH1 resulted in differential patterning within hiPSC colonies due to cellular self-organization, while retaining an epithelial pluripotent phenotype. Knockdown induction stimulates a transient wave of differential gene expression within the mixed populations that stabilized in coordination with observed self-organization. Mosaic patterning enables genetic interrogation of emergent multicellular properties, which can facilitate better unders...
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Developmental Biology Stem Cells and Regenerative Medicine Source Type: research

The DWORF micropeptide enhances contractility and prevents heart failure in a mouse model of dilated cardiomyopathy
Calcium (Ca2+) dysregulation is a hallmark of heart failure and is characterized by impaired Ca2+sequestration into the sarcoplasmic reticulum (SR) by the SR-Ca2+-ATPase (SERCA). We recently discovered a micropeptide named DWORF (DWarfOpenReadingFrame) that enhances SERCA activity by displacing phospholamban (PLN), a potent SERCA inhibitor. Here we show that DWORF has a higher apparent binding affinity for SERCA than PLN and that DWORF overexpression mitigates the contractile dysfunction associated with PLN overexpression, substantiating its role as a potent activator of SERCA. Additionally, using a well-characterized mous...
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Cell Biology Source Type: research

The randomness that shapes our DNA
Just 5% of the human genome is subject to neutral evolution, but this process remains central to understanding the history of human migration across the Earth. (Source: eLife)
Source: eLife - October 9, 2018 Category: Biomedical Science Tags: Genetics and Genomics Source Type: research

BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands
TOPBP1 and its fission yeast homologueRad4, are critical players in a range of DNA replication, repair and damage signalling processes. They are composed of multiple BRCT domains, some of which bind phosphorylated motifs in other proteins. They thus act as multi-point adaptors bringing proteins together into functional combinations, dependent on post-translational modifications downstream of cell cycle and DNA damage signals. We have now structurally and/or biochemically characterised a sufficient number of high-affinity complexes for the conserved N-terminal region of TOPBP1 and Rad4 with diverse phospho-ligands, includin...
Source: eLife - October 8, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Structural Biology and Molecular Biophysics Source Type: research

Dopamine neuron glutamate cotransmission evokes a delayed excitation in lateral dorsal striatal cholinergic interneurons
Dopamine neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr dopamine neuron terminals in mouse brain slices pauses the firing of cholinergic interneurons in both the medial and lateral subregions, while in the lateral subregion the pause is shorter due to a subsequent excitation. This excitation is mediated mainly by metabotropic glutamate receptor 1 (mGluR1) and partially by dopamine D1-like receptors coupled to transient receptor potential channel 3 and 7. DA ...
Source: eLife - October 8, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

The allosteric activation of cGAS underpins its dynamic signaling landscape
Cyclic G/AMP synthase (cGAS) initiates type-1 interferon responses against cytosolic double-stranded (ds)DNA, which range from antiviral gene expression to apoptosis. The mechanism by which cGAS shapes this diverse signaling landscape remains poorly defined. We find that substrate-binding and dsDNA length-dependent binding are coupled to the intrinsic dimerization equilibrium of cGAS, with its N-terminal domain potentiating dimerization. Notably, increasing the dimeric fraction by raising cGAS and substrate concentrations diminishes duplex length-dependent activation, but does not negate the requirement for dsDNA. These re...
Source: eLife - October 8, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Immunology and Inflammation Source Type: research

Motor thalamus supports striatum-driven reinforcement
Reinforcement has long been thought to require striatal synaptic plasticity. Indeed, direct striatal manipulations such as self-stimulation of direct-pathway projection neurons (dMSNs) are sufficient to induce reinforcement within minutes. However, it's unclear what role, if any, is played by downstream circuitry. Here, we used dMSN self-stimulation in mice as a model for striatum-driven reinforcement and mapped the underlying circuitry across multiple basal ganglia nuclei and output targets. We found that mimicking the effects of dMSN activation on downstream circuitry, through optogenetic suppression of basal ganglia out...
Source: eLife - October 8, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Correction: Two single-point mutations shift the ligand selectivity of a pheromone receptor between two closely related moth species
(Source: eLife)
Source: eLife - October 5, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research

Multiple serine transposase dimers assemble the transposon-end synaptic complex during IS < i > 607 < /i > -family transposition
IS607-family transposons are unusual because they do not have terminal inverted repeats or generate target site duplications. They encode two protein-coding genes, but onlytnpA is required for transposition. Our X-ray structures confirm that TnpA is a member of the serine recombinase (SR) family, but the chemically-inactive quaternary structure of the dimer, along with the N-terminal location of the DNA binding domain, are different from other SRs. TnpA dimers from IS1535 cooperatively associate with multiple subterminal repeats, which together with additional nonspecific binding, form a nucleoprotein filament on one trans...
Source: eLife - October 5, 2018 Category: Biomedical Science Tags: Biochemistry and Chemical Biology Chromosomes and Gene Expression Source Type: research

Simulation of spontaneous G protein activation reveals a new intermediate driving GDP unbinding
Activation of heterotrimeric G proteins is a key step in many signaling cascades. However, a complete mechanism for this process, which requires allosteric communication between binding sites that are ~30 Å apart, remains elusive. We construct an atomically-detailed model of G protein activation by combining three powerful computational methods: metadynamics, Markov state models (MSMs), and CARDS analysis of correlated motions. We uncover a mechanism that is consistent with a wide variety of structu ral and biochemical data. Surprisingly, the rate-limiting step for GDP release correlates with tilting rather than tran...
Source: eLife - October 5, 2018 Category: Biomedical Science Tags: Computational and Systems Biology Structural Biology and Molecular Biophysics Source Type: research

Crystal structure of the full Swi2/Snf2 remodeler Mot1 in the resting state
Swi2/Snf2 ATPases remodel protein:DNA complexes in all of the fundamental chromosome ‑associated processes. The single‑subunit remodeler Mot1 dissociates TATA box-binding protein (TBP):DNA complexes and provides a simple model for obtaining structural insights into the action of Swi2/Snf2 ATPases. Previously we reported how the N-terminal domain of Mot1 it binds TBP, NC2 and DNA , but the location of the C-terminal ATPase domain remained unclear (Butryn et al., 2015). Here, we report the crystal structure of the near full-length Mot1 fromChaetomium thermophilum.Our data show that Mot1 adopts a ring like structure with ...
Source: eLife - October 5, 2018 Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research

Feedback optimizes neural coding and perception of natural stimuli
Growing evidence suggests that sensory neurons achieve optimal encoding by matching their tuning properties to the natural stimulus statistics. However, the underlying mechanisms remain unclear. Here we demonstrate that feedback pathways from higher brain areas mediate optimized encoding of naturalistic stimuli via temporal whitening in the weakly electric fishApteronotus leptorhynchus. While one source of direct feedback uniformly enhances neural responses, a separate source of indirect feedback selectively attenuates responses to low frequencies, thus creating a high-pass neural tuning curve that opposes the decaying spe...
Source: eLife - October 5, 2018 Category: Biomedical Science Tags: Neuroscience Source Type: research