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  • Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma
    eLife (IF 7.08) Pub Date : 2020-07-10
    Alicia M Darnell; Allison N Lau; Anna M Westermark; Christopher R Chin; David A Tuveson; Evan C Lien; Giulia Biffi; Jared R Mayers; Kiera M Sapp; Laura V Danai; Matthew G Vander Heiden; Nicholas J Matheson; Omer Yilmaz; Raphael Ferreira; Sharanya Sivanand; Shawn M Davidson; Tyler Jacks; Vasilena Gocheva; Zhaoqi Li

    Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more

    更新日期:2020-07-10
  • Miga mediated endoplasmic reticulum-mitochondria contact sites regulate neuronal homeostasis
    eLife (IF 7.08) Pub Date : 2020-07-10
    Chao Tong; Jia Zhou; Jun-Ping Liu; Lingna Xu; Liquan Wang; Weina Shang; Xi Wang; Yunyi Qiu

    Endoplasmic reticulum (ER)–mitochondria contact sites (ERMCSs) are crucial for multiple cellular processes such as calcium signaling, lipid transport, mitochondrial dynamics, and autophagosome biogenesis. However, the molecular organization, functions, and regulation of ERMCS are not fully understood in higher eukaryotes. Also, the physiological roles of altered ERMCSs are not well defined. In this

    更新日期:2020-07-10
  • Real-time in vivo imaging of extracellular ATP in the brain with a hybrid-type fluorescent sensor
    eLife (IF 7.08) Pub Date : 2020-07-10
    Daisuke Asanuma; Hirokazu Sakamoto; Hiroshi Sekiya; Kaname Satoh; Kenjiro Hanaoka; Kenji Takikawa; Kenzo Hirose; Masamitsu Iino; Nami Kitajima; Shigeyuki Namiki; Shodai Takahashi; Yasuteru Urano

    Adenosine 5' triphosphate (ATP) is a ubiquitous extracellular signaling messenger. Here, we describe a method for in-vivo imaging of extracellular ATP with high spatiotemporal resolution. We prepared a comprehensive set of cysteine-substitution mutants of ATP-binding protein, Bacillus FoF1-ATP synthase e subunit, labeled with small-molecule fluorophores at the introduced cysteine residue. Screening

    更新日期:2020-07-10
  • Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice
    eLife (IF 7.08) Pub Date : 2020-07-10
    David Marcinek; Dongsheng Duan; Ellen Quarles; Gennifer Merrihew; Hazel H Szeto; Henk L Granzier; Huiliang Zhang; Jeremy Whitson; Lindsay K Pino; Lu Wang; Mariya Sweetwyne; Matthew D Campbell; Matthew J Gaffrey; Michael J MacCoss; Nathan Basisty; Ngoc-Han Nguyen; Peter Rabinovitch; Tong Zhang; Wei-Jun Qian; Ying Ann Chiao; Ying Sonia Ting; Yongping Yue

    Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards

    更新日期:2020-07-10
  • Evolutionarily distant I domains can functionally replace the essential ligand-binding domain of Plasmodium TRAP
    eLife (IF 7.08) Pub Date : 2020-07-10
    Chafen Lu; Dennis Klug; Friedrich Frischknecht; Jessica Kehrer; Julia Sattler; Léanne Strauss; Mirko Singer; Sarah Goellner; Timothy A Springer

    Inserted (I) domains function as ligand-binding domains in adhesins that support cell adhesion and migration in many eukaryotic phyla. These adhesins include integrin αβ heterodimers in metazoans and single subunit transmembrane proteins in apicomplexans such as TRAP in Plasmodium and MIC2 in Toxoplasma. Here we show that the I domain of TRAP is essential for sporozoite gliding motility, mosquito salivary

    更新日期:2020-07-10
  • An adipokine feedback regulating diurnal food intake rhythms in mice
    eLife (IF 7.08) Pub Date : 2020-07-09
    Anthony H Tsang; Christiane E Koch; Cosima X Schmidt; Henrik Oster; Jana-Thabea Kiehn

    Endogenous circadian clocks have evolved to anticipate 24-hour rhythms in environmental demands. Recent studies suggest that circadian rhythm disruption is a major risk factor for the development of metabolic disorders in humans. Conversely, alterations in energy state can disrupt circadian rhythms of behavior and physiology, creating a vicious circle of metabolic dysfunction. How peripheral energy

    更新日期:2020-07-09
  • Different dendritic domains of the GnRH neuron underlie the pulse and surge modes of GnRH secretion in female mice
    eLife (IF 7.08) Pub Date : 2020-07-09
    Allan E Herbison; Hui Long; Li Wang; Qifeng Lyu; Shel Yeo; Wenya Guo; Xi Shen; Yanping Kuang; Zhexuan Wang

    The gonadotropin-releasing hormone (GnRH) neurons exhibit pulse and surge modes of activity to control fertility. They also exhibit an unusual bipolar morphology comprised of a classical soma-proximal dendritic zone and an elongated secretory process that can operate as both a dendrite and an axon, termed a ‘dendron’. We show using expansion microscopy that the highest density of synaptic inputs to

    更新日期:2020-07-09
  • Cell lineage-dependent chiral actomyosin flows drive cellular rearrangements in early C. elegans development
    eLife (IF 7.08) Pub Date : 2020-07-09
    Alexander Mietke; Lokesh G Pimpale; Stephan W Grill; Teije C Middelkoop

    Proper positioning of cells is essential for many aspects of development. Daughter cell positions can be specified via orienting the cell division axis during cytokinesis. Rotatory actomyosin flows during division have been implied in specifying and reorienting the cell division axis, but how general such reorientation events are, and how they are controlled, remains unclear. We followed the first

    更新日期:2020-07-09
  • Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo
    eLife (IF 7.08) Pub Date : 2020-07-09
    Brandon Brown; Brittany N Ulrich; Diane M Papazian; Fadi A Issa; Jui-Yi Hsieh; Meng-chin A Lin

    Mutations in KCNC3, which encodes the Kv3.3 K+ channel, cause spinocerebellar ataxia 13 (SCA13). SCA13 exists in distinct forms with onset in infancy or adulthood. Using zebrafish, we tested the hypothesis that infant- and adult-onset mutations differentially affect the excitability and viability of Purkinje cells in vivo during cerebellar development. An infant-onset mutation dramatically and transiently

    更新日期:2020-07-09
  • A high-throughput small molecule screen identifies farrerol as a potentiator of CRISPR/Cas9-mediated genome editing
    eLife (IF 7.08) Pub Date : 2020-07-09
    Jiaqing Yang; Jiayu Chen; Jiayu Yu; Jing Zhang; Ke Wei; Mengting Wang; Shaorong Gao; Weina Zhang; Xiaodong Zhao; Xiaojun Xu; Xiaoping Wan; Ying Jiang; Yu Chen; Zhiyong Mao

    Directly modulating the choice between homologous recombination (HR) and non-homologous end joining (NHEJ) - two independent pathways for repairing DNA double-strand breaks (DSBs) - has the potential to improve the efficiency of gene targeting by CRISPR/Cas9. Here, we have developed a rapid and easy-to-score screening approach for identifying small molecules that affect the choice between the two DSB

    更新日期:2020-07-09
  • Mechanical inhibition of isolated Vo from V/A-ATPase for proton conductance
    eLife (IF 7.08) Pub Date : 2020-07-08
    Atsuko Nakanishi; Aya Furuta; Jun-ichi Kishikawa; Kaoru Mitsuoka; Keiichi Namba; Ken Yokoyama; Masatada Tamakoshi; Takayuki Kato

    V-ATPase is an energy converting enzyme, coupling ATP hydrolysis/synthesis in the hydrophilic V1 domain, with proton flow through the Vo membrane domain, via rotation of the central rotor complex relative to the surrounding stator apparatus. Upon dissociation from the V1 domain, the Vo domain of the eukaryotic V-ATPase can adopt a physiologically relevant auto-inhibited form in which proton conductance

    更新日期:2020-07-08
  • Concentration-dependent mortality of chloroquine in overdose
    eLife (IF 7.08) Pub Date : 2020-07-08
    Bruno Megarbane; Frederic J Baud; James A Watson; Jean-Luc Clemessy; Joel Tarning; Nicholas J White; Richard M Hoglund

    Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models

    更新日期:2020-07-08
  • Modular output circuits of the fastigial nucleus for diverse motor and nonmotor functions of the cerebellar vermis
    eLife (IF 7.08) Pub Date : 2020-07-08
    Hirofumi Fujita; Sascha du Lac; Takashi Kodama

    The cerebellar vermis, long associated with axial motor control, has been implicated in a surprising range of neuropsychiatric disorders and cognitive and affective functions. Remarkably little is known, however, about the specific cell types and neural circuits responsible for these diverse functions. Here, using single-cell gene expression profiling and anatomical circuit analyses of vermis output

    更新日期:2020-07-08
  • Learning-related population dynamics in the auditory thalamus
    eLife (IF 7.08) Pub Date : 2020-07-08
    Adi Mizrahi; Ariel Gilad; Ido Maor

    Learning to associate sensory stimuli with a chosen action involves a dynamic interplay between cortical and thalamic circuits. While the cortex has been widely studied in this respect, how the thalamus encodes learning-related information is still largely unknown. We studied learning-related activity in the medial geniculate body (MGB; Auditory thalamus), targeting mainly the dorsal and medial regions

    更新日期:2020-07-08
  • Gradients in the biophysical properties of neonatal auditory neurons align with synaptic contact position and the intensity coding map of inner hair cells
    eLife (IF 7.08) Pub Date : 2020-07-08
    Alexander L Markowitz; Radha Kalluri

    Sound intensity is encoded by auditory neuron subgroups that differ in thresholds and spontaneous rates. Whether variations in neuronal biophysics contributes to this functional diversity is unknown. Because intensity thresholds correlate with synaptic position on sensory hair cells, we combined patch clamping with fiber labeling in semi-intact cochlear preparations in neonatal rats from both sexes

    更新日期:2020-07-08
  • Resident macrophages acquire innate immune memory in staphylococcal skin infection
    eLife (IF 7.08) Pub Date : 2020-07-08
    Aaron James Forde; Florens Lohrmann; Jakob Zimmermann; Julia Kolter; Mercedes Gomez de Agüero; Neftali Jose Ramirez; Philipp Henneke; Reinhild Feuerstein

    Staphylococcus aureus (S. aureus) is a common colonizer of healthy skin and mucous membranes. At the same time, S. aureus is the most frequent cause of skin and soft tissue infections. Dermal macrophages (Mφ) are critical for the coordinated defense against invading S. aureus, yet they have a limited life span with replacement by bone marrow derived monocytes. It is currently poorly understood whether

    更新日期:2020-07-08
  • Eco-evolutionary dynamics of nested Darwinian populations and the emergence of community-level heredity
    eLife (IF 7.08) Pub Date : 2020-07-07
    Amaury Lambert; Guilhem Doulcier; Paul B Rainey; Silvia De Monte

    Interactions among microbial cells can generate new chemistries and functions, but exploitation requires establishment of communities that reliably recapitulate community-level phenotypes. Using mechanistic mathematical models, we show how simple manipulations to population structure can exogenously impose Darwinian-like properties on communities. Such scaffolding causes communities to participate

    更新日期:2020-07-07
  • Ways to increase equity, diversity and inclusion
    eLife (IF 7.08) Pub Date : 2020-07-07
    Andy Tay; Carolina Paz Quezada; Charlotte M de Winde; Devang Mehta; Florencia Fernández-Chiappe; Hedyeh Ebrahimi; Julia L Riley; Shyam M Saladi; Tracey Weissgerber; Vinodh Ilangovan; Yaw Bediako

    The eLife Early-Career Advisory Group (ECAG), an international group of early-career researchers committed to improving research culture, calls for radical changes at eLife and other journals to address racism in the scientific community and to make science more diverse and inclusive.

    更新日期:2020-07-07
  • Clustered gamma-protocadherins regulate cortical interneuron programmed cell death
    eLife (IF 7.08) Pub Date : 2020-07-07
    Andrea R Hasenstaub; Ankita Chatterjee; Arturo Alvarez-Buylla; Benjamin Rakela; Julien Spatazza; Michael P Stryker; Tom Maniatis; Viraj Pande; Walter R Mancia Leon

    Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Here we show that loss of clustered gamma protocadherins (Pcdhg), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice

    更新日期:2020-07-07
  • Augmented curation of clinical notes from a massive EHR system reveals symptoms of impending COVID-19 diagnosis
    eLife (IF 7.08) Pub Date : 2020-07-07
    AJ Venkatakrishnan; Akash Anand; Amy W Williams; Andrew Badley, MD; Arjun Puranik; Brian W Pickering; Douglas Challener; Eli Silvert; FNU Shweta; Gregory Gores; Hugo Solomon; John C O'Horo; John Halamka; Karthik Murugadoss; Martin Kang; Maryam Mahmood; Matt Liebers; Paschalis Vergidis; Philippe R Bauer; Praveen Anand; Rakesh Barve; Raymund R Razonable; Sairam Bade; Samir Awasthi; Stacey Rizza; Tyler

    Understanding temporal dynamics of COVID-19 patient symptoms could provide fine-grained resolution to guide clinical decision-making. Here, we use deep neural networks over an institution-wide platform for the augmented curation of clinical notes from 77,167 patients subjected to COVID-19 PCR testing. By contrasting Electronic Health Record (EHR)-derived symptoms of COVID-19-positive (COVIDpos; n=2

    更新日期:2020-07-07
  • Muscle-derived Myoglianin regulates Drosophila imaginal disc growth
    eLife (IF 7.08) Pub Date : 2020-07-07
    Aidan J Peterson; Ambuj Upadhyay; Michael B O'Connor; Myung-Jun Kim

    Organ growth and size are finely tuned by intrinsic and extrinsic signaling molecules. In Drosophila, the BMP family member Dpp is produced in a limited set of imaginal disc cells and functions as a classic morphogen to regulate pattern and growth by diffusing throughout imaginal discs. However, the role of TGFβ/Activin-like ligands in disc growth control remains ill-defined. Here we demonstrate that

    更新日期:2020-07-07
  • Dopamine role in learning and action inference
    eLife (IF 7.08) Pub Date : 2020-07-07
    Rafal Bogacz

    This paper describes a framework for modelling dopamine function in the mammalian brain. It proposes that both learning and action planning involve processes minimizing prediction errors encoded by dopaminergic neurons. In this framework, dopaminergic neurons projecting to different parts of the striatum encode errors in predictions made by the corresponding systems within the basal ganglia. The dopaminergic

    更新日期:2020-07-07
  • Tumor control via targeting PD-L1 with chimeric antigen receptor modified NK cells
    eLife (IF 7.08) Pub Date : 2020-07-07
    Carter Van Waes; Clint T Allen; Houssein Abdul Sater; James Gulley; James W Hodge; Jay Friedman; Jeffrey Schlom; John H Lee; Kellsye P Fabian; Michelle R Padget; Patrick Soon-Shiong; Paul E Clavijo; Sarah Greene; Yvette Robbins

    Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head

    更新日期:2020-07-07
  • Earliest infections predict the age distribution of seasonal influenza A cases
    eLife (IF 7.08) Pub Date : 2020-07-07
    Edward A Belongia; Huong Q McLean; Philip Arevalo; Sarah Cobey

    Seasonal variation in the age distribution of influenza A cases suggests that factors other than age shape susceptibility to medically attended infection. We ask whether these differences can be partly explained by protection conferred by childhood influenza infection, which has lasting impacts on immune responses to influenza and protection against new influenza A subtypes (phenomena known as original

    更新日期:2020-07-07
  • A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm
    eLife (IF 7.08) Pub Date : 2020-07-07
    Alan E Mast; Amy Justice; Angelica M Walker; B Kirtley Amos; Bruce Aronow; Christiane Alvarez; Daniel Jacobson; Erica T Prates; J Izaak Miller; Mike R Garvin

    Neither the disease mechanism nor treatments for COVID-19 are currently known. Here we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS, that produces the nonapeptide angiotensin1-9 from

    更新日期:2020-07-07
  • Trends in snakebite deaths in India from 2000 to 2019 in a nationally representative mortality study
    eLife (IF 7.08) Pub Date : 2020-07-07
    David Warrell; Geetha Menon; Kapila Piyasena; Mehak Bhatia; Patrick Brown; Prabha Sati; Prabhat Jha; Rashmi Rodrigues; Rehana Begum; Romulus Whitaker; Sze Hang Fu; Wilson Suraweera

    The World Health Organization call to halve global snakebite deaths by 2030 will require substantial progress in India. We analyzed 2833 snakebite deaths from 611,483 verbal autopsies in the nationally representative Indian Million Death Study from 2001 to 2014, and conducted a systematic literature review from 2000 to 2019 covering 87,590 snakebites. We estimate that India had 1.2 million snakebite

    更新日期:2020-07-07
  • Super-resolution microscopy reveals majorly mono- and dimeric presenilin1/γ-secretase at the cell surface
    eLife (IF 7.08) Pub Date : 2020-07-07
    Abril Angélica Escamilla-Ayala; Caroline Berlage; Hideaki Mizuno; Karin Poersch; Laura Paparelli; Lucia Chavez-Gutierrez; Magali Mondin; Marcelle Koenig; Maximilian H Ulbrich; Ragna Sannerud; Sebastian Munck; Wendy Vermeire; Wim Annaert

    γ-Secretase is a multi-subunit enzyme whose aberrant activity is associated with Alzheimer’s disease and cancer. While its structure is atomically resolved, γ-secretase localization in the membrane in situ relies mostly on biochemical data. Here, we combined fluorescent tagging of γ-secretase subunits with super-resolution microscopy in fibroblasts. Structured illumination microscopy revealed single

    更新日期:2020-07-07
  • Consistent patterns of distractor effects during decision making
    eLife (IF 7.08) Pub Date : 2020-07-06
    Alizée Lopez-Persem; Bolton K H Chau; Chun-Kit Law; Matthew F S Rushworth; Miriam C Klein-Flügge

    The value of a third potential option or distractor can alter the way in which decisions are made between two other options. Two hypotheses have received empirical support: that a high value distractor improves the accuracy with which decisions between two other options are made and that it impairs accuracy. Recently, however, it has been argued that neither observation is replicable. Inspired by neuroimaging

    更新日期:2020-07-06
  • Stable and dynamic representations of value in the prefrontal cortex
    eLife (IF 7.08) Pub Date : 2020-07-06
    Erin L Rich; Joni D Wallis; Pierre Enel

    Optimal decision-making requires that stimulus-value associations are kept up to date by constantly comparing the expected value of a stimulus with its experienced outcome. To do this, value information must be held in mind when a stimulus and outcome are separated in time. However, little is known about the neural mechanisms of working memory (WM) for value. Contradicting theories have suggested WM

    更新日期:2020-07-06
  • PTEN and DNA-PK determine sensitivity and recovery in response to WEE1 inhibition in human breast cancer
    eLife (IF 7.08) Pub Date : 2020-07-06
    Aldwin Suryo Rahmanto; Andrä Brunner; Charles Spruck; Erik Fredlund; Henrik Johansson; Janne Lehtiö; Johanna Viiliäinen; Juha K Rantala; Lars-Gunnar Larsson; Marcela Franco; Mohiuddin Gazi; Oliver Frings; Olle Sangfelt

    Inhibition of WEE1 kinase by AZD1775 has shown promising results in clinical cancer trials, but markers predicting AZD1775 response are lacking. Here we analysed AZD1775 response in a panel of human breast cancer (BC) cell lines by global proteome/transcriptome profiling and identified two groups of basal-like BC (BLBCs): ‘PTEN low’ BLBCs were highly sensitive to AZD1775 and failed to recover following

    更新日期:2020-07-06
  • Extrinsic Activin signaling cooperates with an intrinsic temporal program to increase mushroom body neuronal diversity
    eLife (IF 7.08) Pub Date : 2020-07-06
    Anthony M Rossi; Claude Desplan

    Temporal patterning of neural progenitors leads to the sequential production of diverse neuronal types. To better understand how extrinsic cues interact with intrinsic temporal programs to contribute to temporal patterning, we studied the Drosophila mushroom body neural progenitors (neuroblasts). Each of these four neuroblasts divides ~250 times to sequentially produce only three main neuronal types

    更新日期:2020-07-06
  • The head direction circuit of two insect species
    eLife (IF 7.08) Pub Date : 2020-07-06
    Barbara Webb; Ioannis Pisokas; Stanley Heinze

    Recent studies of the Central Complex in the brain of the fruit fly have identified neurons with activity that tracks the animal's heading direction. These neurons are part of a neuronal circuit with dynamics resembling those of a ring attractor. The homologous circuit in other insects has similar topographic structure but with significant structural and connectivity differences. We model the connectivity

    更新日期:2020-07-06
  • Movement initiation and grasp representation in premotor and primary motor cortex mirror neurons
    eLife (IF 7.08) Pub Date : 2020-07-06
    Alexander Kraskov; Maneesh Sahani; Steven Jack Jerjian

    Pyramidal tract neurons (PTNs) within macaque rostral ventral premotor cortex (F5) and primary motor cortex (M1) provide direct input to spinal circuitry and are critical for skilled movement control. Contrary to initial hypotheses, they can also be active during action observation, in the absence of any movement. A population-level understanding of this phenomenon is currently lacking. We recorded

    更新日期:2020-07-06
  • Profiling of myristoylation in Toxoplasma gondii reveals an N-myristoylated protein important for host cell penetration
    eLife (IF 7.08) Pub Date : 2020-07-03
    Alex Hunt; Bastien Touquet; Bethan Alexandra Wallbank; Caia Dominicus; Edward J Bartlett; Edward W Tate; Isabelle Tardieux; Joanna Claire Young; Luis Vigetti; Malgorzata Broncel; Moritz Treeck; Stefania Federico; Stephanie D Nofal; Stephen Matthews

    N-myristoylation is a ubiquitous class of protein lipidation across eukaryotes and N-myristoyl transferase (NMT) has been proposed as an attractive drug target in several pathogens. Myristoylation often primes for subsequent palmitoylation and stable membrane attachment, however, growing evidence suggests additional regulatory roles for myristoylation on proteins. Here we describe the myristoylated

    更新日期:2020-07-03
  • Chemical and structural investigation of the paroxetine-human serotonin transporter complex
    eLife (IF 7.08) Pub Date : 2020-07-03
    Daniele Antermite; Dongxue Yang; Eric Gouaux; James A Bull; Jonathan A Coleman; Vikas Navratna

    Antidepressants target the serotonin transporter (SERT) by inhibiting serotonin reuptake. Structural and biochemical studies aiming to understand binding of small-molecules to conformationally dynamic transporters like SERT often require thermostabilizing mutations and antibodies to stabilize a specific conformation, leading to questions about relationships of these structures to the bonafide conformation

    更新日期:2020-07-03
  • Vestigial auriculomotor activity indicates the direction of auditory attention in humans
    eLife (IF 7.08) Pub Date : 2020-07-03
    Andreas Schroeer; Daniel J Strauss; Farah I Corona-Strauss; Philipp Flotho; Ronny Hannemann; Steven A Hackley

    Unlike dogs and cats, people do not point their ears as they focus attention on novel, salient, or task-relevant stimuli. Our species may nevertheless have retained a vestigial pinna-orienting system that has persisted as a 'neural fossil’ within in the brain for about 25 million years. Consistent with this hypothesis, we demonstrate that the direction of auditory attention is reflected in sustained

    更新日期:2020-07-03
  • Temporal selectivity declines in the aging human auditory cortex
    eLife (IF 7.08) Pub Date : 2020-07-03
    Jonas Obleser; Julia Erb; Lea-Maria Schmitt

    Current models successfully describe the auditory cortical response to natural sounds with a set of spectro-temporal features. However, these models have hardly been linked to the ill-understood neurobiological changes that occur in the aging auditory cortex. Modelling the hemodynamic response to a rich natural sound mixture in N=64 listeners of varying age, we here show that in older listeners' auditory

    更新日期:2020-07-03
  • Human Fcγ-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in Lyme arthritis
    eLife (IF 7.08) Pub Date : 2020-07-02
    André Gessner; Anja Lux; Anne Baerenwaldt; Carmen Reitinger; Diane Dudziak; Falk Nimmerjahn; Heike Danzer; Joachim Glaesner; Lukas Heger; Thomas Harrer

    Pathogen specific antibody responses need to be tightly regulated to generate protective but limit self-reactive immune responses. While loss of humoral tolerance has been associated with microbial infections, the pathways involved in balancing protective versus autoreactive antibody responses in humans are incompletely understood. Studies in classical mouse model systems have provided evidence that

    更新日期:2020-07-02
  • Receptor-driven, multimodal mapping of cortical areas in the macaque monkey intraparietal sulcus
    eLife (IF 7.08) Pub Date : 2020-07-02
    Daniele Impieri; Karl Zilles; Lucija Rapan; Meiqi Niu; Nicola Palomero-Gallagher; Thomas Funck

    The intraparietal sulcus (IPS) is structurally and functionally heterogeneous. We performed a quantitative cyto- and receptor architectonical analysis to provide a multimodal map of the macaque IPS. We identified 17 cortical areas, including novel areas PEipe, PEipi (external and internal subdivisions of PEip), and MIPd. Multivariate analyses of receptor densities resulted in a grouping of areas based

    更新日期:2020-07-02
  • Evolution of a plant gene cluster in Solanaceae and emergence of metabolic diversity
    eLife (IF 7.08) Pub Date : 2020-07-02
    Bethany M Moore; Bryan J Leong; Craig A Schenck; Federica Brandizzi; Peipei Wang; Pengfei Cao; Pengxiang Fan; Rachel Combs; Robert L Last; Shin-Han Shiu; Yann-Ru Lou

    Plants produce phylogenetically and spatially restricted, as well as structurally diverse specialized metabolites via multistep metabolic pathways. Hallmarks of specialized metabolic evolution include enzymatic promiscuity and recruitment of primary metabolic enzymes and examples of genomic clustering of pathway genes. Solanaceae glandular trichomes produce defensive acylsugars, with sidechains that

    更新日期:2020-07-02
  • Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling
    eLife (IF 7.08) Pub Date : 2020-07-02
    Adrienne W Paton; Benedikt M Kessler; Emma J Fenech; Federica Lari; James C Paton; John C Christianson; Katrin Bagola; Mads Gyrd-Hansen; Marie Laétitia-Thézénas; Philip D Charles; Roman Fischer

    Ubiquitin ligases (E3s) embedded in the endoplasmic reticulum (ER) membrane regulate essential cellular activities including protein quality control, calcium flux, and sterol homeostasis. At least 25 different, transmembrane domain (TMD)-containing E3s are predicted to be ER-localised, but for most their organisation and cellular roles remain poorly defined. Using a comparative proteomic workflow,

    更新日期:2020-07-02
  • Global sleep homeostasis reflects temporally and spatially integrated local cortical neuronal activity
    eLife (IF 7.08) Pub Date : 2020-07-02
    Christopher W Thomas; Laura E McKillop; Mathilde CC Guillaumin; Peter Achermann; Vladyslav V Vyazovskiy

    Sleep homeostasis manifests as a relative constancy of its daily amount and intensity. Theoretical descriptions define ‘Process S’, a variable with dynamics dependent on global sleep-wake history, and reflected in electroencephalogram (EEG) slow wave activity (SWA, 0.5–4 Hz) during sleep. The notion of sleep as a local, activity-dependent process suggests that activity history must be integrated to

    更新日期:2020-07-02
  • Cortical ChAT+ neurons co-transmit acetylcholine and GABA in a target-and brain-region specific manner
    eLife (IF 7.08) Pub Date : 2020-07-02
    Adam J Granger; Andrea F Zanello; Arpiar Saunders; Bernardo L Sabatini; Brian W Chow; Chenghua Gu; Corey C Harwell; Karina Bistrong; Keiramarie Robertson; Mahmoud El-Rifai; Miguel Turrero García; Vicente Nuñez; Wengang Wang

    The mouse cerebral cortex contains neurons that express choline acetyltransferase (ChAT) and are a potential local source of acetylcholine. However, the neurotransmitters released by cortical ChAT+ neurons and their synaptic connectivity are unknown. We show that the nearly all cortical ChAT+ neurons in mice are specialized VIP+ interneurons that release GABA strongly onto other inhibitory interneurons

    更新日期:2020-07-02
  • Homeostatic plasticity fails at the intersection of autism-gene mutations and a novel class of common genetic modifiers
    eLife (IF 7.08) Pub Date : 2020-07-01
    Giulia Zunino; Graeme W Davis; Joon-Yong An; Özgür Genç; Richard D Fetter; Stephan J Sanders; Yelena Kulik

    We identify a set of common phenotypic modifiers that interact with five independent autism gene orthologs (RIMS1, CHD8, CHD2, WDFY3, ASH1L) causing a common failure of presynaptic homeostatic plasticity (PHP) in Drosophila. Heterozygous null mutations in each autism gene are demonstrated to have normal baseline neurotransmission and PHP. However, PHP is sensitized and rendered prone to failure. A

    更新日期:2020-07-01
  • Exciting inhibition in primates
    eLife (IF 7.08) Pub Date : 2020-07-01
    Wim Vanduffel; Xiaolian Li

    A new genetic marker enables precise control over a group of inhibitory neurons in monkeys.

    更新日期:2020-07-01
  • Divergent sensory investment mirrors potential speciation via niche partitioning across Drosophila
    eLife (IF 7.08) Pub Date : 2020-06-30
    Bill S Hansson; Ian W Keesey; Markus Knaden; Veit Grabe

    The examination of phylogenetic and phenotypic characteristics of the nervous system, such as behavior and neuroanatomy, can be utilized as a means to assess speciation. Recent studies have proposed a fundamental tradeoff between two sensory organs, the eye and the antenna. However, the identification of ecological mechanisms for this observed tradeoff have not been firmly established. Our current

    更新日期:2020-06-30
  • HA stabilization promotes replication and transmission of swine H1N1 gamma influenza viruses in ferrets
    eLife (IF 7.08) Pub Date : 2020-06-30
    Andrew S Bowman; Charles J Russell; Guohua Yang; Hyunsuh Kim; Jennifer DeBeauchamp; Jeri Carol Crumpton; Lei Li; Lisa Kercher; Meng Hu; Richard J Webby; Robert G Webster; Xiu-Feng Wan

    Pandemic influenza A viruses can emerge from swine, an intermediate host that supports adaptation of human-preferred receptor-binding specificity by the hemagglutinin (HA) surface antigen. Other HA traits necessary for pandemic potential are poorly understood. For swine influenza viruses isolated in 2009–2016, gamma-clade viruses had less stable HA proteins (activation pH 5.5–5.9) than pandemic clade

    更新日期:2020-06-30
  • Alcids 'fly' at efficient Strouhal numbers in both air and water but vary stroke velocity and angle
    eLife (IF 7.08) Pub Date : 2020-06-30
    Anthony Lapsansky; Bret W Tobalske; Daniel Zatz

    Birds that use their wings for 'flight' in both air and water are expected to fly poorly in each fluid relative to single-fluid specialists; i.e., these jacks-of-all-trades should be the masters of none. Alcids exhibit exceptional dive performance while retaining aerial flight. We hypothesized that alcids maintain efficient Strouhal numbers and stroke velocities across air and water, allowing them

    更新日期:2020-06-30
  • Generation of inner ear hair cells by direct lineage conversion of primary somatic cells
    eLife (IF 7.08) Pub Date : 2020-06-30
    Alexander L Markowitz; Chichou Huang; Haoze V Yu; James Lee; Juan Llamas; Justin Ichida; Litao Tao; Louise Menendez; Neil Segil; Radha Kalluri; Suhasni Gopalakrishnan; Talon Trecek; Xizi Wang

    The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide

    更新日期:2020-06-30
  • An atlas for hemocytes in an insect
    eLife (IF 7.08) Pub Date : 2020-06-30
    Dominique Ferrandon; Samuel Liegeois

    Single-cell RNA sequencing has revealed distinct subpopulations of hemocytes in fruit fly larvae.

    更新日期:2020-06-30
  • Structure of MlaFB uncovers novel mechanisms of ABC transporter regulation
    eLife (IF 7.08) Pub Date : 2020-06-30
    Damian C Ekiert; Evelyn M Teran; Georgia L Isom; Gira Bhabha; Ljuvica R Kolich; Mark R MacRae; Nicolas Coudray; Sabrina I Giacometti; Ya-Ting Chang

    ABC transporters facilitate the movement of diverse molecules across cellular membranes, but how their activity is regulated post-translationally is not well understood. Here we report the crystal structure of MlaFB from E. coli, the cytoplasmic portion of the larger MlaFEDB ABC transporter complex, which drives phospholipid trafficking across the bacterial envelope to maintain outer membrane integrity

    更新日期:2020-06-30
  • Membrane characteristics tune activities of endosomal and autophagic human VPS34 complexes
    eLife (IF 7.08) Pub Date : 2020-06-30
    Christopher M Johnson; Glenn Robert Masson; Izabella Niewczas; Jerome Boulanger; Jonathan Clark; Ksenia Rostislavleva; Lauren McGinney; Roger L Williams; Shirley Tremel; Yohei Ohashi

    The lipid kinase VPS34 orchestrates diverse processes, including autophagy, endocytic sorting, phagocytosis, anabolic responses and cell division. VPS34 forms various complexes that help adapt it to specific pathways, with complexes I and II being the most prominent ones. We found that physicochemical properties of membranes strongly modulate VPS34 activity. Greater unsaturation of both substrate and

    更新日期:2020-06-30
  • Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants
    eLife (IF 7.08) Pub Date : 2020-06-30
    Allison L Hicks; Deborah A Williamson; George Taiaroa; Kevin C Ma; Marc Lipsitch; Melinda Ashcroft; Stephen M Kissler; Tatum D Mortimer; Yonatan H Grad

    Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate antibiotic use. However, because such assays infer resistance based on known genetic markers, their utility will wane with the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance to ensure early detection of novel resistance

    更新日期:2020-06-30
  • Genomics against gonorrhoea
    eLife (IF 7.08) Pub Date : 2020-06-30
    Nicholas Medland

    Surveillance strategies based on whole genome sequencing could help with the early identification and detection of new forms of drug-resistant gonorrhoea.

    更新日期:2020-06-30
  • Parvalbumin interneurons provide spillover to newborn and mature dentate granule cells
    eLife (IF 7.08) Pub Date : 2020-06-30
    Allison R Fusilier; Anastasia J Niver; Chelsea M Griffith; Jacques I Wadiche; Jose Carlos Gonzalez; Linda Overstreet-Wadiche; Ming-Chi Tsai; Richard H Kramer; Ryan J Vaden

    Parvalbumin-expressing interneurons (PVs) in the dentate gyrus provide activity-dependent regulation of adult neurogenesis as well as maintain inhibitory control of mature neurons. In mature neurons, PVs evoke GABAA postsynaptic currents (GPSCs) with fast rise and decay phases that allow precise control of spike timing, yet synaptic currents with fast kinetics do not appear in adult-born neurons until

    更新日期:2020-06-30
  • Transient role of the middle ear as a lower jaw support across mammals
    eLife (IF 7.08) Pub Date : 2020-06-30
    Abigail S Tucker; Jane Catherine Fenelon; Marilyn B Renfree; Neal Anthwal; Stephen D Johnston

    Mammals articulate their jaws using a novel joint between the dentary and squamosal bones. In eutherian mammals, this joint forms in the embryo, supporting feeding and vocalisation from birth. In contrast, marsupials and monotremes exhibit extreme altriciality and are born before the bones of the novel mammalian jaw joint form. These mammals need to rely on other mechanisms to allow them to feed. Here

    更新日期:2020-06-30
  • A Tgfbr1/Snai1-dependent developmental module at the core of vertebrate axial elongation
    eLife (IF 7.08) Pub Date : 2020-06-29
    Anahi Binagui-Casas; Ana Nóvoa; Anastasiia Lozovska; André Dias; Daniel Sobral; Filip J Wymeersch; Gabriel G Martins; Moises Mallo; Valerie Wilson

    Formation of the vertebrate postcranial body axis follows two sequential but distinct phases. The first phase generates pre-sacral structures (the so-called primary body) through the activity of the primitive streak on axial progenitors within the epiblast. The embryo then switches to generate the secondary body (post-sacral structures), which depends on axial progenitors in the tail bud. Here we show

    更新日期:2020-06-29
  • Inhibition stabilization is a widespread property of cortical networks
    eLife (IF 7.08) Pub Date : 2020-06-29
    Alessandro Sanzeni; Bradley Akitake; Caitlin E Leedy; Hannah C Goldbach; Mark H Histed; Nicolas Brunel

    Many cortical network models use recurrent coupling strong enough to require inhibition for stabilization. Yet it has been experimentally unclear whether inhibition-stabilized network (ISN) models describe cortical function well across areas and states. Here, we test several ISN predictions, including the counterintuitive (paradoxical) suppression of inhibitory firing in response to optogenetic inhibitory

    更新日期:2020-06-29
  • A non-mosaic transchromosomic mouse model of Down syndrome carrying the long arm of human chromosome 21
    eLife (IF 7.08) Pub Date : 2020-06-29
    Alena Savonenko; Anna J Moyer; Atsuo Ogura; Atsushi Hasegawa; Benjamin Devenney; Dan Wu; Denise AS Batista; Feng J Gao; Joan T Richtsmeier; Junhua Yang; Kanako Kazuki; Kei Hiramatsu; Kimiko Inoue; Liliana D Florea; Masato Takiguchi; Meifang Xiao; Miho Yamakawa; Mitsuo Oshimura; Nandini Singh; Naohiro Noda; Naoyo Kajitani; Narumi Ogonuki; Narumi Uno; Ritsuko Shimizu; Roger H Reeves; Sachiko Miyagawa-Tomita;

    Animal models of Down syndrome (DS), trisomic for human chromosome 21 (HSA21) genes or orthologs, provide insights into better understanding and treatment options. The only existing transchromosomic (Tc) mouse DS model, Tc1, carries a HSA21 with over 50 protein coding genes (PCGs) disrupted. Tc1 is mosaic, compromising interpretation of results. Here, we 'clone' the 34 MB long arm of HSA21 (HSA21q)

    更新日期:2020-06-29
  • The Role of Rif1 in telomere length regulation is separable from its role in origin firing
    eLife (IF 7.08) Pub Date : 2020-06-29
    Calla B Shubin; Carol W Greider

    To examine the established link between DNA replication and telomere length, we tested whether firing of telomeric origins would cause telomere lengthening. We found that RIF1 mutants that block Protein Phosphatase 1 (PP1) binding activated telomeric origins but did not elongate telomeres. In a second approach, we found overexpression of ∆N-Dbf4 and Cdc7 increased DDK activity and activated telomeric

    更新日期:2020-06-29
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