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  • Identifying the immune interactions underlying HLA class I disease associations
    eLife (IF 7.551) Pub Date : 2020-04-02
    Bisrat J Debebe; Lies Boelen; James C Lee; IAVI Protocol C Investigators; Chloe L Thio; Jacquie Astemborski; Gregory Kirk; Salim I Khakoo; Sharyne M Donfield; James J Goedert; Becca Asquith

    Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms in the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8+ T cell responses which are restricted

    更新日期:2020-04-03
  • Intermediate progenitors support migration of neural stem cells into dentate gyrus outer neurogenic niches
    eLife (IF 7.551) Pub Date : 2020-04-02
    Branden R Nelson; Rebecca D Hodge; Ray AM Daza; Prem Prakash Tripathi; Sebastian J Arnold; Kathleen J Millen; Robert F Hevner

    The hippocampal dentate gyrus (DG) is a unique brain region maintaining neural stem cells (NCSs) and neurogenesis into adulthood. We used multiphoton imaging to visualize for genetically defined progenitor subpopulations in live slices across key stages of mouse DG development testing decades old static models of DG formation, with molecular identification, genetic-lineage tracing, and mutant analyses

    更新日期:2020-04-03
  • Super-resolution microscopy reveals coupling between mammalian centriole subdistal appendages and distal appendages
    eLife (IF 7.551) Pub Date : 2020-04-03
    Weng Man Chong; Won-Jing Wang; Chien-Hui Lo; Tzu-Yuan Chiu; Ting-Jui Chang; You-Pi Liu; Barbara Tanos; Gregory Mazo; Meng-Fu Bryan Tsou; Wann-Neng Jane; T Tony Yang; Jung-Chi Liao

    Subdistal appendages (sDAPs) are centriolar elements observed proximal to the distal appendages (DAPs) in vertebrates. Despite their obvious presence, structural and functional understanding of sDAPs remains elusive. Here, by combining super-resolved localization analysis and CRISPR-Cas9 genetic perturbation, we find that, although DAPs and sDAPs are primarily responsible for distinct functions in

    更新日期:2020-04-03
  • KIT ligand protects against both light-induced and genetic photoreceptor degeneration
    eLife (IF 7.551) Pub Date : 2020-04-03
    Huirong Li; Lili Lian; Bo Liu; Yu Chen; Jinglei Yang; Shuhui Jian; Jiajia Zhou; Ying Xu; Xiaoyin Ma; Jia Qu; Ling Hou

    Photoreceptor degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become readily available. Here we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor

    更新日期:2020-04-03
  • Cell-type diversity and regionalized gene expression in the planarian intestine
    eLife (IF 7.551) Pub Date : 2020-04-02
    David J Forsthoefel; Nicholas I Cejda; Umair W Khan; Phillip A Newmark

    Proper function and repair of the digestive system are vital to most animals. Deciphering the mechanisms involved in these processes requires an atlas of gene expression and cell types. Here, we applied laser-capture microdissection (LCM) and RNA-seq to characterize the intestinal transcriptome of Schmidtea mediterranea, a planarian flatworm that can regenerate all organs, including the gut. We identified

    更新日期:2020-04-03
  • Proteome dynamics during homeostatic scaling in cultured neurons
    eLife (IF 7.551) Pub Date : 2020-04-02
    Aline Ricarda Dörrbaum; Beatriz Alvarez-Castelao; Belquis Nassim-Assir; Julian D Langer; Erin M Schuman

    Protein turnover, the net result of protein synthesis and degradation, enables cells to remodel their proteomes in response to internal and external cues. Previously, we analyzed protein turnover rates in cultured brain cells under basal neuronal activity and found that protein turnover is influenced by subcellular localization, protein function, complex association, cell type of origin, and by the

    更新日期:2020-04-03
  • CSF1R blockade induces macrophage ablation and results in mouse choroidal vascular atrophy and RPE disorganization
    eLife (IF 7.551) Pub Date : 2020-04-01
    Xiao Yang; Lian Zhao; Maria M Campos; Mones Abu-Asab; Davide Ortolan; Nathan Hotaling; Kapil Bharti; Wai T Wong

    The choroid, which provides vascular supply to the outer retina, demonstrates progressive degeneration in aging and age-related macular degeneration (AMD). However mechanisms that maintain or compromise choroidal homeostasis are obscure. We discovered that the ablation of choroidal macrophages via CSF1R blockade was associated with choroidal vascular atrophy and retinal pigment epithelial (RPE) changes

    更新日期:2020-04-01
  • Delta glutamate receptor conductance drives excitation of mouse dorsal raphe neurons
    eLife (IF 7.551) Pub Date : 2020-04-01
    Stephanie C Gantz; Khaled Moussawi; Holly S Hake

    The dorsal raphe nucleus is the predominant source of central serotonin, where neuronal activity regulates complex emotional behaviors. Action potential firing of serotonin dorsal raphe neurons is driven via a1-adrenergic receptors (a1-AR) activation. Despite this crucial role, the ion channels responsible for a1-AR-mediated depolarization are unknown. Here, we show in mouse brain slices that a1-AR-mediated

    更新日期:2020-04-01
  • Functionally heterogeneous human satellite cells identified by single cell RNA sequencing
    eLife (IF 7.551) Pub Date : 2020-04-01
    Emilie Barruet; Steven M Garcia; Katharine Striedinger; Jake Wu; Solomon Lee; Lauren Byrnes; Alvin Wong; Sun Xuefeng; Stanley Tamaki; Andrew S Brack; Jason H Pomerantz

    Although heterogeneity is recognized within the murine satellite cell pool, a comprehensive understanding of distinct subpopulations and their functional relevance in human satellite cells is lacking. We used a combination of single cell RNA sequencing and flow cytometry to identify, distinguish, and physically separate novel subpopulations of human PAX7+ satellite cells (Hu-MuSCs) from normal muscles

    更新日期:2020-04-01
  • Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex
    eLife (IF 7.551) Pub Date : 2020-04-01
    Ryan S D'Souza; Jun Y Lim; Alper Turgut; Kelly Servage; Junmei Zhang; Kim Orth; Nisha Sosale; Matthew Lazzara; Jeremy Allegood; James E Casanova

    Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. Many studies have shown that FA disassembly requires Ca2+ influx, however our understanding of this process remains incomplete. Here we show that Ca2+ influx via STIM1/Orai1 calcium channels, which cluster near FAs, leads to activation of the GTPase Arf5 via the Ca2+-activated GEF IQSec1

    更新日期:2020-04-01
  • Deep evolutionary analysis reveals the design principles of fold A glycosyltransferases
    eLife (IF 7.551) Pub Date : 2020-04-01
    Rahil Taujale; Aarya Venkat; Liang-Chin Huang; Zhongliang Zhou; Wayland Yeung; Khaled M Rasheed; Sheng Li; Arthur S Edison; Kelley W Moremen; Natarajan Kannan

    Glycosyltransferases (GTs) are prevalent across the tree of life and regulate nearly all aspects of cellular functions. The evolutionary basis for their complex and diverse modes of catalytic functions remain enigmatic. Here, based on deep mining of over half million GT-A fold sequences, we define a minimal core component shared among functionally diverse enzymes. We find that variations in the common

    更新日期:2020-04-01
  • Mutations associated with human neural tube defects display disrupted planar cell polarity in Drosophila
    eLife (IF 7.551) Pub Date : 2020-04-01
    Ashley C Humphries; Sonali Narang; Marek Mlodzik

    Planar cell polarity (PCP) and neural tube defects (NTDs) are linked, with a subset of NTD patients found to harbour mutations in PCP genes, but there is limited data on whether these mutations disrupt PCP signaling in vivo. The core PCP gene Van Gogh (Vang), Vangl1/2 in mammals, is the most specific for PCP. We thus addressed potential causality of NTD-associated Vangl1/2 mutations, from either mouse

    更新日期:2020-04-01
  • β3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes
    eLife (IF 7.551) Pub Date : 2020-03-31
    Sophie Schobesberger; Peter T Wright; Claire Poulet; Jose L Sanchez Alonso Mardones; Catherine Mansfield; Andreas Friebe; Sian E Harding; Jean-Luc Balligand; Viacheslav O Nikolaev; Julia Gorelik

    Cardiomyocyte b3-adrenoceptors (b3-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of b3-AR/cGMP signals underpinning this protection in health and disease

    更新日期:2020-03-31
  • Gating and selectivity mechanisms for the lysosomal K+channel TMEM175
    eLife (IF 7.551) Pub Date : 2020-03-31
    SeCheol Oh; Navid Paknejad; Richard K Hite

    Transmembrane protein 175 (TMEM175) is a K+-selective ion channel expressed in lysosomal membranes, where it establishes a membrane potential essential for lysosomal function and its dysregulation is associated with the development of Parkinson's Disease. TMEM175 is evolutionarily distinct from all known channels, predicting novel ion-selectivity and gating mechanisms. Here we present cryo-EM structures

    更新日期:2020-03-31
  • SARS-CoV-2 (COVID-19) by the numbers
    eLife (IF 7.551) Pub Date : 2020-03-31
    Yinon M Bar-On; Avi Flamholz; Rob Phillips; Ron Milo

    The current SARS-CoV-2 pandemic is a harsh reminder of the fact that, whether in a single human host or a wave of infection across continents, viral dynamics is often a story about the numbers. In this snapshot, our aim is to provide a one-stop, curated graphical source for the key numbers that help us understand the virus driving our current global crisis. The discussion is framed around two broad

    更新日期:2020-03-31
  • Incomplete vesicular docking limits synaptic strength under high release probability conditions
    eLife (IF 7.551) Pub Date : 2020-03-31
    Gerardo Malagon; Takafumi Miki; Van Tran; Laura Gomez; Alain Marty

    Central mammalian synapses release synaptic vesicles in dedicated structures called docking/release sites. It has been assumed that when voltage-dependent calcium entry is sufficiently large, synaptic output attains a maximum value of one synaptic vesicle per action potential and per site. Here we use deconvolution to count synaptic vesicle output at single sites (mean site number per synapse: 3.6)

    更新日期:2020-03-31
  • The primary structural photoresponse of phytochrome proteins captured by a femtosecond X-ray laser
    eLife (IF 7.551) Pub Date : 2020-03-31
    Elin Claesson; Weixiao Yuan Wahlgren; Heikki Takala; Suraj Pandey; Leticia Castillon; Valentyna Kuznetsova; Léocadie Henry; Matthijs Panman; Melissa Carrillo; Joachim Kübel; Rahul Nanekar; Linnéa Isaksson; Amke Nimmrich; Andrea Cellini; Dmitry Morozov; Michał Maj; Moona Kurttila; Robert Bosman; Eriko Nango; Rie Tanaka; Tomoyuki Tanaka; Luo Fangjia; So Iwata; Shigeki Owada; Keith Moffat; Gerrit Groenhof;

    Phytochrome proteins control the growth, reproduction, and photosynthesis of plants, fungi, and bacteria. Light is detected by a bilin cofactor, but it remains elusive how this leads to activation of the protein through structural changes. We present serial femtosecond X-ray crystallographic data of the chromophore-binding domains of a bacterial phytochrome at delay times of 1 ps and 10 ps after photoexcitation

    更新日期:2020-03-31
  • Approaching boiling point stability of an alcohol dehydrogenase through computationally-guided enzyme engineering
    eLife (IF 7.551) Pub Date : 2020-03-31
    Friso S Aalbers; Maximilian JLJ Fürst; Stefano Rovida; Milos Trajkovic; J Rubén Gómez Castellanos; Sebastian Bartsch; Andreas Vogel; Andrea Mattevi; Marco W Fraaije

    Enzyme instability is an important limitation for the investigation and application of enzymes. Therefore, methods to rapidly and effectively improve enzyme stability are highly appealing. In this study we applied a computational method (FRESCO) to guide the engineering of an alcohol dehydrogenase. Of the 177 selected mutations, 25 mutations brought about a significant increase in apparent melting

    更新日期:2020-03-31
  • Cryo-EM structures of S-OPA1 reveal its interactions with membrane and changes upon nucleotide binding
    eLife (IF 7.551) Pub Date : 2020-03-31
    Danyang Zhang; Yan Zhang; Jun Ma; Chunmei Zhu; Tongxin Niu; Wenbo Chen; Xiaoyun Pang; Yujia Zhai; Fei Sun

    Mammalian mitochondrial inner membrane fusion is mediated by optic atrophy 1 (OPA1). Under physiological conditions, OPA1 undergoes proteolytic processing to form a membrane-anchored long isoform (L-OPA1) and a soluble short isoform (S-OPA1). A combination of L-OPA1 and S-OPA1 is essential for efficient membrane fusion; however, the relevant mechanism is not well understood. In this study, we investigate

    更新日期:2020-03-31
  • Application of optogenetic Amyloid-β distinguishes between metabolic and physical damage in neurodegeneration
    eLife (IF 7.551) Pub Date : 2020-03-31
    Chu Hsien Lim; Prameet Kaur; Emelyne Teo; Vanessa Yuk Man Lam; Fangchen Zhu; Caroline Kibat; Jan Gruber; Ajay S Mathuru; Nicholas S Tolwinski

    The brains of Alzheimer's Disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation

    更新日期:2020-03-31
  • TMEM87a/Elkin1, a component of a novel mechanoelectrical transduction pathway, modulates melanoma adhesion and migration
    eLife (IF 7.551) Pub Date : 2020-03-31
    Amrutha Patkunarajah; Jeffrey H Stear; Mirko Moroni; Lioba Schroeter; Jedrzej Blaszkiewicz; Jacqueline LE Tearle; Charles D Cox; Carina Fuerst; Oscar Sanchez-Carranza; Maria del Angel Ocana Fernandez; Raluca Fleischer; Murat Eravci; Christoph Weise; Boris Martinac; Maté Biro; Gary R Lewin; Kate Poole

    Mechanoelectrical transduction is a cellular signalling pathway where physical stimuli are converted into electro-chemical signals by mechanically activated ion channels. We describe here the presence of mechanically activated currents in melanoma cells that are dependent on TMEM87a, which we have renamed Elkin1. Heterologous expression of this protein in PIEZO1-deficient cells, that exhibit no baseline

    更新日期:2020-03-31
  • Visually-updated hand state estimates modulate the proprioceptive reflex independently of motor task requirements
    eLife (IF 7.551) Pub Date : 2020-03-31
    Sho Ito; Hiroaki Gomi

    Fast signaling from vision and proprioception to muscle activation plays essential roles in quickly correcting movement. Though many studies have demonstrated modulation of the quick sensorimotor responses as depending on context in each modality, the contribution of multimodal information has not been established. Here, we examined whether state estimates contributing to stretch reflexes are represented

    更新日期:2020-03-31
  • Ion Channels: Taking a close look at a large-pore channel
    eLife (IF 7.551) Pub Date : 2020-03-31
    Pablo S Gaete; Jorge E Contreras

    The structure of pannexin 1, a channel protein with a large pore, has been determined for the first time.

    更新日期:2020-03-31
  • Fibronectin is a smart adhesive that both influences and responds to the mechanics of early spinal column development
    eLife (IF 7.551) Pub Date : 2020-03-31
    Emilie Guillon; Dipjyoti Das; Dörthe Jülich; Abdel-Rahman Hassan; Hannah Geller; Scott Holley

    An extracellular matrix of Fibronectin adheres the neural tube to the two flanking columns of paraxial mesoderm and is required for normal vertebrate development. Here, we find that the bilaterally symmetric interfaces between the zebrafish neural tube and paraxial mesoderm function as optimally engineered adhesive lap joints with rounded edges, graded Fibronectin ‘adhesive’ and an arced adhesive spew

    更新日期:2020-03-31
  • GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab
    eLife (IF 7.551) Pub Date : 2020-03-31
    Daiki Kato; Tomonori Yaguchi; Takashi Iwata; Yuki Katoh; Kenji Morii; Kinya Tsubota; Yoshiaki Takise; Masaki Tamiya; Haruhiko Kamada; Hiroki Akiba; Kouhei Tsumoto; Satoshi Serada; Tetsuji Naka; Ryohei Nishimura; Takayuki Nakagawa; Yutaka Kawakami

    Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1

    更新日期:2020-03-31
  • Mycobacterium tuberculosis exploits host ATM kinase for survival advantage through SecA2 secretome
    eLife (IF 7.551) Pub Date : 2020-03-30
    Savita Lochab; Yogendra Singh; Sagar Sengupta; Vinay Kumar Nandicoori

    Mycobacterium tuberculosis (Mtb) produces inflections in the host signaling networks to create a favorable milieu for survival. The virulent Mtb strain, Rv caused double strand breaks (DSBs) whereas the non-virulent Ra strain triggered single stranded DNA generation. The effectors secreted by SecA2 pathway were essential and adequate for the genesis of DSBs. Accumulation of DSBs mediated through Rv

    更新日期:2020-03-30
  • Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure
    eLife (IF 7.551) Pub Date : 2020-03-30
    Andrea Ruiz-Velasco; Min Zi; Susanne S Hille; Tayyiba Azam; Namrita Kaur; Juwei Jiang; Binh Nguyen; Karolina Sekeres; Pablo Binder; Lucy Collins; Fay Pu; Han Xiao; Kaomei Guan; Norbert Frey; Elizabeth J Cartwright; Oliver J Müller; Xin Wang; Wei Liu

    Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI

    更新日期:2020-03-30
  • Theoretical relation between axon initial segment geometry and excitability
    eLife (IF 7.551) Pub Date : 2020-03-30
    Sarah Goethals; Romain Brette

    In most vertebrate neurons, action potentials are triggered at the distal end of the axon initial segment (AIS). Both position and length of the AIS vary across and within neuron types, with activity, development and pathology. What is the impact of AIS geometry on excitability? Direct empirical assessment has proven difficult because of the many potential confounding factors. Here we carried a principled

    更新日期:2020-03-30
  • Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages
    eLife (IF 7.551) Pub Date : 2020-03-30
    Maeva Dupont; Shanti Souriant; Luciana Balboa; Thien-Phong Vu Manh; Karine Pingris; Stella Rousset; Céline Cougoule; Yoann Rombouts; Renaud Poincloux; Myriam Ben Neji; Carolina Allers; Deepak Kaushal; Marcelo J Kuroda; Susana Benet; Javier Martinez-Picado; Nuria Izquierdo-Useros; Maria del Carmen Sasiain; Isabelle Maridonneau-Parini; Olivier Neyrolles; Christel Vérollet; Geanncarlo Lugo-Villarino

    While tuberculosis (TB) is a risk factor in HIV-1-infected individuals, the mechanisms by which Mycobacterium tuberculosis (Mtb) worsens HIV-1 pathogenesis remain scarce. We showed that HIV-1 infection is exacerbated in macrophages exposed to TB-associated microenvironments due to tunneling nanotube (TNT) formation. To identify molecular factors associated with TNT function, we performed a transcriptomic

    更新日期:2020-03-30
  • Reversible promoter methylation determines fluctuating expression of acute phase proteins
    eLife (IF 7.551) Pub Date : 2020-03-30
    Shi-Chao Zhang; Ming-Yu Wang; Jun-Rui Feng; Yue Chang; Shang-Rong Ji; Yi Wu

    Acute phase reactants (APRs) are secretory proteins exhibiting large expression changes in response to proinflammatory cytokines. Here we show that the expression pattern of a major APR, i.e. human C-reactive protein (CRP), is casually determined by DNMT3A and TET2-tuned promoter methylation status. CRP features a CpG-poor promoter with its CpG motifs located in binding sites of STAT3, C/EBP-β and

    更新日期:2020-03-30
  • Increase of circulating IGFBP-4 following genotoxic stress and its implication for senescence
    eLife (IF 7.551) Pub Date : 2020-03-30
    Nicola Alessio; Tiziana Squillaro; Giovanni Di Bernardo; Giovanni Galano; Roberto De Rosa; Mariarosa AB Melone; Gianfranco Peluso; Umberto Galderisi

    Senescent cells secrete several molecules, collectively named senescence-associated secretory phenotype (SASP). In the SASP of cells that became senescent following several in vitro chemical and physical stress, we identified the IGFBP-4 protein that can be considered a general stress mediator. This factor appeared to play a key role in senescence-paracrine signaling. We provided evidences showing

    更新日期:2020-03-30
  • Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline
    eLife (IF 7.551) Pub Date : 2020-03-30
    Jonathan R Volpatti; Yukari Endo; Jessica Knox; Linda Groom; Stephanie Brennan; Ramil Noche; William J Zuercher; Peter Roy; Robert T Dirksen; James J Dowling

    Ryanodine receptor type I-related myopathies (RYR1-RMs) are a common group of childhood muscle diseases associated with severe disabilities and early mortality for which there are no available treatments. The goal of this study is to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a discovery pipeline using nematode, zebrafish, and mammalian cell models. We first performed

    更新日期:2020-03-30
  • Integrating prediction errors at two time scales permits rapid recalibration of speech sound categories
    eLife (IF 7.551) Pub Date : 2020-03-30
    Itsaso Olasagasti; Anne-Lise Giraud

    Speech perception presumably arises from internal models of how specific sensory features are associated with speech sounds. These features change constantly (e.g. different speakers, articulation modes etc.), and listeners need to recalibrate their internal models by appropriately weighing new versus old evidence. Models of speech recalibration classically ignore this volatility. The effect of volatility

    更新日期:2020-03-30
  • Prediction signals in the cerebellum: beyond supervised motor learning
    eLife (IF 7.551) Pub Date : 2020-03-30
    Court Hull

    While classical views of cerebellar learning have suggested that this structure predominantly operates according to an error-based supervised learning rule to refine movements, emerging evidence suggests that the cerebellum may also harness a wider range of learning rules to contribute to a variety of behaviors, including cognitive processes. Together, such evidence points to a broad role for cerebellar

    更新日期:2020-03-30
  • Bacterial Immunity: An adaptable defense
    eLife (IF 7.551) Pub Date : 2020-03-30
    Michael A Schelling; Dipali G Sashital

    The response of bacteria to the threat posed by phages depends on their local environment.

    更新日期:2020-03-30
  • Drosophila TRIM32 cooperates with glycolytic enzymes to promote cell growth
    eLife (IF 7.551) Pub Date : 2020-03-30
    Simranjot Bawa; David S Brooks; Kathryn E Neville; Marla Tipping; Md Abdul Sagar; Joseph A Kollhoff; Geetanjali Chawla; Brian V Geisbrecht; Jason M Tennessen; Kevin W Eliceiri; Erika R Geisbrecht

    Cell growth and/or proliferation may require the reprogramming of metabolic pathways, whereby a switch from oxidative to glycolytic metabolism diverts glycolytic intermediates towards anabolic pathways. Herein, we identify a novel role for TRIM32 in the maintenance of glycolytic flux mediated by biochemical interactions with the glycolytic enzymes Aldolase and Phosphoglycerate mutase. Loss of Drosophila

    更新日期:2020-03-30
  • A branched heterochronic pathway directs juvenile-to-adult transition through two LIN-29 isoforms
    eLife (IF 7.551) Pub Date : 2020-03-30
    Chiara Azzi; Florian Aeschimann; Anca Neagu; Helge Großhans

    Robust organismal development relies on temporal coordination of disparate physiological processes. In Caenorhabditis elegans, the heterochronic pathway controls a timely juvenile-to-adult (J/A) transition. This regulatory cascade of conserved proteins and small RNAs culminates in accumulation of the transcription factor LIN-29, which triggers coordinated execution of transition events. We report that

    更新日期:2020-03-30
  • Measuring the distribution of fitness effects in somatic evolution by combining clonal dynamics with dN/dS ratios
    eLife (IF 7.551) Pub Date : 2020-03-30
    Marc J Williams; Luis Zapata; Benjamin Werner; Chris P Barnes; Andrea Sottoriva; Trevor A Graham

    The distribution of fitness effects (DFE) defines how new mutations spread through an evolving population. The ratio of non-synonymous to synonymous mutations (dN/dS) has become a popular method to detect selection in somatic cells. However the link, in somatic evolution, between dN/dS values and fitness coefficients is missing. Here we present a quantitative model of somatic evolutionary dynamics

    更新日期:2020-03-30
  • Co-evolution within structured bacterial communities results in multiple expansion of CRISPR loci and enhanced immunity
    eLife (IF 7.551) Pub Date : 2020-03-30
    Nora C Pyenson; Luciano A Marraffini

    Type II CRISPR-Cas systems provide immunity against phages and plasmids that infect bacteria through the insertion of a short sequence from the invader’s genome, known as the ‘spacer’, into the CRISPR locus. Spacers are transcribed into guide RNAs that direct the Cas9 nuclease to its target on the invader. In liquid cultures, most bacteria acquire a single spacer. Multiple spacer integration is a rare

    更新日期:2020-03-30
  • Reducing RSV hospitalisation in a lower-income country by vaccinating mothers-to-be and their households
    eLife (IF 7.551) Pub Date : 2020-03-27
    Samuel PC Brand; Patrick Munywoki; David Walumbe; Matthew J Keeling; David James Nokes

    Respiratory syncytial virus is the leading cause of lower respiratory tract infection among infants. RSV is a priority for vaccine development. In this study, we investigate the potential effectiveness of a two-vaccine strategy aimed at mothers-to-be, thereby boosting maternally acquired antibodies of infants, and their household cohabitants, further cocooning infants against infection. We use a dynamic

    更新日期:2020-03-27
  • Optimization of energy state transition trajectory supports the development of executive function during youth
    eLife (IF 7.551) Pub Date : 2020-03-27
    Zaixu Cui; Jennifer Stiso; Graham L Baum; Jason Z Kim; David R Roalf; Richard F Betzel; Shi Gu; Zhixin Lu; Cedric H Xia; Xiaosong He; Rastko Ciric; Desmond J Oathes; Tyler M Moore; Russell T Shinohara; Kosha Ruparel; Christos Davatzikos; Fabio Pasqualetti; Raquel E Gur; Ruben C Gur; Danielle S Bassett; Theodore D Satterthwaite

    Executive function develops during adolescence, yet it remains unknown how structural brain networks mature to facilitate activation of the fronto-parietal system, which is critical for executive function. In a sample of 946 human youths (ages 8-23y) who completed diffusion imaging, we capitalized upon recent advances in linear dynamical network control theory to calculate the energetic cost necessary

    更新日期:2020-03-27
  • A calibrated optogenetic toolbox of stable zebrafish opsin lines
    eLife (IF 7.551) Pub Date : 2020-03-27
    Paride Antinucci; Adna Dumitrescu; Charlotte Deleuze; Holly J Morley; Kristie Leung; Tom Hagley; Fumi Kubo; Herwig Baier; Isaac H Bianco; Claire Wyart

    Optogenetic actuators with diverse spectral tuning, ion selectivity and kinetics are constantly being engineered providing powerful tools for controlling neural activity with subcellular resolution and millisecond precision. Achieving reliable and interpretable in vivo optogenetic manipulations requires reproducible actuator expression and calibration of photocurrents in target neurons. Here, we developed

    更新日期:2020-03-27
  • Stimulus salience determines defensive behaviors elicited by aversively conditioned serial compound auditory stimuli
    eLife (IF 7.551) Pub Date : 2020-03-27
    Sarah Hersman; David Allen; Mariko Hashimoto; Salvador Ignacio Brito; Todd E Anthony

    Assessing the imminence of threatening events using environmental cues enables proactive engagement of appropriate avoidance responses. The neural processes employed to anticipate event occurrence depend upon which cue properties are used to formulate predictions. In serial compound stimulus (SCS) conditioning in mice, repeated presentations of sequential tone (CS1) and white noise (CS2) auditory stimuli

    更新日期:2020-03-27
  • Unc-4 acts to promote neuronal identity and development of the take-off circuit in the Drosophila CNS
    eLife (IF 7.551) Pub Date : 2020-03-27
    Haluk Lacin; W Ryan Williamson; Gwyneth M Card; James B Skeath; James W Truman

    The Drosophila ventral nerve cord (VNC) is composed of thousands of neurons born from a set of individually identifiable stem cells. The VNC harbors neuronal circuits required to execute key behaviors, such as flying and walking. Leveraging the lineage-based functional organization of the VNC, we investigated the developmental and molecular basis of behavior by focusing on lineage-specific functions

    更新日期:2020-03-27
  • Point of View: Mitigating the impact of conference and travel cancellations on researchers’ futures
    eLife (IF 7.551) Pub Date : 2020-03-27
    Tracey Weissgerber; Yaw Bediako; Charlotte M de Winde; Hedyeh Ebrahimi; Florencia Fernández-Chiappe; Vinodh Ilangovan; Devang Mehta; Carolina Paz Quezada; Julia L Riley; Shyam M Saladi; Sarvenaz Sarabipour; Andy Tay

    The need to protect public health during the current COVID-19 pandemic has necessitated conference cancellations on an unprecedented scale. As the scientific community adapts to new working conditions, it is important to recognize that some of our actions may disproportionately affect early-career researchers and scientists from countries with limited research funding. We encourage all conference organizers

    更新日期:2020-03-27
  • Endogenous siRNAs promote proteostasis and longevity in germline less C. elegans
    eLife (IF 7.551) Pub Date : 2020-03-26
    Moran Cohen-Berkman; Reut Dudkevich; Shani Ben-Hamo; Alla Fishman; Yehuda Salzberg; Hiba Waldman Ben-Asher; Ayelet T Lamm; Sivan Henis-Korenblit

    How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in C. elegans, we reveal an unprecedented role for endo-siRNA

    更新日期:2020-03-27
  • Cell-specific exon methylation and CTCF binding in neurons regulates calcium ion channel splicing and function
    eLife (IF 7.551) Pub Date : 2020-03-26
    Eduardo Javier López Soto; Diane Lipscombe

    Cell-specific alternative splicing modulates myriad cell functions and is disrupted in disease. The mechanisms governing alternative splicing are known for relatively few genes and typically focus on RNA splicing factors. In sensory neurons, cell-specific alternative splicing of the presynaptic CaV channel Cacna1b gene modulates opioid sensitivity. How this splicing is regulated is unknown. We find

    更新日期:2020-03-27
  • An atypical DYRK kinase connects quorum-sensing with posttranscriptional gene regulation in Trypanosoma brucei
    eLife (IF 7.551) Pub Date : 2020-03-26
    Mathieu Cayla; Lindsay McDonald; Paula MacGregor; Keith Matthews

    The sleeping sickness parasite, Trypanosoma brucei, uses quorum sensing (QS) to balance proliferation and transmission potential in the mammal bloodstream. A signal transduction cascade regulates this process, a component of which is a divergent member of the DYRK family of protein kinases, TbDYRK. Phylogenetic and mutational analysis in combination with activity and phenotypic assays revealed that

    更新日期:2020-03-27
  • Building customizable auto-luminescent luciferase-based reporters in plants
    eLife (IF 7.551) Pub Date : 2020-03-25
    Arjun Khakhar; Colby G Starker; James C Chamness; Nayoung Lee; Sydney Stokke; Cecily Wang; Ryan Swanson; Furva Rizvi; Takato Imaizumi; Daniel F Voytas

    Bioluminescence is a powerful biological signal that scientists have repurposed as a reporter for gene expression in plants and animals. However, there are downsides associated with the need to provide a substrate to these reporters, including its high cost and non-uniform tissue penetration. In this work we reconstitute a fungal bioluminescence pathway (FBP) in planta using a composable toolbox of

    更新日期:2020-03-26
  • UBP12 and UBP13 negatively regulate the activity of the ubiquitin-dependent peptidases DA1, DAR1 and DAR2
    eLife (IF 7.551) Pub Date : 2020-03-25
    Hannes Vanhaeren; Ying Chen; Mattias Vermeersch; Liesbeth De Milde; Valerie De Vleeschhauwer; Annelore Natran; Geert Persiau; Dominique Eeckhout; Geert De Jaeger; Kris Gevaert; Dirk Inzé

    Protein ubiquitination is a very diverse post-translational modification leading to protein degradation or delocalization, or altering protein activity. In Arabidopsis thaliana, two E3 ligases, BIG BROTHER (BB) and DA2, activate the latent peptidases DA1, DAR1 and DAR2 by mono-ubiquitination at multiple sites. Subsequently, these activated peptidases destabilize various positive regulators of growth

    更新日期:2020-03-26
  • A roadmap for gene functional characterisation in crops with large genomes: Lessons from polyploid wheat
    eLife (IF 7.551) Pub Date : 2020-03-24
    Nikolai M Adamski; Philippa Borrill; Jemima Brinton; Sophie A Harrington; Clémence Marchal; Alison R Bentley; William D Bovill; Luigi Cattivelli; James Cockram; Bruno Contreras-Moreira; Brett Ford; Sreya Ghosh; Wendy Harwood; Keywan Hassani-Pak; Sadiye Hayta; Lee T Hickey; Kostya Kanyuka; Julie King; Marco Maccaferrri; Guy Naamati; Curtis J Pozniak; Ricardo H Ramirez-Gonzalez; Carolina Sansaloni; Ben

    Understanding the function of genes within staple crops will accelerate crop improvement by allowing targeted breeding approaches. Despite their importance, a lack of genomic information and resources has hindered the functional characterisation of genes in major crops. The recent release of high-quality reference sequences for these crops underpins a suite of genetic and genomic resources that support

    更新日期:2020-03-26
  • Global genome diversity of the Leishmania donovani complex
    eLife (IF 7.551) Pub Date : 2020-03-25
    Susanne U Franssen; Caroline Durrant; Olivia Stark; Bettina Moser; Tim Downing; Hideo Imamura; Jean-Claude Dujardin; Mandy J Sanders; Isabel Mauricio; Michael A Miles; Lionel F Schnur; Charles L Jaffe; Abdelmajeed Nasereddin; Henk Schallig; Matthew Yeo; Tapan Bhattacharyya; Mohammad Z Alam; Matthew Berriman; Thierry Wirth; Gabriele Schönian; James A Cotton

    Protozoan parasites of the Leishmania donovani complex – L. donovani and L. infantum – cause the fatal disease visceral leishmaniasis. We present the first comprehensive genome-wide global study, with 151 cultured field isolates representing most of the geographical distribution. L. donovani isolates separated into five groups that largely coincide with geographical origin but vary greatly in diversity

    更新日期:2020-03-26
  • Peer Review: Publishing in the time of COVID-19
    eLife (IF 7.551) Pub Date : 2020-03-25
    Michael B Eisen; Anna Akhmanova; Timothy E Behrens; Detlef Weigel

    eLife is making changes to its policies on peer review in response to the impact of COVID-19 on the scientific community.

    更新日期:2020-03-26
  • Developmental Variability: Exerting an influence on evolution
    eLife (IF 7.551) Pub Date : 2020-03-25
    Charles C Roseman

    Experiments on mice have shown that developmental processes are influencing the generation of phenotypic variation in a way that shapes evolution.

    更新日期:2020-03-26
  • Identification of slit3 as a locus affecting nicotine preference in zebrafish and human smoking behaviour
    eLife (IF 7.551) Pub Date : 2020-03-25
    Judit García-González; Alistair J Brock; Matthew O Parker; Riva J Riley; David Joliffe; Ari Sudwarts; Muy-Teck Teh; Elisabeth M Busch-Nentwich; Derek L Stemple; Adrian R Martineau; Jaakko Kaprio; Teemu Palviainen; Valerie Kuan; Robert T Walton; Caroline H Brennan

    To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F3 sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F0 fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F3 fish, one in

    更新日期:2020-03-26
  • TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models
    eLife (IF 7.551) Pub Date : 2020-03-23
    Jay Li; Chun-Chi Liang; Samuel S Pappas; William T Dauer

    Genetic redundancy can be exploited to identify therapeutic targets for inherited disorders. We explored this possibility in DYT1 dystonia, a neurodevelopmental movement disorder caused by a loss-of-function (LOF) mutation in the TOR1A gene encoding torsinA. Prior work demonstrates that torsinA and its paralog torsinB have conserved functions at the nuclear envelope. This work established that low

    更新日期:2020-03-24
  • Long non-coding RNA GRASLND enhances chondrogenesis via suppression of interferon type II signaling pathway
    eLife (IF 7.551) Pub Date : 2020-03-23
    Nguyen PT Huynh; Catherine C Gloss; Jeremiah Lorentz; Ruhang Tang; Jonathan M Brunger; Audrey McAlinden; Bo Zhang; Farshid Guilak

    The roles of long noncoding RNAs (lncRNAs) in musculoskeletal development, disease, and regeneration remain poorly understood. Here, we identified the novel lncRNA GRASLND (originally named RNF144A-AS1) as a regulator of mesenchymal stem cell (MSC) chondrogenesis. GRASLND, a primate-specific lncRNA, is upregulated during MSC chondrogenesis and appears to act directly downstream of SOX9, but not TGF-b3

    更新日期:2020-03-24
  • Cross-species cortical alignment identifies different types of anatomical reorganization in the primate temporal lobe
    eLife (IF 7.551) Pub Date : 2020-03-23
    Nicole Eichert; Emma C Robinson; Katherine L Bryant; Saad Jbabdi; Mark Jenkinson; Longchuan Li; Kristine Krug; Kate E Watkins; Rogier B Mars

    Evolutionary adaptations of temporo-parietal cortex are considered to be a critical specialization of the human brain. Cortical adaptations, however, can affect different aspects of brain architecture, including local expansion of the cortical sheet or changes in connectivity between cortical areas. We distinguish different types of changes in brain architecture using a computational neuroanatomy approach

    更新日期:2020-03-24
  • Identification of a molecular basis for the juvenile sleep state
    eLife (IF 7.551) Pub Date : 2020-03-23
    Leela Chakravarti Dilley; Milan Szuperak; Naihua N Gong; Charlette E Williams; Ricardo Linares Saldana; David S Garbe; Mubarak Hussain Syed; Rajan Jain; Matthew S Kayser

    Across species, sleep in young animals is critical for normal brain maturation. The molecular determinants of early life sleep remain unknown. Through an RNAi-based screen, we identified a gene, pdm3, required for sleep maturation in Drosophila. Pdm3, a transcription factor, coordinates an early developmental program that prepares the brain to later execute high levels of juvenile adult sleep. PDM3

    更新日期:2020-03-24
  • Kainate-type of glutamate receptors regulate development of glutamatergic synaptic circuitry in the rodent amygdala
    eLife (IF 7.551) Pub Date : 2020-03-23
    Maria Ryazantseva; Jonas Englund; Alexandra Shintyapina; Johanna Huupponen; Vasilii Shteinikov; Asla Pitkänen; Juha Partanen; Sari E Lauri

    Perturbed information processing in the amygdala has been implicated in developmentally originating neuropsychiatric disorders. However, little is known on the mechanisms that guide formation and refinement of intrinsic connections between amygdaloid nuclei. We demonstrate that in rodents the glutamatergic connection from basolateral to central amygdala (BLA-CeA) develops rapidly during the first ten

    更新日期:2020-03-24
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